literature review on pentavalent vaccine

• Research Article
• Open access
• Published: 15 September 2023

Prevalence and factors associated with pentavalent vaccination: a cross-sectional study in Southern China

• Jianing Xu 1 , 2   na1 ,
• Yujie Cui 2   na1 ,
• Chuican Huang 3   na1 ,
• Yuanyuan Dong 1 , 4 ,
• Yunting Zhang 4 ,
• Lichun Fan 3 ,
• Guohong Li   ORCID: orcid.org/0000-0003-0445-5363 1 , 2 &
• Fan Jiang 5 , 6 , 7  

Infectious Diseases of Poverty volume  12 , Article number:  84 ( 2023 ) Cite this article

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Metrics details

Immunization is one of the most far-reaching and cost-effective strategies for promoting good health and saving lives. A complex immunization schedule, however, may be burdensome to parents and lead to reduced vaccine compliance and completion. Thus, it is critical to develop combination vaccines to reduce the number of injections and simplify the immunization schedule. This study aimed to investigate the current status of the pentavalent diphtheria-tetanus-acellular pertussis inactivated poliomyelitis and Haemophilus influenzae type B conjugate (DTaP-IPV/Hib) vaccination in Southern China as well as explore the factors in the general population associated with uptake and the differences between urban and rural populations.

A cross-sectional study was conducted with recently enrolled kindergarten students in Hainan Province between December 2022 and January 2023. The study employed a stratified multistage cluster random sampling method. Information regarding the demographic characteristics and factors that influence decisions were collected from the caregivers of children via an online questionnaire. Multivariate logistic regression was used to determine the factors associated with the status of DTap-IPV/Hib vaccinations.

Of the 4818 valid responses, 95.3% of children were aged 3–4 years, and 2856 (59.3%) held rural hukou . Coverage rates of the DTaP-IPV/Hib vaccine, from 1 to 4 doses, were 24.4%, 20.7%, 18.5%, and 16.0%, respectively. Caregivers who are concerned about vaccine efficacy [adjusted odds ratio (a OR ) = 1.53, 95% confidence interval ( CI ): 1.30–1.79], the manufacturer (a OR  = 2.05, 95% CI : 1.69–2.49), and a simple immunization schedule (a OR  = 1.26, 95% CI : 1.04–1.54) are factors associated with a higher likelihood of vaccinating children against DTaP-IPV/Hib. In addition, caregivers in urban areas showed more concern about the vaccine price ( P  = 0.010) and immunization schedule ( P  = 0.022) in regard to vaccinating children.

Conclusions

The DTaP-IPV/Hib vaccine coverage rate in Hainan Province remains low. Factors such as lower socioeconomic status, cultural beliefs, concerns about vaccine safety, and cost may hinder caregivers from vaccinating their children. Further measures, such as health education campaigns to raise knowledge and awareness, and encouragement of domestic vaccine innovation, which would reduce out-of-pocket costs, could be implemented to improve the coverage of DTap-IPV/Hib vaccination.

Graphical Abstract

Early child development (ECD) is an essential element of the Sustainable Development Goals and serves as the foundation of adult health and well-being [ 1 ]. Although substantive progress has been made in tackling under-5 mortality, with a reduction in the number of childhood deaths from 5.9 million in 2015 to 5 million in 2021, many children who survive are not able to thrive due to the threat of infectious diseases [ 2 ]. Among the five major areas of ECD, the area of health emphasizes childhood immunization. Vaccines annually prevent 2–3 million fatalities and safeguard millions more from disease and disability [ 3 ]. As one of the most far-reaching health interventions, immunization is an incredibly cost-effective strategy for promoting good health and saving lives. A study in 94 low- and middle-income countries estimated that every US dollar (USD) 1 invested in immunization generates a return of USD 51.8 in broader societal benefits of people who live longer and healthier lives [ 4 ].

The World Health Organization (WHO) developed Immunization Agenda 2030 to reduce mortality and morbidity from vaccine-preventable diseases (VPDs) from the period of 2021 to 2030 [ 5 ]. The current National Immunization Program (NIP) in China provides, at no cost, vaccines for eligible-aged children to prevent 12 VPDs and reduce by 99% the incidence of these diseases [ 6 ]. In addition, the number of recommended vaccines during childhood has increased significantly. Currently, children can receive ~ 20 injections by the age of 2 years to complete their immunization schedule, although the number of injections may increase in the coming years due to an increasing number of new diseases and vaccines. Evidence suggests, however, that a complex immunization schedule may be burdensome to parents and healthcare providers and can even lead to reduced vaccine compliance and completion [ 7 , 8 ].

To address these concerns, many international organizations recommend that countries develop combination vaccines, which can be produced by grouping multiple antigens into one injection [ 9 , 10 ]. In 2010, the Chinese National Medical Products Administration approved the pentavalent diphtheria-tetanus-acellular pertussis inactivated poliomyelitis and Haemophilus influenzae type B conjugate vaccine (DTaP-IPV/Hib) (Pentaxim ® , Sanofi Pasteur Limited, Marcy l’Etoile, France), which can prevent more than five high incidences of morbidity and mortality diseases [ 11 ]. Until now, it was the highest degree of combination vaccines available in China. Numerous studies have demonstrated the good immunogenicity and safety profile of the DTaP-IPV/Hib combination vaccine, which is equal to the separately administered vaccine components [ 12 , 13 ]. The DTaP-IPV/Hib combination vaccine offers a safe and effective alternative for reducing the number of injections from 12 to 4, which can reduce pain and discomfort and prevent potential side effects for children, save time and money, and reduce the loss of productivity for caregivers [ 14 , 15 ]. Notably, China, as the sole WHO member country that has not incorporated the Hib vaccine into its NIP, exhibits a relatively low national coverage rate of only 33%, thereby experiencing a significant residual burden of Hib disease [ 16 ]. The use of the DTaP-IPV/Hib combination vaccine could contribute to enhancing Hib coverage, which allows for better and wider protection against infectious diseases and decreases the cost of disease management [ 17 ].

The DTap-IPV/Hib vaccination rates in many developed countries are far higher and were 94.4% in England and over 93.7% in Canada [ 18 , 19 ]. The vaccine is imported, optional, and self-paid (Category 2), and the DTap-IPV/Hib vaccination rate in China significantly varies across different regions, but the overall rates are low. According to previous studies, the DTap-IPV/Hib vaccine coverage exhibited variations, with rates that range from 18.51% in Hangzhou during 2017 to 6.28% in Chongqing during 2015 [ 20 , 21 ]. Considering the financial responsibility of caregivers in China to fully cover the cost of the DTap-IPV/Hib vaccine through out-of-pocket payments, it becomes imperative to assess the actual immunization status and the factors that influence DTap-IPV/Hib vaccine uptake within the country. Nevertheless, it is unfortunate that there is a lack of comprehensive information available about the utilization of the DTap-IPV/Hib vaccine and the factors that influence its uptake within the Chinese context.

In 2018, the Chinese government made the strategic decision to establish Hainan Province as the nation’s inaugural free trade port, operating under the socialist system. To facilitate the importation of pharmaceuticals and sanitary equipment, Hainan Free Trade Port (HFTP) has implemented a range of convenient and preferential laws and policies. This development is expected to enhance the accessibility of imported vaccines for local residents [ 22 ]. Hence, this study aimed to investigate the current status of DTap-IPV/Hib vaccination in Hainan Province as an example and explore the potential influencing factors in the general population as well as the differences between urban and rural populations. The study also sought to provide recommendations for increasing the vaccination rate, including tailored preparation to address hesitancy, and build vaccine literacy in China.

Study design and ethic

This study is part of a larger cross-sectional survey on the intervention strategies for ECD, which includes, among others, immunization, responsive caregiving, and early learning. The survey was conducted with a population of newly enrolled kindergarteners in Hainan Province from December 12, 2022, to January 8, 2023. Although it is mandatory for all 3-year-old children who reside in Hainan Province to enroll in kindergarten, there may be variations in the actual age at which they are enrolled (95% of the children were 3–4 years old, but there were a few children who were 2 or 5 years old). Ethics approval was obtained from the Research Ethics Board of the Hainan Women and Children’s Medical Center (2020-002). This paper includes data only from vaccination surveys and uses components of the cross-sectional questionnaire relevant to the aims of this paper.

Study participants and randomization

Newly enrolled kindergarteners in Hainan Province in 2022 were recruited, and those who had foreign nationality or studied in special education schools were excluded. A stratified multistage cluster random sampling approach was employed for the cross-sectional study. First, primary sampling units (PSUs) were set at the county-level administrative region. There are a total of 3 groups and 24 categories of PSUs, including 8 municipal districts, 6 county-level cities, and 10 counties/autonomous counties. Half of the units in each group were randomly selected.

We then defined secondary sampling units (SSUs) based on the kindergarten’s ownership (public or private) and level (provincial/demonstration level; first, second, or third level in city/county; and unrated level). There are a total of 120 categories of SSUs. In each SSU, one or two kindergartens were randomly selected, and all the enrolled children in the junior grade were invited to participate in the survey (Fig.  1 ). Random sampling was conducted, using a list of random numbers, by an individual epidemiologist who was not involved in any other research activities of this survey. A total of 8478 children from 180 kindergartens were randomly selected as participants. All caregivers of children who participated in the study were informed about the intention of the study and gave their electronic informed consent at the beginning of the online survey.

Stratified sample units of kindergartens of different levels in Hainan. There are 4 prefecture-level cities, 5 county-level cities, and 10 counties/autonomous counties in the Hainan administrative division. Among the 4 prefecture-level cities, there are 4 municipal districts each in Haikou and Sanya Cities. Danzhou City is taken as a county-level city, as it governs only streets and towns. We deleted Sansha City due to underpopulation. Thus, there is a total of 3 groups and 24 categories of primary sampling units, including 8 municipal districts, 6 county-level cities, and 10 counties/autonomous counties

Sample size and power analysis

The sample size was calculated with the following formula based on an error α  = 0.05, \(Z_{1 - \alpha /2}\)  = 1.96, and allowance error δ = 0.02: \(n = \left( {\frac{{Z_{1 - \alpha /2} }}{\delta }} \right)^{2} \times p \times \left( {1 - p} \right)\) . Based on the whole ECD study, we adopted the early Human Capability Index to more comprehensively assess the development of children. In accordance with our preliminary pilot study, the estimated risk of poor development was found to be 18%, which is slightly lower than the average rate of 20%, observed within the Chinese population [ 23 ]. Assuming a conservative estimate of 20% for the risks of poor development in Hainan, we determined that the calculated sample size required was 1537. After estimating 70% valid data, the total number of participants was expected to be 2196.

Data collection and quality control

Based on a review of the literature, we developed a structured questionnaire to collect data on demographic characteristics and factors that influence the choices of the DTaP-IPV/Hib vaccine. We implemented expert consultation to ensure the scientific validity and rationale of the questionnaire. We then conducted a pilot study with a random sample of 128 caregivers in two kindergartens to ensure the comprehension of the questionnaire. After the pilot study, a few modifications were made to ensure that the questions were comprehensible and interpreted as intended. The results of the pilot study were not included in the main study.

The data collection was carried out by the Maternal and Children Health Care System in Hainan Province, China. At the beginning of the survey, we provided standard training for the head of each PSU, who then provided training and guidance to the kindergartens within their jurisdiction to ensure that they carried out this survey, following the uniform process. The kindergarten representatives were responsible for checking the children’s personal information and guiding parents or caregivers to finish the online survey within two weeks.

In addition, a web-based questionnaire and research management platform were set up. The selected kindergartens were requested to upload the properly formatted information about their children (including name, gender, kindergarten, class, and date of birth) to the questionnaire platform, and the questionnaire platform generated a unique login code for each child [ 24 ]. Both the link to the research and the unique login code were distributed to parents through the Maternal and Children Health Care System and kindergarten teachers. The questionnaire collection process is strictly quality controlled by various levels of regulatory systems. Using the login code, all parents accessed the online questionnaire to double-check the child’s personal information and gave informed consent to participate in the survey.

After collecting questionnaires, we excluded those with missing important and obvious logical errors. Valid data with complete basic information and DTaP-IPV/Hib vaccination status were included in the analysis.

Using the researcher-designed questionnaire, we obtained the general demographic characteristics of the participants, including children’s age, gender, hukou (the location of registered residency of the child), and ethnic group; administrative division, rank, and type of kindergartens; premature delivery, basic medical insurance, commercial medical insurance, number of children in the family, and previous vaccination status in NIP; caregivers’ relationship with the children, education level, and employment status; and annual household income.

Acceptance of vaccination is an outcome behavior that results from a complex decision-making process that can be potentially influenced by a wide range of factors. As caregivers play a key role in vaccination, we also assessed their influence using the “3Cs” model, which was first proposed to the WHO EURO Vaccine Communications Working Group in 2011. The “3Cs” model is a professionally validated theoretical framework for vaccination determinants, comprised of confidence, convenience, and complacency factors [ 25 ]. We designed eight questions that were incorporated into the 3Cs in our study. To make subsequent analysis clearer, we categorized responses into two categories: “Yes” or “No.”

Statistical analysis

All variables were categorical and represented as frequencies with percentages. The characteristics of participants who had previously been vaccinated for DTaP-IPV/Hib and those who had not were compared using a chi-square test.

The relationship between the explanatory variables (demographic characteristics of caregivers and children) and the outcome variable (vaccinating their children against DTaP-IPV/Hib) was examined by multivariate logistic regression. The outcome variable was dichotomized into “Vaccinated” (at least 1 dose) and “Unvaccinated.” An adjusted odds ratio (a OR ) with a 95% confidence interval ( CI ) for each variable were calculated.

A comprehensive non-responder analysis was conducted. The available data from the Hainan Women and Children’s Medical Center system were used to conduct an analysis of non-response to evaluate whether the non-responders differed systematically from the responders of the survey. Then, a subgroup analysis was performed, which examined differences in the variables among the groups. All statistics were managed by Microsoft Excel version 2010 (Microsoft Corporation, Redmond, WA, USA) and analyzed using SPSS version 24.0 (SPSS Inc., Chicago, IL, USA). Two-sided P -values < 0.05 were considered significant.

Demographic characteristics of respondents

A total of 4818 valid questionnaires were analyzed in this study, for a valid response rate of 56.8% (Fig.  2 ). Of the 4818 responses, most were aged ≤ 3 years (75.2%), the majority were from the Han population (80.4%), and 2856 (59.3%) held rural hukou . Almost two-thirds of the families had more than one child (66.1%), and the vast majority (92.5%) of children completed the immunization program of Hainan Province at the target age. Among the respondents, mothers predominated (75.3%), 70.0% of the caregivers were employed, and 31.6% had a 4-year college or associate’s degree. With regard to non-NIP vaccine determinants, the safety (51.0%) and efficacy (44.1%) of the vaccine are the two core issues with which caregivers have always been concerned, and more than one-third (39.3%) of caregivers depend heavily on doctors’ vaccination advice. Details are provided in Table 1 .

Flowchart of sample selection

Factors associated with DTaP-IPV/Hib vaccination

The immunization coverage rates of the DTaP-IPV/Hib vaccine, from 1 to 4 doses, were 24.4%, 20.7%, 18.5%, and 16.0%, respectively, in Hainan Province. In the multivariate regression model, DTaP-IPV/Hib vaccination status differed significantly in terms of the children’s hukou ( P  < 0.001), and ethnic group ( P  < 0.001); administrative division ( P  < 0.001) and rank of kindergartens ( P  < 0.001); basic medical insurance ( P  < 0.004), commercial medical insurance ( P  < 0.001), and previous vaccination status in NIP ( P  < 0.001); caregivers’ education level ( P  < 0.001) and employment status ( P  < 0.045); and annual household income ( P  < 0.003). We then adjusted all socioeconomic and demographic characteristics of respondents. Caregivers who feel positively toward vaccine efficacy (a OR  = 1.53, 95% CI : 1.30–1.79), the manufacturer (a OR  = 2.05, 95% CI : 1.69–2.49), and immunization schedule (a OR  = 1.26, 95% CI : 1.04–1.54) are more likely to vaccinate their children against DTaP-IPV/Hib. Those who are more concerned about vaccine safety (a OR  = 0.58, 95% CI : 0.50–0.68) and price (a OR  = 0.73, 95% CI : 0.60–0.88) are less likely to vaccinate their children against DTaP-IPV/Hib (Table 2 ).

Assessing non-response bias

The analyses showed that responders ( n  = 4818) were comparable to non-responders ( n  = 3660) with regard to gender and age. Responders, however, were significantly more often of Han ethnicity and were county or autonomous county-, provincial-, or demonstration-level kindergarteners, or public kindergarteners compared to non-responders ( P  < 0.001) (Table 3 ). The subgroup analysis results for variables with differences are displayed in Additional file 1 : Tables S1–S4.

Factors associated with DTaP-IPV/Hib vaccination in urban and rural areas

In China, hukou represents the location of the registered residency of the children, which is approximately equal to the living residence. Our results showed that caregivers in both urban and rural groups are concerned about vaccine safety, efficacy, and the manufacturer ( P  < 0.001). Disparities were observed, however, in terms of the convenience dimension related to vaccine price and immunization schedule. Specifically, the urban group exhibited greater concerns regarding vaccine price ( P  = 0.010) and adherence to the immunization schedule ( P  = 0.022) in terms of vaccination against DTaP-IPV/Hib (Fig.  3 ).

Factors associated with DTaP-IPV/Hib vaccination in urban and rural areas. We adjusted the socioeconomic and demographic characteristics of respondents. a OR adjusted odds ratio; CI confidence interval

The vaccination of children, the main target population, can have far-reaching effects on general health and well-being, cognitive development, and economic productivity. More than 70 vaccines are available for use, and many more are expected to protect against multiple diseases, which will further increase the number of injections and office visits [ 8 , 26 ]. Complex immunization schedules can result in missed or delayed dosing, especially for children under 2 years old. Thus, it is essential to develop combination vaccines to simplify the vaccine schedule. Although the DTaP-IPV/Hib vaccine is the highest degree of combination vaccines available in China, the coverage rates of this vaccine are still low. It is, thus, critical to explore the factors that affect the vaccination rate of DTaP-IPV/Hib. To our knowledge, this is the first large sample investigation of the immunization status and the influencing factors of the DTap-IPV/Hib vaccine in Hainan Province, which includes more than ten million permanent residents. Our findings show that the cumulative coverage rates of the DTap-IPV/Hib vaccine from 1 to 4 doses were 24.4%, 20.7%, 18.5%, and 16.0%, respectively, in Hainan Province, which was higher than other areas in China [ 20 , 21 ].

Consistent with other studies, Voo et al. found that caregivers with higher economic and cultural levels are more likely to vaccinate their children against DTap-IPV/Hib [ 27 ]. This could be explained by research that shows that caregivers with higher economic and cultural levels are inclined to accurately process the evidence regarding vaccination and to have access to more healthcare resources, such as choosing self-paid vaccines [ 28 ]. The cost of an imported DTaP-IPV/Hib vaccine per fully immunized child is estimated to be 2488 Chinese Yuan (CNY), and it is paid out-of-pocket, without any subsidy or insurance coverage. This higher cost may impose a financial burden on families with a lower income, potentially limiting their access to the vaccine and reducing the likelihood of full compliance and completion (Additional file 1 : Table S5). Previous research in China and Japan has found that a subsidy would reduce the out-of-pocket price and increase the coverage of vaccination [ 29 , 30 ].

Currently, the advancement of combined vaccines in China is impeded by numerous technical challenges. These include the absence of the crucial component IPV in the market and the presence of thiomersal in the co-purification process utilized for manufacturing DTaP vaccines, which can adversely affect the immunogenicity of the IPV antigen [ 31 ]. To address these concerns, the government should not only develop innovative vaccine pricing mechanisms and increase financing options but also provide an incentive for domestic manufacturers to research and develop DTap-IPV/Hib vaccines. Moreover, region-specific strategies should be developed based on their disease burden and fiscal capacity [ 32 ].

Our findings reveal that the efficacy and safety of the DTap-IPV/Hib vaccine have played a significant role in influencing its uptake within the general population. Studies in five countries in South America have revealed that safety and efficacy were the two most important factors for caregivers to decide whether to vaccinate their children [ 33 ]. Accurate information about vaccines is vital for caregivers, as they often lack a complete understanding of how vaccines function and struggle to make well-informed decisions about vaccination. Research conducted by Boerner et al. has shown that insufficient information about vaccination or conflicting information from various sources can decrease an individual’s willingness to vaccinate [ 34 ]. Therefore, it is of the utmost importance to communicate information about vaccines in a clear and easily comprehensible manner to overcome barriers to vaccination [ 35 ]. Healthcare providers play a crucial role as trusted sources of information for caregivers, enabling them to enhance their understanding and awareness. France’s implementation experience highlights the effectiveness of health education campaigns led by reputable medical institutions. These campaigns serve as valuable strategies to provide credible and reliable information about the safety and efficacy of vaccines. The ultimate goal is to empower individuals to make informed decisions regarding vaccination and ensure accessible and comprehensive vaccine information and knowledge [ 36 ].

The findings of this study demonstrated a notable disparity in vaccination rates between urban (35.7%) and rural populations (16.6%). In addition, the study revealed that caregivers who expressed concerns about the immunization schedule were more inclined to vaccinate their children against DTaP-IPV/Hib, particularly among those who resided in urban areas. As a combination vaccine, the DTap-IPV/Hib vaccine could simplify the immunization schedule and reduce the total number of required office visits [ 37 ]. Our preliminary research found that the Hib vaccination coverage rate in Hainan Province is 39.7%. Among children who received the Hib vaccine, 61.5% opted for direct vaccination with the DTap-IPV/Hib vaccine (data have not been published). Due to conflicts between routine vaccination times and parents’ working hours, parents in urban areas prefer to pay higher fees to buy time. Time loss related to the number of office visits may prevent parents from completing the immunization schedule on time and result in missed or delayed dosing. Pellissier et al. provided evidence that reducing the number of office visits can lead to time savings and potentially lower indirect costs associated with parental work loss [ 15 ]. Overall, although combination vaccines may cost slightly more than the total cost of their component vaccines, the benefits of vaccination timeliness and compliance and a simplified schedule may outweigh the cost.

This study has several limitations. First, there is a non-response bias in the study results due to the lower response rate. Responders and non-responders may differ in their vaccination status. Thus, we collected the available data to conduct an analysis of non-responders and then conducted a subgroup analysis. Second, the confirmation of vaccination status was based on the caregivers’ self‐reports, which rely on memory rather than medical records. Hence, the information may not accurately reflect the DTaP-IPV/Hib vaccine coverage rate and may be subject to recall bias. Because the newly enrolled children are required to provide vaccination records upon admission to kindergarten in September, however, the probability is less that their parents do not remember or are uncertain about the DTaP-IPV/Hib vaccination status. Third, the sample was selected from one geographic area. The specific context of Hainan Province, which might not represent the whole population in China, could limit the generalizability of the findings. Further research should be undertaken to extend the scope to widely evaluate the vaccination rate and influencing factors in China. Despite the above limitations, this study provides important evidence by which to evaluate the vaccination status and popularization proposals of the DTaP-IPV/Hib vaccine in China.

Our study provides important evidence of the prevalence and determining factors of the DTaP-IPV/Hib vaccination in Hainan Province, China. The coverage rate of the DTaP-IPV/Hib vaccine in Hainan Province remains at a low level but is slightly higher than that found in previous studies conducted in China. Caregivers may be hesitant to vaccinate their children against DTaP-IPV/Hib due to concerns about the vaccine’s safety and price. Thus, more effective health education campaigns should be conducted to publicize and promote access to DTaP-IPV/Hib vaccine knowledge and awareness. Further, the government should provide an incentive for domestic manufacturers to research and develop DTap-IPV/Hib vaccines as well as provide innovative vaccine pricing mechanisms and increase financing options to address the cost concern.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

• Early child development

World Health Organization

Vaccine-preventable diseases

National Immunization Program

Diphtheria-tetanus-acellular pertussis inactivated poliomyelitis and Haemophilus influenzae type B

Hainan Free Trade Port

Primary sampling units

Secondary sampling units

Adjusted odd ratio

Confidential interval

Chinese Yuan

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Acknowledgements

The author appreciates all participants for their time and involvement in this study. The work reported in this publication was supported by the Bill & Melinda Gates Foundation (INV-049539). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has been assigned to the author-accepted manuscript version that might arise from this submission. The funder did not play any role in the study design, data analysis, data interpretation, writing of the paper, or submission for this publication. The content in this paper is solely the responsibility of the authors and does not represent any view of the funder.

This work was supported by the Bill & Melinda Gates Foundation (Grant No. INV-049539); the Key Research and Development Program of Hainan Province (Grant No. ZDYF2020210); the Project of the National Social Science Fund of China (Grant No. 20BGL264); and the Shanghai Public Health System Construction Three‐Year Action Plan (Grant No. GWVI-11.1-48).

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Jianing Xu, Yujie Cui and Chuican Huang contributed equally to this work and share the first authorship.

Authors and Affiliations

School of Public Health, Shanghai Jiao Tong University School of Medicine, 227 South Chong Qing Road, Shanghai, 200025, China

Jianing Xu, Yuanyuan Dong & Guohong Li

China Hospital Development Institute, Shanghai Jiao Tong University, Shanghai, China

Jianing Xu, Yujie Cui & Guohong Li

Department of Child Health Care, Hainan Women and Children’s Medical Center, Haikou, China

Chuican Huang & Lichun Fan

Child Health Advocacy Institute, National Children’s Medical Center, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Yuanyuan Dong & Yunting Zhang

Department of Developmental and Behavioral Pediatrics, National Children’s Medical Center, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, 227 South Chong Qing Road, Shanghai, 200025, China

Pediatric Translational Medicine Institute, National Children’s Medical Center, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Shanghai Center for Brain Science and Brain-Inspired Technology, Shanghai, China

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Contributions

YC, GL, and FJ designed and conceptualized the study. JX and YC drafted the first manuscript and contributed to the interpretation of the results. JX and CH were involved in data cleaning and data analysis. CH and YD collected the data and supervised the project administration. LF, GL, and FJ contributed to the revision of the manuscript and approved the final version. YC, LF, and FJ obtained funding. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Guohong Li or Fan Jiang .

Ethics declarations

Ethics approval and consent to participate.

Ethics approval has been obtained from the Research Ethics Board of the Hainan Women and Children’s Medical Center (2020-002). All participants in the study were informed about the intention of the study and gave their electronic informed consent at the beginning of the online survey.

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The authors declare that they have no competing interests.

Supplementary Information

Additional file 1:.

Table S1 . Multivariate analysis of the potential factors that influence the DTaP-IPV/Hib vaccination by ethnicity. Table S2 . Multivariate analysis of the potential factors that influence the DTaP-IPV/Hib vaccination by kindergarten rank. Table S3 . Multivariate analysis of the potential factors that influence the DTaP-IPV/Hib vaccination by type of kindergarten. Table S4 . Multivariate analysis of the potential factors that influence the DTaP-IPV/Hib vaccination by county-level administrative region. Table S5 . Multivariate analysis of the potential factors that influence the full-course DTaP-IPV/Hib vaccination ( N  = 1174).

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Xu, J., Cui, Y., Huang, C. et al. Prevalence and factors associated with pentavalent vaccination: a cross-sectional study in Southern China. Infect Dis Poverty 12 , 84 (2023). https://doi.org/10.1186/s40249-023-01134-8

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A randomized study to evaluate the safety and immunogenicity of a pentavalent meningococcal vaccine

• Yoonjin Kim   ORCID: orcid.org/0009-0004-2141-2407 1 ,
• Sungyeun Bae 1 ,
• Kyung-Sang Yu 1 ,
• SeungHwan Lee 1 ,
• Chankyu Lee 2 ,
• Jinil Kim 2 ,
• Howard Her 2 &
• Jaeseong Oh 1 , 3 , 4  

npj Vaccines volume  9 , Article number:  140 ( 2024 ) Cite this article

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A randomized, active-controlled, double-blind, first-in-human, phase 1 study was conducted in healthy Korean adults to evaluate the safety, tolerability, and immunogenicity of EuNmCV-5, a new pentavalent meningococcal vaccine targeting serogroups A, C, W, X, and Y. Sixty participants randomly received a single dose of either EuNmCV-5 or MenACWY-CRM, a quadrivalent vaccine containing serogroups A, C, W, and Y. Safety was assessed through monitoring anaphylactic reactions, adverse events for 28 days, and serious adverse events over 180 days. Immunogenicity was assessed via rabbit complement-dependent serum bactericidal antibody (rSBA) assay. EuNmCV-5 was safe, well-tolerated, and elicited a substantial antibody titer increase. The seroprotection rates exceeded 96.7%, and the seroconversion rates were over 85% for all the targeted serogroups. It showed higher seroconversion rates against serogroups A and C ( p  = 0.0016 and 0.0237, respectively) and elicited a substantial increase in GMT for all targeted serogroups compared to the MenACWY-CRM.

ClinicalTrials.gov identifier: NCT05739292.

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Introduction.

N. meningitidis is a gram-negative bacterium, usually residing harmlessly in the human upper respiratory tract as a commensal 1 . In a small proportion of carriers, the pathogen can enter the bloodstream, causing septicemia or meningitis. Invasive meningococcal disease can rapidly progress to death within 48 h of symptom onset 2 . Additionally, 10–20% of survivors of meningococcal meningitis develop long-term neurologic sequelae such as hearing loss, intellectual disability, or other neurological disorders 3 . While invasive meningococcal disease frequently appears in small outbreaks, specific regions often experience devastating epidemics. This is the case in the African meningitis belt, the region in sub-Saharan Africa stretching from Senegal in the west to Ethiopia in the east 4 .

N. meningitidis is classified into 12 serogroups based on the antigenic differences of their capsular polysaccharides 1 , and six serogroups (A, B, C, W, X, Y) cause the most invasive cases globally 5 . In the African meningitis belt, serogroup A was the primary cause of the disease. However, since the implementation of meningococcal vaccines targeting serogroup A in 2010, no confirmed cases of serogroup A have been reported in the meningitis belt since 2017 6 . Recent meningococcal outbreaks in the region have mostly been due to serogroups C and W, with some reports also indicating outbreaks caused by serogroup X 6 , 7 .

Currently, most of the licensed meningococcal vaccines do not provide protection against serogroup X 8 , 9 , and Men5CV (MenFive ® , Serum Institute of India Pvt. Ltd., Pune, India) is the only vaccine targeting serogroup X. It held pre-qualification from the World Health Organization (WHO) in July 2023. WHO’s Strategic Advisory Group of Experts on Immunization recommended the inclusion of Men5CV in the routine immunization programs of all countries within the meningitis belt 10 . While Men5CV can be an efficient solution, it requires reconstitution before administration with a provided diluent. This process may be perceived as cumbersome, suggesting a need for further developments in vaccine technology to create more readily deployable alternatives. Given this, EuNmCV-5, developed by EuBiologics Co., Ltd. (Seoul, Republic of Korea), is a pentavalent (A, C, W, X, and Y) meningococcal conjugate vaccine that includes coverage for serogroup X, using a non-toxic mutant of diphtheria toxin (cross-reactive material 197, CRM 197 ) as a carrier protein. It is designed as a single vial, eliminating the reconstitution step. This clinical study aimed to evaluate the safety, tolerability, and immunogenicity of this new pentavalent meningococcal vaccine in comparison with an active comparator in healthy Korean adults who had not previously been vaccinated against or exposed to N. meningitidis .

Participants

Sixty participants were randomized and completed the study as planned (Fig. 1 ). The first participant was screened on March 9, 2023, and the last participant finished the study on October 4, 2023. Most of the participants (76.7%) were females. The mean age at baseline was 39.9 and 39.2 years in the EuNmCV-5 and MenACWY-CRM groups, respectively. Sex, age, and body weight were well distributed between both groups (Table 1 ).

Sixty participants were randomly assigned in a 1:1 ratio to either the intervention vaccine, EuNmCV-5, or the control vaccine, MenACWY-CRM. Clinic visits were scheduled 7 and 28 days after vaccination. A follow-up telephone contact was made 180 days after vaccination.

Safety and tolerability

No anaphylactic reaction was reported within 30 min after vaccination, and none of the participants experienced any life-threatening adverse events. All adverse events were self-limited and resolved without sequelae. The incidence and severity of adverse events were comparable between the EuNmCV-5 and MenACWY-CRM groups. Each adverse event occurred only once per participant.

The most frequently reported solicited local injection-site reaction within 7 days of vaccination was tenderness, occurring in 11 participants (36.7%) in the EuNmCV-5 group and 6 participants (20.0%) in the MenACWY-CRM group (Table 2 ). Among the 30 cases of solicited local injection-site reactions, 18 cases were reported in the EuNmCV-5 group and 12 cases in the MenACWY-CRM group. Within the EuNmCV-5 group, one case was graded as moderate in tenderness, and another was as severe urticaria. All solicited local injection-site reactions in the MenACWY-CRM group were mild in severity. The most frequently reported solicited systemic reactions were fatigue/malaise and myalgia (Table 2 ). In the EuNmCV-5 group, both fatigue/malaise and myalgia were reported by 5 participants (16.7%), and all cases were mild in severity. In the MenACWY-CRM group, 4 participants (13.3%) experienced fatigue/malaise, and an equal number reported myalgia. One case in each category was graded as moderate. Within 28 days of vaccination, the most frequently reported unsolicited adverse event was rhinorrhea, observed in 4 participants (13.3%) in both the EuNmCV-5 and MenACWY-CRM groups (Table 2 ). There were no clinically significant changes in clinical laboratory tests and vital signs before and after the administration of the study vaccines.

Immunogenicity

Although people with a history of meningococcal vaccination, previous meningococcal infection, or recent contact with a person with meningococcal infection within the last 2 weeks were excluded, some participants had high baseline titers before vaccination. This was particularly true for serogroup A (16 out of 30 participants (53.3%) in the EuNmCV-5 group, 18 out of 30 participants (60.0%) in the MenACWY-CRM group).

Twenty-eight days after vaccination, seroconversion against all serogroups was observed in the majority of participants in the EuNmCV-5 group. Specifically, for serogroup X, 26 out of 30 participants (86.7%) in the EuNmCV-5 group demonstrated seroconversion, while only 2 out of 30 participants (6.7%) in the MenACWY-CRM group showed seroconversion ( p  < 0.001). The EuNmCV-5 group exhibited a higher seroconversion rate against serogroups A and C compared to the MenACWY-CRM group ( p  = 0.0016 and 0.0237, respectively) and it showed similarly high seroconversion rates (greater than 90%) in serogroups W and Y (Table 3 ).

After vaccination, 29 (96.7%) of 30 participants in the EuNmCV-5 group had titers of seroprotection (rSBA titer of ≥8, or ≥128) for serogroup X, and 30 (100.0%) for all other serogroups. In the MenACWY-CRM group, 24 (80.0%) to 28 (93.3%) of 30 participants had titers of seroprotection for serogroups A, C, W, and Y. As expected, few number of participants (5 (16.7%) of 30 participants) showed seroprotection for serogroup X. No significant differences were observed in seroprotection rates for serogroups A, W, and Y between the EuNmCV-5 and MenACWY-CRM groups. However, seroprotection rates were higher in the EuNmCV-5 group for serogroups C and X (Table 3 ).

At baseline, there were no significant differences in GMT against all serogroups between the EuNmCV-5 and MenACWY-CRM groups (Fig. 2 ). Notably, the EuNmCV-5 group demonstrated a significantly greater increase in GMT on day 28 than the MenACWY-CRM group for all serogroups. The GMRs (95% CIs) at day 28 were 5.5 (2.3–13.2), 9.0 (2.5–32.4), 6.1 (2.2–16.7), 397.1 (161.8–974.4), 5.0 (2.1–12.0) for serogroup A, C, W, X, and Y, respectively (all of the p  < 0.001). Across all serogroups, the Geometric mean fold increase (GMFI) values were consistently higher for the EuNmCV-5 group. The GMFR values were found to be 8.8, 7.6, 5.2, 425.6, and 9.6, respectively (Table 4 ).

95% confidence intervals were computed using the normal approximation method. Statistical significance is indicated as follows: * = p  < 0.001, ** = p  < 0.0001.

The study demonstrated that EuNmCV-5, the new pentavalent vaccine, was safe and well-tolerated in healthy Korean adults. No significant safety issues related to the vaccines were identified. The incidence and severity of both local and systemic reactions were found to be comparable between the two study vaccines. Both solicited and unsolicited adverse events were mild or moderate in severity and resolved without sequelae.

The SBA assay, using either rabbit (rSBA) or human (hSBA) sera, has demonstrated a high correlation with immunity to invasive meningococcal disease and is globally recommended as a regulatory standard for licensure of all meningococcal vaccines 11 , 12 . Immunogenicity assessment for meningococcal vaccines targeting serogroups A, C, W, or Y typically evaluates the proportion of participants who achieved more than fourfold rise in rSBA titers for each serogroup (seroconversion rate) or the proportion of participants who achieved rSBA titers above a predefined threshold (seroprotection rate). A conservative threshold for titers is considered as ≥1:8 in seronegative individuals and ≥1:128 in seropositive individuals 13 , 14 , 15 . In this study, we applied the same criteria to evaluate the immunogenicity of the study vaccines against serogroup X. This approach has been employed in previous studies on another meningococcal conjugate vaccine targeting serogroup X 13 , 16 . After 28 days following a single dose of vaccination, EuNmCV-5 induced seroconversion in more than 85% of participants for all the targeted serogroups, including serogroup X. This strong immune response was further demonstrated by the proportion of participants achieving a seroprotective titer. Moreover, the GMTs for all serogroups were significantly higher in the EuNmCV-5 group compared to the MenACWY-CRM group.

Some participants had high baseline titers before vaccination, suggesting that some participants might have had prior subclinical infections or acquired natural immunity. However, the baseline titers for each serogroup were comparable to or lower than those previously reported in other meningococcal vaccine studies in South Korea 17 , 18 . Two participants in the MenACWY-CRM group showed seroconversion against serogroup X. A possible explanation could be intraindividual variability in serogroup X antibodies or the presence of cross-reactive antibodies.

Taking all these factors into account, EuNmCV-5 appears to be an easily administered, safe, and potent vaccine candidate. Given the limited sample size and short-term follow-up period in this study, further investigations are needed to evaluate the long-term persistence of antibody levels and to monitor delayed adverse events. Additionally, the next phase 2/3 study of EuNMCV-5 will be conducted in Gambia and Mali. This study will include participants from a broader age range—healthy infants, toddlers, children, adolescents, and adults. It will evaluate the vaccine’s safety and efficacy across various age groups in areas where meningococcal disease is more prevalent.

Study design

A randomized, single-center, active-controlled, double-blind, first-in-human, phase 1 study was conducted to evaluate the safety, tolerability, and immunogenicity of EuNmCV-5, a pentavalent meningococcal conjugate vaccine in healthy Korean adults. The study was conducted in accordance with the Good Clinical Practice Guidelines and the principles outlined in the Declaration of Helsinki. The protocol was approved by the Institutional Review Board at Seoul National University Hospital (Seoul, Republic of Korea), and all participants provided written informed consent before enrolling in the study.

Eligible participants were randomly assigned in a 1:1 ratio to either the intervention vaccine, EuNmCV-5, or the control vaccine, MenACWY-CRM, and received a single injection of one of the two study vaccines. Due to visual differences between the two study vaccines, unblinded site clinical trial pharmacists and vaccinators were designated. An independent statistician generated a random allocation list in SAS ® software version 9.4 (SAS Institute, Cary, NC, USA), employing block randomization with predetermined block sizes (4 or 6). The random allocation list was sealed in envelopes and provided only to the unblinded clinical trial pharmacists. Unblinded clinical trial pharmacists filled all study vaccines into identical-appearing syringes according to the random allocation list in a secure location. Unblinded vaccinators then administered the allocated drugs to each participant. The unblinded clinical trial pharmacists and vaccinators did not participate in any other procedures.

After vaccination, participants were monitored for 30 min for anaphylactic reaction. Clinic visits were scheduled 7 and 28 days after vaccination. A follow-up telephone contact was made 180 days after vaccination (Fig. 1 ). Diary cards were distributed to participants on the vaccination day and 7 days after to record the duration and severity of solicited and unsolicited adverse events. Solicited adverse events were recorded for the first 7 days, and unsolicited adverse events were recorded through 28 days. The blinded site staff collected data from the diary cards during the scheduled clinic visits. Serious adverse events were tracked through 180 days after vaccination via telephone contact by the blinded site staff.

Blood samples for immunological assessment were collected before vaccination and 28 days after vaccination. The 28-day interval was chosen based on the previous studies on another meningococcal conjugate vaccine, which demonstrated that this timeframe allowed sufficient time for the formation of antibodies 13 , 19 .

Study drugs

The intervention vaccine was EuNmCV-5, a pentavalent meningococcal CRM 197 -conjugated vaccine containing serogroups A, C, W, X, and Y. The control vaccine was MenACWY-CRM (Menveo ® , GlaxoSmithKline, North Carolina, USA), a quadrivalent meningococcal CRM 197 -conjugated vaccine containing serogroups A, C, W, and Y. A quadrivalent vaccine was selected as control as there was no available pentavalent vaccine when the study was designed. EuNmCV-5 was contained in a single vial with a liquid component comprising 10 μg of meningococcal serogroup A and 5 μg each of serogroup C, W, X, and Y. The total recombinant CRM 197 protein in EuNmCV-5 was ~49.5 μg/0.5 mL. MenACWY-CRM was composed of two vials. The first vial contained a powder with 10 μg of meningococcal serogroup A, while the second vial contained a liquid component of 5 μg each of serogroup C, W, and Y. The recombinant CRM 197 protein in MenACWY-CRM was 25.4–65.5 μg/0.5 mL 20 . Just before the administration of MenACWY-CRM, the contents of the first vial were combined with the second vial. Both vaccines were administered as a single dose of 0.5 mL into the deltoid muscle.

Study population

A total of 60 healthy Korean male and female participants, aged 19–55, were recruited for this study. A sample size of 60 was deemed appropriate for this first-in-human study to provide a descriptive evaluation of the safety, tolerability, and immunogenicity of EuNmCV-5. This was based on the participant numbers used for a previous phase 1 study on another meningococcal conjugate vaccine 13 .

Individuals with a history of meningococcal infection or in contact with a person with meningococcal infection within the last 2 weeks were excluded from the study based on self-reporting during the interview. Individuals who had received a previous meningococcal vaccination or had been vaccinated with other vaccines within the last 4 weeks were also excluded. Additionally, individuals with any chronic medical conditions, immunodeficiency, or a history of hypersensitivity to any vaccination were excluded from participation. Through self-reporting during the interview, those who experienced fever (≥38 °C) within 3 days of screening or had a significant acute or chronic infection within 7 days were excluded. Individuals with positive urine drug screens, positive blood screens for hepatitis B/C or HIV, clinically significant laboratory abnormalities (including liver function tests), and positive pregnancy tests were also excluded from the study.

Safety assessment

Safety and tolerability were assessed by clinical laboratory tests, physical examination, vital signs, and monitoring of solicited and unsolicited adverse events. During the initial 7 days following vaccination, participants reported solicited adverse events. Solicited adverse events included both systemic reactions (fever, headache, fatigue/malaise, nausea, vomiting, myalgia, arthralgia, chill, rash, and acute allergic reaction) and local injection-site reactions (pain, tenderness, erythema/redness, induration/swelling, and urticaria). Erythema/redness or induration/swelling was classified as life-threatening if necrosis occurred, severe if the diameter was ≥10.0 cm, moderate if 5.1–9.9 cm, and mild if ≤5.0 cm. Fever was classified as life-threatening if the temperature was >40.0 °C, severe if 39.0–40.0 °C, moderate if 38.5–38.9 °C, and mild if 38.0–38.4 °C. Other adverse events were graded as follows: mild (no interference with normal activities), moderate (some interference with normal activities), severe (prevention of normal activities), and life-threatening.

Safety parameters included anaphylactic reaction occurring within 30 min post-vaccination, solicited adverse events recorded within 7 days post-vaccination, unsolicited adverse events documented within 28 days post-vaccination, and serious adverse events monitored over 180 days following vaccination.

Immunogenicity assessment

For the immunogenicity assessment, ~20 mL of blood was collected before vaccination (day 0) and day 28, using serum-separating tubes and stored at room temperature for a minimum of 30 minutes to a maximum of 2 hours. Blood samples were centrifuged at 4 °C and 1900  g for 20 minutes. Approximately 1.0 mL of supernatant was stored at −70 °C until analysis. The serum samples were tested with a rabbit complement-dependent serum bactericidal antibody (rSBA) assay. The Department of Health and Social Care at UK Health Security Agency (UKHSA, London, UK) measured the rSBA titers against five target serogroups: A, C, W, X, and Y. The target strains in the rSBA assays were serogroup A F8238, serogroup C C11, serogroup Y s1975, serogroup W M01 240070, and serogroup X BF 2/97. The rSBA assay method was adapted as previously published 21 . The lower limit of quantitation (LLOQ) was set at a titer of four. Antibody titers below LLOQ were considered to have a value of half the LLOQ.

Immunogenicity parameters included the proportion of participants with seroconversion, defined as individuals who had an increase of at least 4 times rSBA titer at day 28. This was characterized as a post-vaccination titer of ≥32 for seronegative participants whose baseline titer is <8 or a ≥ 4-fold increase in post-vaccination titer for seropositive participants whose baseline titer is ≥8. Additionally, the proportion of participants achieving seroprotection was defined as individuals with an rSBA titer of ≥8 at day 28 or those with an rSBA titer of ≥128 at day 28. The seroprotection threshold has been validated as an effective indicator of protection in both seronegative and seropositive individuals in prior studies of other meningococcal conjugate vaccines 13 , 14 , 15 . Furthermore, geometric mean titers (GMTs) for each serogroup at day 28 were assessed, along with GMT ratios (GMRs) comparing the EuNmCV-5 and MenACWY-CRM groups. GMFI from baseline and their ratios (geometric mean fold increase ratio, GMFR) between the two groups were also presented for each serogroup.

Statistical analysis

Safety data were analyzed for the participants who were administered the study vaccines. Solicited and unsolicited adverse events were analyzed by the number and percentage of participants experiencing each event.

Immunogenicity data were analyzed for the participants who received the study vaccines and with post-vaccination immunogenicity data. The immunogenicity parameters of each serogroup were summarized separately based on the treatment. GMTs were calculated by transforming the titers to a logarithmic scale, computing the mean on the transformed scale, and converting the mean value back to the original scale. To assess the differences in GMTs between the two study vaccines, 95% confidence intervals (CIs) were computed using the normal approximation method. Additionally, independent t-tests were conducted on the log2-transformed titers to compare the means. The seroconversion rate and seroprotection of the two study vaccines, along with their 95% CIs, were calculated using the normal approximation method. Seroconversion rate and seroprotection rates were compared between treatment groups using the Chi-squared test or Fisher’s exact test. Significance was set at p  < 0.05 (two-sided). All data analyses and statistical computations were done with SAS ® software version 9.4 (SAS Institute, Cary, NC, USA).

Data availability

Due to the privacy of study participants, the data supporting this study’s findings are not openly available. However, they are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the principal investigators, study coordinators, and healthcare workers involved in this study. We also thank YeongOk Baik, Youngjin Choi, and Mihee Noh of EuBiologics for their support during the study. This study was sponsored by EuBiologics Co., Ltd., Seoul, Republic of Korea. The funder played a role in study design, data collection, analysis, and interpretation of data.

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Yoonjin Kim, Sungyeun Bae, Kyung-Sang Yu, SeungHwan Lee & Jaeseong Oh

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Chankyu Lee, Jinil Kim & Howard Her

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Jaeseong Oh

Clinical Research Institute, Jeju National University Hospital, Jeju, Republic of Korea

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All authors met the International Committee for Medical Journal Editors criteria for authorship. Y.J. Kim, C.K Lee, J.I. Kim, and H. Her, primarily contributed to the data interpretation and manuscript preparation. S.Y. Bae and K.S. Yu reviewed the final paper. J.S. Oh was responsible for overall supervision of the project and review of the final paper. S.H. Lee was the principal investigator of this study. All authors had full access to masked data in the study and had final responsibility for the decision to submit for publication.

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C.K.L., J.I.K., and H.H. are full-time employees of EuBiologics Co., Ltd., Seoul, Republic of Korea, but declare no non-financial competing interests. All other authors declare no competing financial or non-financial interests.

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Kim, Y., Bae, S., Yu, KS. et al. A randomized study to evaluate the safety and immunogenicity of a pentavalent meningococcal vaccine. npj Vaccines 9 , 140 (2024). https://doi.org/10.1038/s41541-024-00935-8

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Literature review to identify evidence of secondary transmission of pentavalent human-bovine reassortant rotavirus vaccine (RV5) strains to unvaccinated subjects

Affiliations.

• 1 MSD Research and Development (China) Co., Ltd., Beijing, China.
• 2 Merck & Co., Inc., Rahway, NJ, USA.
• 3 MSD France, Lyon, France. Electronic address: [email protected].
• PMID: 38355319
• DOI: 10.1016/j.vaccine.2024.01.083

Background: Rotavirus is the leading cause of severe diarrhea in infants and young children. Live attenuated vaccines can lead to horizontal transmission with the risk of vaccine-derived disease in contacts. Transmission of pentavalent human-bovine reassortant rotavirus vaccine (RV5) strains leading to clinical disease was not well evaluated in the pivotal clinical trials, and only a few case reports have been described in the literature.

Methods: We performed a systematic literature review to investigate secondary transmission of RV5 strains to unvaccinated subjects globally. We searched Embase, Medline for English papers, CNKI, Wan Fang for Chinese papers, and other resources (i.e., conference papers with full text) from January 2005 to June 2021. Eligibility criteria for inclusion were original articles based on non-interventional studies (case-control studies, cohort studies, cross-sectional studies) using RV5 strain transmission as outcomes. Other study or publication types were excluded, such as pre-clinical studies, interventional studies and case reports. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was used, and study quality was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies and the JBI checklist for cross-sectional studies to assess the risk of bias.

Results: The search generated 2,089 articles in total. Seven articles met all inclusion criteria, including six cohort studies and one cross-sectional study. All studies underwent quality assessment and complied with the quality criteria of the NOS or JBI checklist, respectively. Overall, none of the seven studies identified RV5 vaccine-type transmission to an unvaccinated population, in either hospitals or nurseries under a close contact environment. One study reported that 1% of unvaccinated infants had gastrointestinal symptoms, but all symptoms were attributed to other clinical conditions.

Conclusions: We found no evidence of horizontal transmission of RV5 strains to unvaccinated infants in a context of a limited amount and the descriptive nature of the identified studies.

Keywords: Rotavirus; Secondary Transmission; Vaccine.

Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Peer-reviewed

Research Article

Timeliness of immunisation with the pentavalent vaccine at different levels of the health care system in the Lao People’s Democratic Republic: A cross-sectional study

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliations Lao-Lux Laboratory, Institut Pasteur du Laos, Vientiane, Lao PDR, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Grand-Duchy of Luxembourg

Roles Conceptualization, Data curation, Writing – review & editing

Current address: Department of Hygiene and Health Promotion, Ministry of Health, Vientiane, Lao PDR

Affiliation Lao Tropical and Public Health Institute, Vientiane, Lao PDR

Current address: National Center for Laboratory and Epidemiology, Vientiane, Lao PDR

Current address: Lao-Oxford-Mahosot Hospital Wellcome Trust Research Unit, Vientiane, Lao PDR

Current address: Saarland University, Homburg, Germany

Roles Methodology, Writing – review & editing

Current address: Institute of Research and Education Development, University of Health Sciences, Vientiane, Lao PDR

Affiliation Lao-Lux Laboratory, Institut Pasteur du Laos, Vientiane, Lao PDR

Roles Data curation, Writing – review & editing

Affiliation Luxembourg Development Cooperation Agency, Vientiane, Lao PDR

Affiliation Children Hospital, Vientiane, Lao PDR

Roles Conceptualization, Writing – review & editing

Affiliation Expanded Programme on Immunisation, Vientiane, Lao People’s Democratic Republic

Affiliations Lao Tropical and Public Health Institute, Vientiane, Lao PDR, Département de Médecine Sociale et Préventive, Université Laval, Québec, Canada

Roles Conceptualization, Funding acquisition, Supervision, Writing – original draft, Writing – review & editing

• Lisa Hefele, 
• Sengdavanh Syphan, 
• Dalouny Xayavong, 
• Anousin Homsana, 
• Daria Kleine, 
• Phetsavanh Chanthavilay, 
• Phonethipsavanh Nouanthong, 
• Kinnaly Xaydalasouk, 
• Outavong Phathammavong, 

• Published: December 8, 2020
• https://doi.org/10.1371/journal.pone.0242502
• Reader Comments

The timely administration of vaccines is considered to be important for both individual and herd immunity. In this study, we investigated the timeliness of the diphtheria-tetanus-whole cell pertussis-hepatitis B- Haemophilus influenzae type b (pentavalent) vaccine, scheduled at 6, 10 and 14 weeks of age in the Lao People’s Democratic Republic. We also investigated factors associated with delayed immunization.

1162 children aged 8–28 months who had received the full course of the pentavalent vaccine at different levels of the health care system were enrolled. Vaccination dates documented in hospital records and/or immunisation cards were recorded. Age at vaccination and time intervals between doses were calculated. Predictors for timely completion with the pentavalent vaccine at 24 weeks were assessed by bivariate and multivariable analyses.

Several discrepancies in dates between vaccination documents were observed. In general, vaccination with the pentavalent vaccine was found to be delayed, especially in health care settings below the provincial hospital level. Compared to the central hospital level, less participants who were vaccinated at the district/health center level received the third dose by 16 (48% at the central hospital level vs. 7.1% at the district and 12.4% at the health center level) and 24 weeks of age (94.4% at the central hospital level vs 64.6% at the district-outreach and 57.4% at the health center level) respectively. In logistic regression analyses, lower education level of the mother as well as vaccination by outreach service, were independently associated with delayed completion of vaccination.

We observed a general delay of vaccination, especially at lower ranked facilities, which correlated with indicators of poor access to health services. This highlights the need for further improving health equity in rural areas. Age-appropriate vaccination should become a quality indicator for the national immunization programme. In addition, we recommend further training of the health care staff regarding the importance of reliable documentation of dates.

Citation: Hefele L, Syphan S, Xayavong D, Homsana A, Kleine D, Chanthavilay P, et al. (2020) Timeliness of immunisation with the pentavalent vaccine at different levels of the health care system in the Lao People’s Democratic Republic: A cross-sectional study. PLoS ONE 15(12): e0242502. https://doi.org/10.1371/journal.pone.0242502

Editor: Florian Fischer, Charite Universitatsmedizin Berlin, GERMANY

Received: March 31, 2020; Accepted: November 3, 2020; Published: December 8, 2020

Copyright: © 2020 Hefele et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Due to ethical restrictions and participant confidentiality, the data set cannot be made publicly available. However, the data can be requested from Institut Pasteur du Laos, after obtaining permission from the National Ethics Committee for Health Research (NECHR) in the Lao PDR. The contact person for the NECHR in the Lao PDR is Dr Khampheng Phongluxa (Tel: +856-21 250670-207 and 208; Email: [email protected] ; Website: http://www.laohrp.com ). The Institut Pasteur du Laos can be contacted through the website ( https://www.pasteur.la/contact/ ), by phone (Tel: +856-21 285321) or by email through Antoine des Graviers ( [email protected] ).

Funding: This work was supported by the Ministry of Foreign and European Affairs, Luxembourg (project “Luxembourg-Laos Partnership for Research and Capacity Building in Infectious Disease Surveillance II”) and the Luxembourg Institute of Health and the AUF (l’Agence universitaire de la Francophonie). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: Dr. Nouanthong has been a member of the independent National Immunization Technical Advisory Group in Lao PDR since August 2017. The other authors declared no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction

The timely administration of vaccines is considered to be important for both individual and community immunity. Studies in the UK [ 1 ], China [ 2 ], the USA [ 3 ] and lower-income countries such as Senegal [ 4 ], Sri Lanka [ 5 ], Malawi [ 6 ] and India [ 7 , 8 ] have investigated the impact of timeliness on vaccination. Delayed vaccinations of children may increase the risk of infection before vaccination, compromising the success of the intervention as well as herd immunity. On the other hand, vaccinations given too early or without sufficient interval between the doses may not be fully protective [ 1 ].

In the Lao People´s Democratic Republic (PDR), the expanded programme on immunization (EPI) is one of the most successful public health programmes and routine vaccination coverage has increased for more than ten years. Currently, the National Immunization Programme in Lao PDR includes vaccines against tuberculosis, measles, rubella, diphtheria, tetanus, pertussis, H . influenzae type b, polio, pneumococcal disease and Japanese encephalitis. Vaccination of children with vaccines included in the National Immunization Program is free of charge.

The estimated coverage for the 3 rd dose of the pentavalent diphtheria-tetanus-pertussis-hepatitis B- Haemophilus influenzae type b vaccine (pentavalent vaccine) was 84% [ 9 ] nationwide in 2018 and 84.1% specifically in Bolikhamxay province in 2017 [ 10 ]. However, it was reported in 2012 that only a small number of children had received all 3 doses of the pentavalent vaccine by the recommended age of 4 months in Lao PDR [ 11 ]. While there are clear national recommendations for delivery of the pentavalent vaccine doses in Lao PDR, little is known at which age children actually receive the vaccine within the National Immunization Program and whether this may impact the immune response. The pentavalent vaccine is scheduled at 6, 10 and 14 weeks of age. Vaccination schedules vary between countries. Vaccination with the DTP-containing vaccine in Thailand follows a 2-4-6 months schedule with a booster vaccination at 4 years [ 12 ]. The United States of America follow the same schedule for the primary vaccination but include a booster at 15 months [ 13 ] while some European countries such as Germany, Luxembourg and Belgium follow a 2-3-4 months schedule but differ with respect to the timing of the booster dose [ 14 ]. Generally, the minimum age of vaccination for the DTP-containing vaccine is six weeks and the recommended spacing between the doses is four weeks. Vaccination doses given too early after the first one may result in an impaired vaccine response [ 13 ]. However, there is no consensus on definitions for vaccination timeliness [ 15 ].

Achieving a high coverage with the (monovalent) hepatitis B birth dose is important to prevent mother-to-child transmission of Hepatitis B. Even though the birth dose was introduced in Lao PDR in 2003, the nationwide coverage was only 55% in 2018 [ 16 ]. Therefore, the birth dose coverage continues to be an important issue in Lao PDR.

In Lao PDR, central hospitals (CH) in Vientiane Capital represent the highest level of the health care system, followed by provincial hospitals (PH), district hospitals (DH) and health centers (HC) [ 17 ]. CHs are tertiary care facilities, PHs and DHs provide health promotion, disease prevention and treatment services, but are limited in capacity and expertise. HCs provide only basic medical services, including immunization services and maternal, new-born and child health services [ 18 , 19 ]. For vaccinations, the parents tend to rely on the nearest health care facility. Although vaccination for children is free, not all families can afford out-of-pocket payments for travel and sustain the loss of a day's work. Typically, health care facilities (HCF) such as HC or DH provide immunization services to several villages within a flexible radius. Vaccinations are registered in the yellow child vaccination card, which stays with the family, and the hospital records, which can consist of one registry book at the mother and child department but also includes the vaccination books of the EPI team, typically one vaccination book for each village. Regardless of where the vaccination takes place, the children are usually listed in the book of the home village and in case of outreach vaccination, the books are taken to the villages. The hospital records as well as vaccination cards are standardized and provided by the health offices.

The primary objective of this study was to investigate the timeliness of vaccination with the three doses of the pentavalent routine childhood vaccine in fully vaccinated children in Bolikhamxay province and Vientiane Capital. In addition, the timeliness of Hepatitis B birth dose was assessed. For this purpose, the dates of vaccination as recorded in the vaccination card and hospital records were compared and the proportion of children that received the vaccination with delay was estimated. Furthermore, we investigated risk factors associated with delayed vaccination.

Participants and methods

Participants.

The study took place in the context of a larger vaccine immunogenicity study in Bolikhamxay province and in Vientiane capital in 2017/18 (see S1 File ) [ 20 ]. All participants had received the full course of the pentavalent vaccine, documented in either the hospital records or vaccination card. In Vientiane Capital, 319 children aged 8 to 23 months and their parents/guardians who visited the Children´s Hospital for unrelated health reasons or Measles and Rubella vaccination were enrolled. Bolikhamxay is a central province only about 150 km away from the capital, on the highway to the South. Bolikhamxay comprises 291 villages with 53 964 households including 304 000 inhabitants in 7 districts [ 21 ]. In Bolikhamxay province, 843 children aged 8 to 28 months were recruited, who were vaccinated in the PH, three DHs and ten HCs. Before the start of the sample collection, the study was explained to the head of the participating village and to the parents of the participants by a health care worker. All parents/guardians signed the informed consent form and could withdraw their participation at any time. A standardized questionnaire was designed to collect information about the participant´s socio-economic background, access to health care, history and location of vaccination. The detailed information collected by the questionnaire can be found in S1 Table in S1 File of the previously published study. Vaccination histories were verified and confirmed in the hospital records at the HCF, if available, as well as on the vaccination card. The data was double entered into Epidata [ 22 ] independently before data analysis. Serum samples were collected from participating children to assess antibody levels. The study was approved by the Lao National Ethics Committee (Reference numbers 033/2017/NECHR, 032/2017/NECHR, 031/2017/NECHR, 056/2017/NECHR) and by the internal ethics review board of the Institut Pasteur du Laos.

Vaccination dates

During recent years, the vaccination schedule expanded with the inclusion of new vaccines and/or additional doses, and the layout of vaccination cards and hospital records were gradually adapted. During the review of the vaccination history, we came across different formats and versions of the vaccination card and hospital records. Major changes in format were introduced with the pneumococcal vaccine (PCV13), the inactivated polio vaccine (IPV), the Japanese encephalitis vaccine (JEV) and the second dose of the measles-rubella vaccine (MR). Not all facilities used the latest date version of the hospital records or vaccination cards. However, since the pentavalent vaccine was introduced already in 2009/10, it was included in all versions of the vaccination card and the hospital records inspected in this study [ 23 ].

The vaccination history of the participants was recorded from the hospital records and/or vaccination cards. The age of the participants in weeks at the time of the vaccination with the pentavalent vaccine and with the hepatitis B birth dose was calculated based on the birthdate and the date of the vaccination. Since there is no consensus-definition of “timely vaccination” in lower middle-income countries, as discussed in a review [ 15 ], we used both continuous and categorical measures. The age when receiving each vaccine dose was defined as: “timely” when between 6–7 weeks for dose 1 (pentavalent 1), 10–11 weeks for dose 2 (pentavalent 2) and 14–15 weeks for dose 3 (pentavalent 3) ( Table 1 ). When the participant was older or younger, the vaccination was considered to be “earlier” or “later” than recommended. An interval of 4 weeks is recommended between each dose and intervals shorter than 4 weeks or longer than 5 weeks were considered “shorter” or “longer” than recommended. The National Immunization Programme of the Lao PDR recommends the primary vaccination with the DTP-containing vaccine is completed at 14 weeks and the WHO guidelines specify completing the vaccination course latest at 6 months (24 weeks) of age [ 24 ]. In this study, we considered 16 weeks (in order to give some time margin) and 24 weeks (the latest WHO recommendation for completeness) as cut-off for”early timely” and “late timely” completion of vaccination with the pentavalent vaccine ( Table 1 ). The proportion of participants that had received the pentavalent vaccine by 16 and 24 weeks at each health care level was compared to the level of the CH. Furthermore, we used 24 weeks as a cut-off in order to identify factors associated with the timely completion of the schedule or not.

• PPT PowerPoint slide
• PNG larger image
• TIFF original image

https://doi.org/10.1371/journal.pone.0242502.t001

In order to detect irregularities in the vaccination documents of participants who had both the hospital records and vaccination card available, the time discrepancy between documented vaccination dates was obtained by subtracting the vaccination date in the vaccination card from the vaccination date in the hospital records. Vaccination dates in the vaccination cards were considered more reliable as the cards stay with the mothers and are filled in on the day of the vaccination. Hospital records can also be entered at a later time point and problems with medical documentation has been reported in Lao PDR before [ 25 ]. Therefore, we gave priority to the vaccination cards to calculate the median age at vaccination and the intervals between vaccinations. Whenever the vaccination card was not available, the date in the hospital records was used.

Laboratory analysis

The serum samples were analysed by commercial ELISA kits as described elsewhere [ 20 ]. Protective immunity was considered if the participants had an anti-diphtheria titer ≥0.1 IU/ml, an anti-tetanus titer >0.5 IU/ml, an anti-hepatitis B titer >10 IU/L and an anti- Haemophilus influenzae type b (Hib) titer >1.0μg/ml. A titer ≥22 U/ml was used as indication of exposure to the vaccine antigen for B . pertussis .

Statistical analysis

Data analyses were conducted using R software (version 3.5.3) [ 26 ] with the following packages: “tidyverse” [ 27 ], “lubridate” [ 28 ], “MASS” [ 29 ], “rcompanion” [ 30 ], “lmtest” [ 31 ], “car” [ 32 ], “epitools” [ 33 ], “ggplot2” [ 34 ], “survival” [ 35 ], “survminer” [ 36 ] and “pROC” [ 37 ].

Survival analysis by the Kaplan-Meier method was performed to present timeliness of vaccination for each of the three doses of pentavalent vaccine at any given age ( S3 Fig ), a method suggested by Lauberau et al. (2002) [ 38 ]. For the Kaplan-Meier curve, we used the age at vaccination as based on the date in the vaccination card, and if there was no card available, we used the date in the hospital records. Participants for which the calculated age at vaccination was negative (date of vaccination before date of birth, a documentation error) were excluded.

In order to assess whether any of the socio-demographic or vaccination related factors are associated with the completion of primary vaccination with the pentavalent vaccine by 24 weeks (6 months) of age, Chi‐square test and Fisher’s exact test were performed. Odds ratio (OR), 95% confidence intervals (CI) and p-value were calculated. We performed logistic regression analysis in order to investigate the association between the binomial response variable (completion of vaccination by 24 weeks) and socio-economic or vaccination-related factors. Only variables with p-values <0.2 were included in the generalized linear models (GLMs). The correlation (correlation value >0.5) and/or multicollinearity (variance inflation factor >2–5) of independent variables was checked, and in that event, the variable which was considered to be less important and/or with the lower impact was not included. We performed binary logistic regressions using a stepwise method for removing variables that are not associated with the response variable one by one, while considering both the p-value of the variable and the Akaike Information Criterion. The models were tested for possible interactions. The best fitting model was selected by comparing the AIC weights for a set of fitted models. The final model was assessed in comparison with the null model using a likelihood ratio test. In addition, the individual association of the variables in the model was tested by Wald tests. In order to assess the predictive ability of the model, the area under the curve (AUC) was calculated using the “roc” R function. A p-value <0.05 was considered statistically significant.

Documentation of vaccination

At the CH, the three doses of the pentavalent vaccine were verified in the vaccination card of all participants (100%) from Vientiane. Most of these children (65.5%) were vaccinated with all three doses at the Children´s hospital, the others received some or all of the doses at another CH in Vientiane. In Bolikhamxay, the parents of 620 children (73.6%) presented the vaccination card. The vaccination entries in the hospital records were found for 83.3% of the children and for 56.8%, both sources were available.

Comparison of vaccination cards and hospital records

At the Children’s hospital, it was possible to review the hospital records of all three doses for 88 (27.6%) participants, and for at least one dose for 155 (48.6%) participants. All vaccination dates matched between the vaccination card and hospital records. However, for 8 (2.5%) participants, the birth date entry in vaccination card and hospital records did not match.

In Bolikhamxay, both hospital records and vaccination cards were available from 479 (56.8%) participants. We discovered a number of discrepancies between the two documents. The birth dates of 34 (7.1%) participants differed between vaccination card or hospital records. From the 479 participants in Bolikhamxay with both hospital records and vaccination card, 180 (37.6%) had at least one discrepancy or mismatch between the hospital records & vaccination card date-pairs of at least one of the three doses. From these 180 participants, 43.3% had a mismatch in the dates for pentavalent 1 and 62.8% for pentavalent 3. 17.2% had mismatches for all three date-pairs. The date for pentavalent 3 in the hospital records was before the vaccination card in 71 (39.4%) cases while it was later in only 37 (20.6%) of the 180 participants. The proportion of mismatches increased from pentavalent 1 to 3. At the PH level, only 2.4% to 6.0% of the vaccination dates mismatched from pentavalent 1 to 3 ( Table 2 ). At the DH and HC level, there was a higher proportion of mismatches between vaccination dates at the facility as compared to outreach. The highest proportion of mismatches (41.1%) was found at the health center level among the participants vaccinated directly at the facility. Here, also the largest mean discrepancy between the vaccination card and hospital records was also observed (-9.9 days) (S1 Table in S1 File ).

https://doi.org/10.1371/journal.pone.0242502.t002

Several other observations were made: In some cases (7.8%) among the 180 participants with both records, either pentavalent 2 or 3 or both, the hospital records had the same entry as pentavalent 1 and/or 2 in vaccination card; many of the mismatches differed by less than 7 days for at least 1 date-pair (23.9%); for 9.4% of participants all dates in the hospital records were before the vaccination card; for 7.2%, both the intervals were 4 weeks in the hospital records but not in the vaccination card and at least one of the dates in the hospital records was before the one in the vaccination card. On very few occasions, two doses were denoted with the same date or an obvious mistake was made with respect to the recorded year or the day. Because the vaccination card were less likely to be tampered with, the dates in the vaccination card were given priority in case of mismatches.

Age at vaccination

The median age at vaccination with pentavalent dose 1, 2 and 3, and therefore also the difference between the median age and the recommended age, increased at the lower ranked health care facilities ( Table 3 ) and with each dose, e.g. the median age at the first dose was 6.7 weeks at the central hospital level, but 9.4 weeks at the health center level when participants were vaccinated by outreach services.

https://doi.org/10.1371/journal.pone.0242502.t003

The Kaplan-Meier curve ( S1 Fig ) shows that at the CH level, 50% of the children were vaccinated at the age of 6.7 weeks with pentavalent 1 compared to almost 9 weeks at the HC level. For pentavalent 3, there was a considerable delay at all lower ranked facilities. At the HC outreach level, 50% vaccination coverage was reached at 23.1 weeks (CI: 22.4–24.4) and considerably fewer children were vaccinated by 24 weeks (6 months) of age compared to CH, PH and DH levels ( S1 Fig ).

In order to estimate the timeliness of vaccination, the proportion of participants vaccinated at a given age was calculated ( Fig 1 ). The proportion vaccinated at the recommended 6 weeks of age decreased from 67.7% at the CH to 32.4% at the HC, and outreach vaccination was as low as 12.7%. For pentavalent 2, most of the participants were still vaccinated within a week of delay at the CH and PH (55.5% to 55.8%, respectively). The majority of participants (ranging from 61.1% at the CH to 94.7% for DH outreach) were vaccinated with a delay of 2 or more weeks for pentavalent 3 at all locations.

Arrows indicate recommended week of vaccination. CH = central hospital level, DH = hospital level, HC = health center level. The age at vaccination was calculated based on the vaccination card, and in case the vaccination card was not available, the date in the hospital records was used.

https://doi.org/10.1371/journal.pone.0242502.g001

Compared to the central hospital level, fewer participants who were vaccinated at the district and health center level received the third dose by 16 weeks (48% (95% CI [42.6–53.6]) at the central hospital level vs. 7.1% (95% CI [3.4–10.8]) at the district and 12.4% (95% CI [9.2–15.5] at the health center level) ( S2 Fig ). However, by week 24, more than 90% of the participants at the CH and PH level (94.7% (95% CI [92.2–97.1]) and 92.6% (95% CI [88.8–96.3]) respectively), as well as participants vaccinated directly at the DH level (91.5% (95% CI [86.5–96.6])) had received pentavalent 3. Fewer participants that were vaccinated at the HC level and during DH outreach services were vaccinated with the 3 rd dose by 24 weeks of age (58.4% (95%CI [54–62.7], p<0.0001) ( S2 Fig ) when compared to the CH.

In order to investigate any association between delayed vaccination (defined as age at pentavalent 3 >16 weeks) and seroprotection against any of the five vaccine components, bivariate analyses were performed among those children vaccinated at the CH and PH level. Receiving the 3 rd (last) dose of the pentavalent vaccination more than 16 weeks after birth was not associated with lower seroprotection (S2 Table in S1 File ) in this study.

Interval between vaccination doses

At the CH level, the median interval between pentavalent dose 1 and 2 was 4.7 weeks (S3 Table in S1 File ; S3 Fig ) and only somewhat higher for outreach vaccination at the HC and DH level (5.1 and 5.4 weeks respectively). At the CH and PH level, 62–70% were vaccinated within the recommended interval of 4 weeks between dose 1 and 2 and dose 2 and 3. Considerably less participants were vaccinated within 4-week intervals in lower ranked facilities. Only very few participants were vaccinated within less than 4 weeks (rates ranging from 0.0% to 4.4%) at any health care level.

For most participants at the district and health center level, at least one of the two intervals (pentavalent 1 and 2 and/or pentavalent 2 and 3) was longer than 4 weeks (ranging from 57.1% to 83.2%) (S4 Table in S1 File ).

Predictors for timely completion of vaccination with the pentavalent vaccine

We used timely completion with pentavalent 3 at 24 weeks as binary outcome and performed logistic regression analyses to identify predictors in Bolikhamxay province. The bivariate analyses (S5 Table in S1 File ) showed that being an older mother with a higher education and a higher household income was more often associated with timely vaccination. Markers of inequity in access to health care (delivery at home, no ANC and no hepatitis B birth dose) all were also predictors of delayed vaccinations. Travel time to health care facilities, vaccination by outreach and not belonging to the Tai-Kadai ethnic group emerged as obstacles to timely vaccination.

In logistic regression analyses all variables associated with the outcome with a p<0.2 were included. However, since “place of birth” and “district” correlated with the “place of vaccination”, these variables were excluded from analyses. “Travel time to the next health care facility” was used as surrogate for distance and “received ANC” was used as surrogate for ANC practices in the modelling. The variables “age of participant”, “age of mother”, “number of household members”, “number of siblings” and “travel time to the next health care facility” were included in the logistic model as numeric variables. Several variables remained independently associated with the outcome ( Table 4 ). Participants were more likely to have completed the primary vaccination series by the age of 24 weeks (6 months) if they were not vaccinated by outreach services and if they had received the hepatitis B birth dose. Furthermore, the probability of timely completion increased with age and education of mother but decreased by number of siblings. The fit of the overall model in comparison to the null model was assessed (p-value < 0.0001, AUC = 77.9%).

https://doi.org/10.1371/journal.pone.0242502.t004

Hepatitis B birth dose and recall by health facility

At the CHs in Vientiane Capital, 89.7% had received the birth dose according to vaccination card or hospital records compared to 76% in Bolikhamxay ( Table 5 ). All of the parents of participants from Vientiane Capital stated that their children had received the vaccination at birth (BCG and/or hepatitis B birth dose) at the Children’s hospital or another CH. In Bolikhamxay at HC level, only 28.3% of children whose parents remembered that a vaccination was given at birth had record of the hepatitis B birth dose. These participants were almost exclusively born at home.

https://doi.org/10.1371/journal.pone.0242502.t005

In Bolikhamxay, both hospital records and vaccination card were available from 479 participants and from those, 313 (65.3%) participants had a vaccination date for the birth dose. The vaccination dates matched in both hospital records and vaccination card for 91.7% of these participants.

The hepatitis B birth dose is recommended to be given within 24 h of birth and latest within the first 7 days after birth [ 39 ]. The vast majority of the participants in our study that received the hepatitis B birth dose, did receive it on the day of their birth (93.5%) and only 4.1% did receive it later but within 7 days after the birth date (S6 Table in S1 File ).

Reliable and centralized documentation is important for monitoring vaccination coverage and the quality of immunization programmes. In Bolikhamxay, when both hospital records and vaccination card were available, 38% of children had mismatches in at least one of the vaccination date-pairs, and for 63% of those, the date for pentavalent 3 did not match. At the PH level only 2.4% of mismatches were found for the first dose, but in lower ranked health facilities up to 19% of date pairs mismatched. The mismatches increased with each dose (up to 41% at the HC level). There were also 7.1% mismatches in birthdates between the two vaccination records. Mismatches in calendar days, months or years, are indications that dates are not entered simultaneously and at the same session in the vaccination card and hospital records. Vaccination books are usually assigned to each village and taken along to the village during outreach sessions. When the books or the vaccination card are forgotten, retrospective entry of dates may be common. Vaccination dates may also be entered in the vaccination card in advance as a reminder for the parents, but then vaccination may have taken place at another date. Thus, the importance of written documentation needs to be emphasized at every level of the health system. In particular, the management of hospital vaccination books/records needs to be strengthened, the procedures of record keeping in both the vaccination card and the hospital records should be reviewed, and additional training of the health care staff is required to improve the reliability of entries.

Adherence to the vaccination schedule is considered an important quality aspect of routine immunization, even though there is no generally accepted definition of “timely vaccination” [ 15 ]. We observed a general delay in vaccination with the pentavalent vaccine, especially in health care settings below the PH level. The difference between median age at vaccination and recommended age at vaccination was highest for pentavalent 3. More than half the children vaccinated at the DH and HC level received all three doses later than recommended. The delay at the DH and HC outreach level may reflect challenges with scheduling outreach visits in those villages. If children miss one visit, they may have to wait for the next visit of the health care workers. In our previous study [ 20 ] in this cohort, the place of vaccination was an important predictor for seroprotection. The proportion of protected children was especially low in villages connected to health centers that were located more than one hour of travel time from their district hospital. These findings combined underline the need to strengthen vaccine management in the lower-ranked health care settings. In total, 22% of the children did not complete the immunization series with the pentavalent vaccine by the age of 24 weeks. While we did not find a negative impact of delayed vaccination on seroconversion rates at the CH and PH level, delayed vaccination increases the window of susceptibility and may facilitate disease outbreaks. Since the presence of maternal antibodies may interfere with the infant’s humoral immune response after primary vaccination [ 40 – 42 ], the timing of the first vaccine dose is especially important. However, since the vast majority of the participants in this study were not vaccinated before the scheduled first dose of the pentavalent vaccine at 6 weeks of age, we could not investigate a possible impact of premature vaccination on antibody titers.

In bivariate analyses, essentially all indicators of poor access to health services were very specifically associated with delayed completion of vaccination with the pentavalent vaccine. Since this study included only children who completed vaccination, further studies could investigate whether these are also the risk factors for missing any of the doses of the pentavalent vaccine. After logistic regression analyses, lower education level of the mother, not receiving the hepatitis B birth dose as well as vaccination by outreach service, were independently associated with the delayed completion of full vaccination with the pentavalent vaccine. Due to the geography and infrastructure of the country, around 30% of the villages are classified as remote and are difficult to access. Outreach services should be conducted in at least four rounds per year; however, in 2016, it was estimated that only 9% of remote villages were visited four times [ 43 ]. In contrast to our findings, a study conducted in Sri Lanka found higher timeliness in rural areas compared to urban settings [ 5 ]. The education of the mother has also been shown in other studies [ 2 , 4 , 44 ] to be an important driver on timely immunization or timely completion of specific vaccinations. These results indicate that there is a need to further improve access to health services, especially in remote rural areas.

Almost all participants in Vientiane Capital but only two thirds of the participants living in Bolikhamxay had received the hepatitis B birth dose; however, this is probably a considerable overestimation of recipients in the general population, since we only enrolled participants with a full course of pentavalent vaccination. Recent data estimate the coverage for the birth dose in 2017 to be 55% nationwide [ 45 ]. Even among children who received all three doses of the pentavalent vaccine, only 28.3% had received the hepatitis B birth dose at the health center level in areas covered by outreach. Although the overall number of home births in Lao PDR has decreased from 59% in 2010 [ 46 ] to 35% in 2017 [ 10 ], these findings are still concerning.

There are several limitations to this study. Those include that the specific place of vaccination (either outreach or on-site) was only available by parents’ recall. Since only children with three doses were included, we cannot determine the number of children who missed one or two doses. Our questionnaire may also not have captured all risk factors for delayed vaccination and our findings may not necessarily be valid for the whole country although it shows a typical pattern.

Conclusions

During the past few years, major progress has been made in Lao PDR in vaccine coverage and seroconversions rates. In this study, we observed a general delay of vaccination with the pentavalent vaccine and discrepancies in vaccination records. Vaccination delay was associated with indicators of poor access to health services. To further improve the child vaccination programme, reasons for the discrepancies and inconsistency in vaccination documents should be investigated and training of health care staff in robust documentation and management of health records should be provided. We suggest to include timely completion of vaccination as a quality indicator for the national immunization programme in addition to coverage rates and seroconversion rates.

Supporting information

S1 fig. timeliness of each dose of the pentavalent vaccine according to the age and the health care levels..

A. Timeliness of vaccination with pentavalent 1. B. Timeliness of vaccination with pentavalent 2. C. Timeliness of vaccination with pentavalent 3. Shaded areas indicate the 95% Confidence Interval. Graphs were truncated at 45 weeks to increase visibility. CH = vaccinated at central Hospitals in Vientiane, PH = vaccinated at provincial hospital, DH = vaccinated at district hospital level, HC = vaccinated at health center level. Dashed lines correspond to the median age of vaccination with the pentavalent vaccine. Participants for which the calculated age at vaccination was negative (date of dose before date of birth, indicating a mistake in documentation) were excluded from the graph.

https://doi.org/10.1371/journal.pone.0242502.s001

S2 Fig. Proportion of participants vaccinated with the third dose of the pentavalent vaccine by health care levels.

Mix = participants vaccinated at different health care facilities with one or two of the doses. CH = Central hospital level, DH = District hospital level, HC = health center level. Missing or unreadable dates were excluded from this figure. The age at vaccination was calculated based on the vaccination card, and in case the vaccination card was not available the date in the hospital record was used. The proportion vaccinated at PH, the DH and HC level was compared to the CH level. Data are presented with 95% CI. **** = p<0.0001.

https://doi.org/10.1371/journal.pone.0242502.s002

Difference of interval as recommended in schedule and calculated median interval between pentavalent dose 1 and 2 (A) and pentavalent dose 2 and 3 (B) in weeks according to health care level. The intervals were calculated based on the vaccination cards, and in case the vaccination card was not available the date in the hospital records was used. CH = Central hospital level, DH = District hospital level, HC = health center level. Missing or unreadable dates were excluded from this figure.

https://doi.org/10.1371/journal.pone.0242502.s003

https://doi.org/10.1371/journal.pone.0242502.s004

Acknowledgments

We would like to thank the participants; their families and the health care staff for their participation and assistance. Furthermore, we would like to thank the Luxembourg Development Cooperation for providing support with the logistics throughout the data and sample collection, the administrative staff of the Institute Pasteur du Laos and Dr. Paul Brey for facilitating this research.

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• Open access
• Published: 17 March 2022

Determinants of pentavalent and measles vaccination dropouts among children aged 12–23 months in The Gambia

• Peter A. M. Ntenda 1   na1 ,
• Alick Sixpence 1 ,
• Tisungane E. Mwenyenkulu 2 ,
• Kondwani Mmanga 3 ,
• Angeziwa C. Chirambo 4   na1 ,
• Andy Bauleni 1 &
• Owen Nkoka 5   na1  

BMC Public Health volume  22 , Article number:  520 ( 2022 ) Cite this article

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Every year, vaccination averts about 3 million deaths from vaccine-preventable diseases (VPDs). However, despite that immunization coverage is increasing globally, many children in developing countries are still dropping out of vaccination. Thus, the present study aimed to identify determinants of vaccination dropouts among children aged 12–23 months in The Gambia.

The study utilized cross-sectional data obtained from the Gambia Demographic and Health Survey 2019–20 (GDHS). The percentage of children aged 12–23 months who dropped out from pentavalent and measles vaccination were calculated by (1) subtracting the third dose of pentavalent vaccine from the first dose of Pentavalent vaccine, and (2) subtracting the first dose of measles vaccine from the first dose Pentavalent vaccine. Generalized Estimating Equation models (GEE) were constructed to examine the risk factors of pentavalent and measles vaccinations dropout.

Approximately 7.0% and 4.0% of the 1,302 children aged 12–23 months had dropped out of measles and pentavalent vaccination respectively. The multivariate analyses showed that when caregivers attended fewer than four antenatal care sessions, when children had no health card or whose card was lost, and resided in urban areas increased the odds of pentavalent dropout. On the other hand, when women gave birth in home and other places, when children had no health card, and being an urban areas dweller increased the odds of measles dropout.

Tailored public health interventions towards urban residence and health education for all women during ANC are hereby recommended.

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Vaccination is considered the most successful and cost-effective public health intervention against infectious diseases [ 1 , 2 ]. Each year, about 3 million deaths among children are averted from vaccine-preventable diseases (VPDs) such as diphtheria, tetanus, pertussis, influenza, and measles [ 3 ]. However, by the end of 2020, the global coverage of childhood vaccination dropped from 86% in 2019 to 83% [ 4 ]. It is reported that the coronavirus disease 2019 (COVID-19) pandemic and its associated disruptions have strained health systems as a result, about 23 million under one children did not receive basic vaccines in 2020 [ 4 ]. In The Gambia, the coverage of individual immunization is high (90% or above) except for oral polio vaccine (OPV) 4 and complete immunization which were reported at 85% each in 2020 respectively [ 5 ]. It is known that the high coverages are due to high public awareness, with the accessibility of vaccination services through permanent outreach sites for remote areas and static reproductive and child health (RCH) clinics [ 5 ]. Regarding the multi-dose vaccines, the coverage is reported to be the highest for the first dose and falls in subsequent doses. Precisely, the coverage rates for the initial dose of diphtheria, pertussis, and tetanus (DPT), pneumococcal conjugate vaccine (PCV), and rotavirus vaccine (RV) were reported at 98%, 99%, and 98%, respectively. Nevertheless, the coverages for the last dose of each antigen dropped to 93%, 92%, and 95%, respectively [ 6 ].

Immunization dropout signifies that the child has received the first recommended dose of the vaccine and yet has missed the next recommended dose [ 7 ]. Studies have reported on the various characteristics that influence childhood immunization dropout [ 7 , 8 , 9 , 10 ]. For example, in Ethiopia, it was reported that counseling for mothers about vaccination; fear of vaccine side effects; postnatal care (PNC) attendance, and having a mother who did not receive tetanus toxoid (TT) vaccination were independent factors of vaccination dropout [ 7 ]. In Nepal, mothers with less than 4 or no antenatal care (ANC) visits, long distances to the health facilities, province, and mother without formal employment were reported to be factors associated with vaccination dropout [ 8 ]. Furthermore, in Kenya, having a caregiver with below secondary education and residing >5 km from the health facilities were associated with higher odds of dropping out. On the other hand, caregivers who received reminder text messages were less likely to drop out [ 9 ]. Elsewhere in Ghana, children who had no immunization cards were more likely to drop out compared to those who possessed it [ 10 ]. And finally, in urban Pakistan, in a randomized controlled trial, it was reported that a significant increase in DPT3 completion was estimated in the group that received both redesigned card and center-based education compared with the standard care group [ 11 ].

Over the years, immunization coverage in The Gambia has improved such that the proportion of children aged 12-23 months who received all basic vaccinations increased from 76% in 2013 to 85% in 2019-20 [ 6 ]. However, this coverage is still trailing behind the target that was set by the Global Vaccine Action Plan (GVAP) of 90% coverage for all antigens at the national level and 80% coverage for all antigens at the districts level by 2020 [ 12 ]. These statistics may indicate that a certain proportion of children are dropping out of immunization programs. It is noted that a few researchers have focused on the factors associated with either individual immunization coverage [ 13 ], full immunization [ 13 , 14 ], or non-vaccination in the Gambia [ 2 , 15 ]. However, only one study reported the dropouts between vaccine doses [ 16 ], yet no single associated factor was considered in that study. Therefore, the aim of the present study was to identify the determinants of immunization dropouts among Gambian children aged 12–23 months. The findings of this study will help the program designers to improve the EPI program performance in The Gambia.

Data source, design, and sampling methods

This study used data obtained from the 2019-20 Gambia Demographic and Health Survey (GDHS) [ 6 ]. The GDHS used a cross-section study design and was carried out by The Gambia Bureau of Statistics (GBoS) in conjunction with the Gambia Ministry of Health (MoH) [ 6 ]. The GDHS was designed to yield a nationally representative sample using two-stage cluster sampling technique. Enumeration areas (EAs) were selected with a probability proportional to their size within each sampling stratum in the first stage and yielded 281 EAs [ 6 ]. In the second stage, the households were systematically sampled from the EAs using a household listing [ 6 ]. Thus, the resulting lists of households served as the sampling frame from which a fixed number of 25 households were systematically selected per cluster.

Setting and immunization services in The Gambia

The Expanded Programme on Immunisation (EPI) in The Gambia officially started in May 1979 where six vaccines were recommended [ 13 ]. The ultimate goal was to administer Bacillus Calmette–Guérin (BCG) vaccine against tuberculosis (TB), oral polio vaccine (OPV) against poliomyelitis, DPT vaccine against diphtheria, tetanus and pertussis, and yellow fever vaccine to protect against yellow fever [ 13 , 15 ]. Over the last two decades, the programme has been introducing new and underused vaccines into The Gambian routine services. These vaccines include hepatitis B – HepB (introduced in 1990), Haemophilus influenzae type b – Hib (introduced in 1997), pneumococcal conjugate vaccine – PCV (introduced in 2009), measles-mumps-rubella second dose – MMR (2012), rotavirus vaccine – RV (introduced in 2013), inactivated polio vaccine – IPV (introduced in 2015), meningitis A – MenA (introduced in 2019), and human papillomavirus vaccine – HPV (introduced in 2019) [ 2 , 15 ]. The Gambia routine immunization programme recommends that the BCG, the first dose of polio, first dose of HepB should be given at birth [ 13 ]. Further, it is recommended that the DTP/Hib/HepB combined (Pentavalent vaccine); the second, the third, the fourth dose of polio; PCV and RV should be given at approximately 2, 3 and 4 months respectively [ 13 ]. The measles, yellow fever, fourth dose of polio are recommended to be administered as soon as the child reaches 9 months of age [ 13 ]. While the DTP/Hib/HepB combined and fifth dose polio should be administered at 18 months respectively [ 13 ]. Lastly, vitamin A should be provided every 6 months (from 6 months of age till the child is 59 months) [ 13 ]. Table 1 shows the schedule of the Gambian childhood expanded programme on immunization.

Data collection

All women aged 15-49 years who were either permanent residents of the selected households or visitors who stayed in the households the night before the survey were eligible to be interviewed. Data were collected using face-to-face interviews on the measures of population health, including maternal and child health indicators [ 6 ].

Inclusion and exclusion criteria

The analysis was limited to children of age group 12 to 23 months because children of this age group are expected to have completed all the basic vaccines. However, all children who did not receive an individual vaccine were excluded from the analysis. Furthermore, all children who had missing data on the other covariates were excluded from this study. Figure 1 shows the inclusion and exclusion criteria.

Inclusion and exclusion criteria.

Dependent variable

The dependent variable of the current study was immunization dropout and it indicates that one has received the first recommended dose of vaccine and missed the next recommended dose [ 8 ]. In this study, dropout was defined as the child who received the first antigen of pentavalent but not the third antigen of the Pentavalent or the first antigen of pentavalent but not first antigen of measles [ 12 ]. Furthermore, the Pentavalent dropout rate was calculated by dividing the number of children aged 12–23 months who received pentavalent1 minus the number of children aged 12–23 months who received pentavalent3 divided by the number of children 12–23 months of age who received Pentavalent1 multiplied by 100 (Pentavalent1–Pentavalent3) ÷ Pentavalent1 x 100%) [ 12 ]. It was also calculated as the percentage of children aged 12–23 months who received pentavalent1 and measles1 divided by those who received pentavalent1 multiplied by 100 (Pentavalent1–measles) ÷ Pentavalent1 x 100%) [ 12 ]. The World Health Organization (WHO) recommends that the dropout rates of both the Penta1 to Penta3 and Penta1 to MCV1 should be <10% [ 12 ]. It should be noted that a dropout rate of >10% reflects underutilization of immunization services.

Independent variables

The following characteristics were considered as predictors of immunization dropout after a review of relevant literature [ 8 , 17 ]. Sex of the child (male and female), the birth order (1, 2–3, 4–5, and 6 and above), place of delivery (health facilities or homes and other places), mother’s age (15–24, 25–34, and ≥35 years), the mother’s and husband’s education (no formal education, primary school education, and secondary and higher education), ANC visits (adequate or inadequate visits), immunization card (no card and had the card but its whereabouts was unknown and had the card and its whereabouts was known), the household wealth index (poorest, poorer, middle, richest, and richest), tetanus toxoid injection during pregnancy (received or not received), number of children under the age of 5 years (0–1, 2, 3 or more), distance to the health facility (big problem, not a big problem), amount of media exposure (0, 2, and 3), the place of residence (urban or rural), and local government area (Banjul, Kanifing, Brikama, Mansakonko, Kerewan, Kuntaur, Janjanbureh, and Basse). The household wealth index was generated through a principal component analysis using information easy-to-collect data on a household’s ownership of selected assets, such as televisions and bicycles [ 18 ].

Statistical analysis

All analyses were conducted separately for pentavalent and measles dropout outcomes. Descriptive analyses were performed to describe the baseline characteristics of the study population. Univariate and multivariate analyses were conducted using generalized estimating equations (GEE) for estimating the effects of predictors on the risk of childhood immunization dropouts. Since children residing in the same household, communities, and belonging to the same mother may be more similar to each other, GEE models were used to adjust for the clustering within the household and communities. The results of the multivariate analysis were obtained using adjusted odds ratios (aORs) with their P -values and 95% confidence intervals (CIs). SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA) was used to conduct all of the analyses.

Ethical considerations

All methods were carried out in accordance with the Declaration of Helsinki. The 2019-2020 GDHS was implemented by The GBos in conjunction with the Gambia Ministry of Health. The protocols and procedures for GDHS were reviewed and approved by The Gambian Government/Medical Research Council Joint Ethics Committee and the Institutional Review Board (IRB) of ICF Macro. ICF IRB ensures that the survey complies with the U.S. Department of Health and Human Services regulations for the protection of human subjects (45 CFR 46), while the host country IRB ensures that the survey complies with laws and norms of the nation [ 19 ]. During survey implementation, informed consent was sought from participants prior to each interview and a parent or guardian provided consent prior to participation by children less than 18 years. The authors obtained permission from the DHS program for the use of the data beyond the primary purpose of the survey.

Baseline characteristics of the study sample and dropouts rates

Overall, 1.302 children aged 12–23 months were analyzed in this study. The dropouts for the measles vaccine and the Pentavalent vaccine were reported at 6.8% and 4.3% respectively (Fig. 2 shows the vaccination dropouts). Table 2 presents the baseline characteristics of the study population. More than half of the children (52%) were male and one-third (34.3%) of the children were in the 2–3 birth order. As regards maternal and household characteristics, more than half (54.5%) of respondents were distributed in the age group 25–34 years and 52.2% of respondents had primary school education. Furthermore, about two-thirds (63%) of respondents their husbands had no formal education. A majority of respondents (59.4%) had more than three under-5-year-old children, and a half (47%) of the respondents had access to at least two types of mass media. In terms of health service utilization, a majority (81%) of births occurred in health faculties, 95% had an immunization card, 82% had adequate antenatal visits, and 88% had tetanus toxoid injection during pregnancy. Nearly 31% of respondents had big problems with distance to the nearest health facility. In terms of community characteristics, a majority of respondents were rural (58%).

Percentage of children with Pentavalent 3 and Measles 1 dropouts.

Factors associated with pentavalent vaccine dropout

Table 3 displays univariate and multivariate logistic regression results of pentavalent vaccination dropout. Compared to children whose caregivers had adequate ANC visits, the odds of experiencing pentavalent dropout (aOR: 2.44; 95% CI: 1.16–5.12) were high among children whose caregivers had inadequate ANC visits. Furthermore, the odds of experiencing pentavalent vaccination dropout was much higher among children whose caregivers who had no vaccination card/no longer had a card (aOR: 12.4; 95% CI: 4.09–37.8) and who had a card but its whereabouts were not known (aOR: 32.7; 95% CI: 10.7–100.0) compared with children who had vaccination card and its whereabouts was known. Additionally, the odds of experiencing pentavalent vaccination dropout were significantly higher among children from the urban areas (aOR: 9.30; 95% CI: 2.80–30.9), compared to children from rural areas.

Factors associated with measles vaccine dropout

Table 3 shows also the univariate and multivariate logistic regression results of measles vaccination dropout. Compared to children whose caregivers had given birth in health facility, the odds of experiencing measles dropout (aOR: 1.86; 95% CI: 1.02–3.40) were high among children whose caregivers whose deliveries occurred in homes or other places. Furthermore, the odds of experiencing measles vaccination dropout was much higher among children whose caregivers who had no vaccination card/no longer had a card (aOR: 3.99; 95% CI: 1.42–11.2) compared with children who had vaccination card and its whereabouts were known. Additionally, the odds of experiencing measles vaccination dropout were significantly higher among children from the urban areas (aOR: 6.24; 95% CI: 2.69–14.5), compared to children from rural areas.

The current study aimed to identify determinants of vaccination dropouts among children aged 12–23 months in The Gambia. The initial against subsequent doses of pentavalent vaccine (usually third) is regarded as a tracer indicator. Routinely, dropout is used as an indicator of immunization program performance and low dropout rates indicate good access and utilization of immunization services [ 20 ]. Generally, if an infant defaults to the three doses of pentavalent vaccine, it specifies that there is an access problem while a high dropout rate between Penta1 and the measles immunization suggests a service utilizations problem [ 21 ]. Further, the MCV dropout rate assesses whether the program is able to vaccinate children beyond the first year of life [ 20 ]. The World Health Organization (WHO) recommended that DTP1 to DTP3, BCG to measle-containing virus (MCV1), and MCV1 to MCV2 should be used as the indicators of immunization dropout [ 20 ]. The WHO emphasizes that if the dropout rate is more than 10%, then it indicates that many people are not using the services [ 12 ].

The present study reported that the dropout rates for measles and pentavalent vaccines were 6.8% and 4.3% respectively. These results are somewhat lower than those reported in a previous study [ 16 ] that used data obtained from the 2013 survey and below the 10% cut-off recommended by WHO [ 22 ], thus indicating an improvement in immunization coverage in The Gambia. It is reported that the recent gains in immunization coverage are due to the support from The Global Alliance for Vaccines and Immunizations (Gavi), the Vaccine Alliance which work with the Civil Society Organizations (CSOs), Non-Governmental Organizations (NGOs), WHO, and other United Nation (UN) agencies to support the Government of The Gambia by ensuring that all children receive all their basic vaccinations [ 23 ]. Furthermore, Vaccine Alliance also supports the Gambian government in the procurement and management of all vaccines and cold chain equipment, to ensure a constant supply of vaccines and equipment needed to transport and store vaccines at all levels. This includes constructing storage rooms and equipping facilities with solar-powered cold chain equipment to ensure all vaccines reach all children without losing their potency. Additionally, the vaccine alliance exerts its efforts to increase access to immunization services, through the extension of service delivery points in areas of low coverage attributed to access [ 23 ].

In line with previous literature on childhood immunization in general [ 24 , 25 , 26 ], having less than 4 ANC visits was significantly associated with an increased risk of having pentavalent vaccination dropout. The previous studies have hypothesized, caregivers who underutilize ANC services do not have the chance to receive information about the benefit and schedule of vaccination [ 27 ]. Furthermore, another probable reason for the Pentavalent vaccine dropout maybe that caregivers who default ANC services nor gave birth in health facilities may place little or no value of childhood immunization than their counterparts of the same socioeconomic background and that they may miss out on counseling about child immunization in the postnatal period [ 28 ].

Consistent with prior research on immunization coverage [ 3 , 29 , 30 ], the current study found that women who gave birth at home and other places had increased chances of experiencing measles vaccination dropout. For instance, a study on the impact of maternal health care utilization on routine immunization coverage of children in Nigeria found that ANC attendance irrespective of the number of visits had positive effects on the child being fully immunized after adjusting for covariates [ 31 ]. Additionally, in Ethiopia [ 29 ] it was reported that delivery at health facilities was significantly associated factors with full immunization, likely because some vaccines, such as BCG and OPV 0 are habitually given immediately after birth at the health facilities. Moreover, mothers who gave birth at the health facilities are probably more health-conscious and thus more likely to have their children adhere to the vaccination services.

Consistent with results from prior studies on immunization coverages and immunization dropout [ 10 , 24 , 32 , 33 ], the current study found that children who had no card or had the card but it was displaced were more likely to experience both pentavalent and measles dropouts. Generally, an immunization card is a paper-based platform that is used to record and track immunization coverage [ 34 ]. Prior studies demonstrated that caregivers with child health cards could easily follow the immunization schedule and thus can be able to attain timely immunization for their children [ 24 , 35 ]. Moreover, having a well-kept immunization card with a clearly-labeled schedule can well remind caregivers about timely childhood immunization [ 24 , 36 ]. Researchers in Ghana hypothesized that caregivers may default subsequent vaccination schedule due to ill-treatment they could experience from health care providers when they are informed of the lack of child immunization card i.e. owing to misplacement, loss or spoiled [ 37 ]. Furthermore, elsewhere it was reported that lack of immunization card may mean that some antigens may have been administered to the children but because there are absent records, caregivers could easily forget that no immunizations were given.

The current study also found that immunization dropout varied by area of residence. Specifically, children in the urban settings were more likely to have the Pentavalent and measles immunization dropouts. Many studies on rural-urban inequities in immunization have placed rural children to be at disadvantage both in the proportion receiving full immunization and individual vaccines [ 38 ]. However, other studies have reported that children in rural areas are more likely to complete the required vaccinations [ 39 , 40 ]. The reasons why in some settings children in urban areas have high vaccine coverage and less dropout rate may be that; 1) caregivers may be highly educated thus may have increased autonomy, changes in traditional beliefs, and control over household resources [ 41 ]. In turn, they may have an enhanced healthcare-seeking behavior and may be able to comprehend new health knowledge more quickly [ 24 ], and 2) caregivers may dwell in richer households, thus, they might not have barriers to access services at the health facilities compared to poor families [ 42 ]. Nonetheless, the findings of the current study are in line with previous studies in other developing countries [ 43 , 44 ] where immunization coverage was higher in rural areas than urban townships. One reason that explains high immunization coverages in rural areas is the use of the traditional birth attendants (TBA) and primary health care (PHC) workers that both play a role in encouraging mothers to attend the maternal and child health (MCH) clinics of which these roles do not formally exist in urban areas [ 13 ]. Another possible reason why immunization coverages are high and dropouts are low in rural areas might be due to the establishment and use of outreach clinics. It is established that sustained outreach is an approach for reaching remote areas of the population with limited access to immunization locations [ 45 ]. Outreach clinics encourage health care workers to take vaccines from fixed health facilities and travel to remote locations to immunize children thus minimizing the chances of caregivers defaulting immunization services [ 46 ]. Many low-and-middle-income countries (LMICs), supplement community health volunteers (CHVs) in various essential health services. Indeed, it is reported that CHVs could help improve access to and use of essential health services such as immunization by communities in LMICs [ 47 ]. One of the responsibilities of the CHVs is to regularly visit families in their homes to provide counselling about reproductive, maternal, newborn and child health (RMNCAH) and other health concerns [ 48 ].

Strengths and limitations

The inferences drawn in this study could be generalized to all children aged 12-23 months in The Gambia owing to the use of a nationally representative sample. However, these results should be interpreted with caution: Firstly, the current study utilized a cross-sectional study design, thus causal and temporal inferences cannot be drawn. Second, information on immunization was collected from vaccination cards, thus the findings of this study are prone to recall bias, as the respondents who did not have health cards were asked to recall vaccines a child had received. Thirdly, the datasets used in this study did not report any vaccine stockouts, accessibility of immunization services, and inconsistent scheduling of vaccination supply.

Tailored public health interventions towards the urban residence and health education for all mothers attending maternal and child health services (such as ANC and PNC) on child vaccination completion are hereby recommended. Furthermore, since children without health passports or health profiles had increased chances of dropping out from immunization, it is, therefore, necessary to develop an android based system with automatic reminder functionalities sent to the health workers and wherever possible to the guardians about the next schedule for all children due for vaccination in order to reduce the risk of defaulting immunization services.

Availability of data and materials

The datasets generated and/or analyzed during the present study are available in The DHS Program repository, https://dhsprogram.com/data/available-datasets.cfm

Abbreviations

Acquired Immunodeficiency Syndrome

Antenatal Care

adjusted Odds Ratios

Bacillus Calmette–Guérin

Confidence Intervals

Community Health Volunteers

Coronavirus disease 2019

Diphtheria, Pertussis, and Tetanus

Enumeration Areas

Expanded Programme on Immunisation

Gambia Bureau of Statistics

Gambia Demographic and Health Survey

Generalized Estimating Equations

Global Vaccine Action Plan

hepatitis B

Haemophilus influenzae type b

Human Immunodeficiency Virus

Human Papillomavirus Vaccine

Low-and-Middle-Income-Countries

Measles Containing Virus

Meningitis A

Ministry of Health

New York City

Oral Polio Vaccine

Pneumococcal Conjugate Vaccine

Primary Health Care

Post-natal Care

Reproductive and Child Health

Maternal, New Born and Child Health

Rotavirus Vaccine

Sexually Transmitted Disease

Tuberculosis

Traditional Birth Attendants

United States of America

Vaccine Preventable Diseases

World Health Organization

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Acknowledgements

We sincerely thank The Gambia Bureau of Statistics (GBoS) and The Gambia Ministry of Health for data collection and survey implementation. The authors also give thanks to the MEASURE DHS for providing us with the population-based datasets through their archives which can be downloaded from https://dhsprogram.com/data/dataset/Gambia_Standard-DHS_2019.cfm?flag=1

Contributions

PAMN, ACC, and ON contributed to the conception and design of the study. PAMN acquired data and conducted analyses. PAMN, ON, AB and ACC interpreted the results. PANM, TEM, and KM drafted the first article. ON, AB, AS, and ACC revised the draft critically for important intellectual content. All authors reviewed and approved the final version of the manuscript.

This research did not receive a grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Peter A. M. Ntenda, Angeziwa C. Chirambo and Owen Nkoka contributed equally to this work.

Authors and Affiliations

Malaria Alert Center (MAC), Kamuzu University of Health Sciences (KUHeS), Privative Bag 360, Chichiri, Blantyre, 3, Malawi

Peter A. M. Ntenda, Alick Sixpence & Andy Bauleni

Academy of Medical Sciences (AMS), Malawi University of Science and Technology (MUST), P.O Box 5196, Limbe, Malawi

Tisungane E. Mwenyenkulu

African Field Epidemiology Network, Ministry of Health, Expanded Programme on Immunization, P.O. Box 30377, Lilongwe, Malawi

Kondwani Mmanga

Malawi-Liverpool-Wellcome (MLW) Trust Clinical Research Programme, P.O. Box 30096, Mahtma Ghandi Road, Chichiri, Blantyre, Malawi

Angeziwa C. Chirambo

Institute of Health & Wellbeing (IHW), University of Glasgow, 1st Floor 1055 Great Western Road, Glasgow, G12 0XH, Scotland, UK

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Correspondence to Peter A. M. Ntenda or Owen Nkoka .

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All methods were carried out in accordance with the Declaration of Helsinki. The 2019-2020 GDHS was implemented by The GBos in conjunction with the Gambia Ministry of Health. The current study was reviewed and approved by The Gambian Government/Medical Research Council Joint Ethics Committee and the Institutional Review Board of ICF Macro. ICF IRB ensures that the survey complies with the U.S. Department of Health and Human Services regulations for the protection of human subjects (45 CFR 46), while the host country IRB ensures that the survey complies with laws and norms of the nation [ 19 ]. During survey implementation, informed consent was sought from participants prior each interview and a parent or guardian provided consent prior to participation by a children less than 18 years. The authors obtained permission from the DHS program for the use of the data.

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Ntenda, P.A.M., Sixpence, A., Mwenyenkulu, T.E. et al. Determinants of pentavalent and measles vaccination dropouts among children aged 12–23 months in The Gambia. BMC Public Health 22 , 520 (2022). https://doi.org/10.1186/s12889-022-12914-6

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• Volume 12, Issue 4
• How did the adoption of wP-pentavalent affect the global paediatric vaccine coverage rate? A multicountry panel data analysis
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• http://orcid.org/0000-0003-0301-5657 M Mahmud Khan 1 ,
• Juan Camilo Vargas-Zambrano 2 ,
• http://orcid.org/0000-0003-3651-2959 Laurent Coudeville 2
• 1 Department of Health Policy and Management , University of Georgia , Athens , Georgia , USA
• 2 Global Medical Department , Sanofi Pasteur , Lyon , France
• Correspondence to Dr Laurent Coudeville; laurent.coudeville{at}sanofi.com

Objectives Several studies have highlighted the effects of combination vaccines on immunisation coverage at the national or subnational level. This study examined the effects globally. Worldwide introduction of whole-cell pertussis pentavalent (wP-pentavalent) allowed estimation of incremental coverage effects of combination vaccines on the third doses of diphtheria, tetanus, pertussis (DTP3); hepatitis B (HepB3) and Haemophilus influenzae type B (Hib3).

Design Multicountry panel data analysis.

Data sources Country-level vaccine coverage data of WHO/UNICEF for the years 1980–2018.

Methods Linear mixed models were used to estimate the effects of wP-pentavalent introduction by incorporating proxy variables to control for time trend and other time-dependent changes in the immunisation programmes.

Results Introduction of combination vaccines may have improved the coverage of DTP3 by 3percentage points(95% CI 2.5% to 3.6%) globally compared with the coverage in the pre-combination vaccine era. The comparison of coverage rates of HepB3 and Hib3 in before and after wP-pentavalent periods indicates that the introduction of combination vaccines improved the coverage by 10.1 percentage points (95% CI 8.4% to 11.7%) for HepB3 and 9.9 (95% CI 7.1% to 12.7%) for Hib3 in countries that introduced those antigens prior to adoption of wP-pentavalent. Even though the incremental coverage increase of DTP3 appears quite modest, it is still a significant result, especially because DTP vaccine has been in the national immunisation programmes of all countries for about 24 years prior to the introduction of wP-pentavalent. Additionally, the introduction of pentavalent also allowed inclusion of Hib and HepB in the vaccine schedule for a large number of countries (85 and 37, respectively, of the 102 countries included in our analysis).

Conclusion The findings suggest that development of combination vaccines with additional antigens is likely to help sustain and improve coverage of existing as well as new childhood vaccines.

• public health
• paediatric infectious disease & immunisation
• infectious diseases

Data availability statement

Data are available in a public, open access repository. Main source of data is UNICEF-WHO vaccine coverage data. In case of missing information, country-specific immunisation programme information was accessed to update the data set. The code and data, that allow reproducing results presented in this article, are available in an online repository ( https://gitlab.com/SPMEGModels/pentavalent_coverage.git ).

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjopen-2021-053236

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Strengths and limitations of this study

This study estimated coverage impact of pentavalent introduction on the third doses of diphtheria, tetanus, pertussis (DTP); hepatitis B (HepB) and Haemophilus influenzae type B (Hib) using country-year observations that show use of the antigens in the immunisation schedule.

All countries where whole-cell pertussis pentavalent vaccines were being used in their National Immunization Programs by 2018 were included for the analysis.

WHO/UNICEF-reported coverage rates were used to define the year of introduction of pentavalent for countries that did not use HepB and/or Hib prior to pentavalent.

The HepB coverage model was based on 67 countries while the Hib coverage model had only 17 countries. The proportion of countries by income level was similar between HepB and third dose of DTP but Hib model had relatively more high-income countries. If the number and country characteristics create any bias in the empirical estimation, the bias should be higher for Hib.

Introduction

The adoption of Expanded Program on Immunization (EPI) in 1974 by the WHO was instrumental in improving the coverage of vaccines against six preventable diseases (tuberculosis, poliomyelitis, diphtheria, tetanus, pertussis and measles). The initial WHO’s target was to achieve high rates of vaccine coverage (90%) worldwide against these diseases by 1990. 1 The programme was successful in lowering the under-5 mortality from 17 million in 1970 to 12.8 million in 1990 and to 10.5 million in 2000. 2 Despite initial significant improvements, about 3 million children died from pneumococcal diseases, measles, hepatitis B (HepB) and Haemophilus influenzae type B (Hib) infections in 1999–2000. 3 Effective vaccines were available to prevent these deaths but most children in the low and lower middle-income countries did not have access to the vaccines due to several factors, including the fact that they were not included in the National Immunization Program (NIP). 4 By 2000, less than 10% of low-income countries had adopted HepB vaccination and less than 5% had introduced Hib vaccine. 4 This situation improved significantly after the creation of Gavi, the vaccine alliance in 2000. Gavi provided financial support, health systems and immunisation activities strengthening, technical country assistance among others to low-income countries for the adoption of new antigens in their immunisation schedule including HepB and Hib. Introduction of whole-cell pertussis (wP)-pentavalent vaccines not only allowed the simultaneous delivery of two new antigens such as HepB and Hib, but also reduced the number of shots from nine to three compared with the shots needed when all the vaccines, that is, the vaccines against diphtheria, tetanus, wP (DTwP vaccine ×3), HepB (×3) and Hib (×3) were to be delivered separately. 5 Therefore, the introduction of pentavalent (DTwP–Hib–HepB) vaccines is considered to have helped the increase in coverage with either no increase or reductions in the number of shots, easing the introduction of vaccines against other diseases. In 2020, the 20th anniversary of Gavi’s support for pentavalent introduction, 73 low-income countries of the world had adopted pentavalent vaccines in their routine immunisation programmes. From 2001 to 2020, introduction of pentavalent vaccines (DTwP–Hib–HepB) is estimated to have averted 10 million deaths and 390 million disability-adjusted life years, generating a total economic benefit of $250 billion from only the Hib and HepB components of these pentavalent vaccines. 6 During this period, Gavi’s total disbursements on pentavalent vaccines procurement were less than $4.0 billion, 7 implying high economic return on investment.

Several studies have highlighted the benefits of combination vaccines in improving vaccine coverage rates. A national cohort study conducted in Australia in 2013–2014 found that a combined measles–mumps–rubella–varicella (MMRV) vaccine improved coverage of measles vaccination by 4% and on-time immunisation with the second MMR dose increasing from 59% to 72%. 8 Two other studies reported significant improvements in varicella vaccine coverage with the adoption of MMRV. 9 10 Comparison of two groups of children in the USA, one group receiving combination vaccines DT acellular pertussis (DTaP)–inactivated poliovirus vaccine (IPV)–HepB and the other group receiving the vaccines separately, found that vaccination completion was higher in the ‘combination vaccines’ group. The combination vaccines group was also more likely to receive the vaccines in a timely manner. 11 12 In general, combination vaccines help parents and providers to overcome the complexity of vaccination schedules, increasing coverage and improving the timeliness of vaccination. 13

A literature review by Maman et al identified a number of benefits of adopting combination vaccines and the benefits obtained were categorised into two groups: societal value and public health/economic value. 14 The societal values of combination vaccines were improved compliance and timeliness of vaccination, better protection against childhood diseases, lower likelihood of pain and suffering, and fewer potential local injection site side effects due to reduced number of injections, better acceptance of combination vaccines from parents, willingness to pay additional money by parents to avoid extra injections, reduced opportunity cost of time for parents and caregivers as the number of visits needed to healthcare providers declines to receive childhood vaccines, improved efficiency of healthcare providers due to lower time input needed to administer one injection rather than multiple injections, improved safety of healthcare providers with the reduction in the risk of needle-stick injury. 14 Another systematic review found a host of psychological predictors associated with not vaccinating a child. Although combination vaccines were not the focus of the review, a number of concerns and barriers to improve immunisation identified were clearly related to the number of injections received by children during immunisation visits. 15 For example, few specific reasons cited as discouraging childhood immunisation were ‘injections are traumatic’, ‘logistic barrier or inconvenient time’, ‘need for receiving multiple doses’, etc. A relatively small study reported that 37% of children deferred some of the vaccine doses during a visit and the deferment was strongly associated with the number of vaccine injections due at the visit. 16

By 2018, about 86% of children of the world were fully immunised against diphtheria, tetanus and pertussis (DTP) defined by the coverage of the third dose of DTP (DTP3). 17 Coverage of all childhood vaccines has consistently improved over the years since 1980 but the improvements have slowed significantly since 2010. 18 For example, coverage of DTP3 increased just 2% from 2000 to 2018 (84% to 86%), resulting in more than 94 million under-5 children still undervaccinated or unvaccinated in the year 2018, that is, without accounting for late doses which are not routinely measured. Moreover, geographical difference in childhood immunisation coverage varied from about 76% in Africa to more than 90% in the European region. Many countries in the European, North American and Latin American, Asia-Pacific and Middle East regions use aP-combination vaccines rather than the wP-containing combination vaccines and it is known that use of acellular-type combination vaccines explains a part of the coverage gap between those countries and the low and lower middle-income countries. In any case, adoption of combination vaccines is considered one of the potential approaches for improving vaccine coverage rates to reach the WHO target of 90%. 17

To ensure continued success of childhood vaccination and further improvements in child survival, in all countries, especially the low and middle low income, vaccination coverage rates will have to improve. Even though significant progress has been achieved, further improvements will require addressing the underlying causes of vaccine hesitancy. With the recommendation from WHO in 2014 of at least one dose of IPV in the immunisation schedule, 19 an additional injection has been added. The upcoming licensure of currently under development wP-IPV hexavalent (DTwP–HepB–Hib–IPV) vaccines, 20–23 and their potential introductions in NIPs, may help increase IPV coverage where it is low and sustain it where it is high. Given that wP-pentavalent vaccines began to be introduced in different countries of the world since 2000, analysis of the effects of introduction of pentavalent on completion of the third DTP primary dose (DTP3) will provide important information about the value of more complete combination vaccines to expand vaccine coverage rates.

Thus, the objective of the paper is to examine the effect of introducing whole-cell pentavalent vaccine on the coverage of DTP3, third doses of Hib (Hib3) and HepB (HepB3). Rather than looking at one country or one region, the perspective of the analysis is all countries where wP-pentavalent vaccines are being used in their NIPs. Since the adoption of wP-pentavalent vaccines has become generalised and widespread due to the support low-income and lower middle-income countries have received from Gavi, it should be possible to quantify the effect of wP-pentavalent vaccine adoption on the coverage rates of different childhood vaccines at the global level. To our knowledge, this is the first study that has been conducted with an analysis at the global level.

Conceptual model of vaccine uptake

A study found that 23% parents in the USA considered too many antigens in the vaccine schedule as creating ‘antigenic overload’. 24 This perception is not supported by scientific evidence; in fact, it has clearly been demonstrated that cumulative vaccine antigen exposure is associated with higher level of protection against non-vaccine-targeted infections. 25 Even maximum single-day antigen exposure shows no adverse effect on protection against infectious diseases. Therefore, the increasing number of vaccines in the schedule actually increases the benefit of vaccination. Pollard and Bijker 26 present a comprehensive review of studies on these topics.

Data and data sources

Vaccination data of different countries of the world are available through several sources including WHO, UNICEF and country-level immunisation programmes. The WHO/UNICEF Estimates of National Immunization Coverage (WUENIC) is the principal source of information for this analysis. 27 The WUENIC information goes through a few quality checks including the consideration of contextual factors like stock-outs. In case of very few missing information, country-level programme information was accessed to obtain a complete set of vaccine coverage data by antigens for the years 1980–2018. Information on economic status of the countries around 2018 was obtained from the World Development Indicators of the World Bank. 28 Based on the World Bank classification, countries were categorised as either low income, lower middle income, upper middle income and high income.

Introduction of pentavalent vaccines, by definition, adds Hib and HepB in the NIP if the country did not have these vaccines prior to the adoption of the combination vaccines. For these countries, coverage of Hib and HepB will show significant increase with pentavalent introduction simply because these antigens are part of the pentavalent vaccines. As such, inclusion of these countries in the estimation of ‘coverage effect’ of pentavalent vaccines on Hib and HepB will overestimate the effects and were excluded from the analysis. Therefore, we included in the analysis only the observations (countries and years) that indicate administration of Hib and HepB vaccines prior to the introduction of pentavalent. This allows the estimation of incremental coverage of vaccines due to the introduction of combination vaccines.

Although the full data set had 195 countries by 2017/2018 (last year of data used), 132 countries included wP-pentavalent vaccines in their immunisation schedule and data on these countries were used in the empirical analysis. For 30 countries, information on a number of relevant variables, including the date of introduction of pentavalent vaccines, was not available in the data set and these countries were excluded from the analysis resulting in 102 pentavalent vaccine-using countries.

Only the countries using wP-pentavalent in the vaccination schedule were included in the empirical model excluding the aP-pentavalent-using countries. The wP vaccines are associated with significantly higher incidence and severity of adverse events compared with the aP vaccines 29 and considering these two vaccine types as perfect substitutes will bias the results. In addition, there are significant differences in the presentation of the two vaccines which affect the method of vaccine administration and delivery. For example, in most cases, whole-cell vaccines are supplied in multidose vials while aP vaccines are supplied as single dose or in prefilled syringes with Hib as a powder for reconstitution. The differences in vaccine administration approach may also affect coverage of these and other vaccines in the schedule. It should be noted here that a number of countries switched from wP to aP after the introduction of pentavalent vaccines and these countries were not included in the analysis so that the estimation can focus on the effects of wP-pentavalent vaccines only.

The empirical model

For the empirical analysis, a pooled cross-section and time series data set was built with a panel of countries. The year of introduction or adoption of pentavalent vaccines was obtained, and the year of introduction was used to define a variable representing ‘post-pentavalent introduction dummy’. Our statistical approach was based on a linear mixed model as well as a logistic regression model for the analysis of panel data. 30

Therefore, the empirical model for explaining vaccine coverage rates should be:

In the mixed-effect model, random effect was limited to intercept and the estimated linear equation can be written for the antigen i as:

Data analysis

The analysis was performed with R V.4.0.4 34 and RStudio 35 using the lme4 package 36 and the cAIC4 package. 33 The R code and data used for generating the results presented in this article are available in an online repository ( https://gitlab.com/SPMEGModels/pentavalent_coverage.git ).

Patient and public involvement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

Table 1 compares the characteristics and geographical locations of all countries using wP-pentavalent and the countries in our DTP coverage model. Since the EPI introduced the DTP as one of the vaccines in 1970s, almost all countries should be in the DTP coverage model except those with missing BCG or measles coverage information. As expected, the proportion of high-income countries declines from 29.7% to 12.1% when only the countries using wP-pentavalent were selected. Relative importance of high-income countries further declines (and importance of low income and lower middle income increases) when countries with wP-pentavalent as well as no missing information on BCG, measles and year of adoption of pentavalent were considered.

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Characteristics of countries using wP-pentavalent vaccines and countries in the DTP coverage estimation model

As indicated in the Methods section, analysis of vaccine coverage due to introduction of combination vaccines used data only for the countries and years where/when the target vaccines existed prior to the introduction of wP-pentavalent vaccines. Similarly, incremental coverage effect of combination vaccines on HepB and Hib can be estimated only for the countries (and years) that introduced these vaccines prior to pentavalent ( online supplemental figure S1 ).

Supplemental material

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Plot of observed coverage and predicted DTP3 coverage rates from the empirical model. Observed: average annual DTP3 coverage across countries considered in the analysis for DTP3 (102 countries); estimated with pentavalent effect: average annual DTP3 coverage estimated for the reference model with the pentavalent effect included; estimated without pentavalent effect: average annual DTP3 coverage estimated for the reference model with the pentavalent effect included. DTP3, third dose of diphtheria, tetanus, pertussis.

Table 1 shows that the empirical analysis of DTP included 102 countries where DTP existed prior to the introduction of wP-pentavalent vaccines, and other relevant variables like coverage of BCG and measles vaccines were available for these countries. Table 2 reports the characteristics of the countries that satisfy the inclusion criteria for the HepB and Hib vaccine coverage models. Of the 132 countries, 67 and 17 countries adopted HepB and Hib, respectively, prior to the introduction of wP-pentavalent vaccines. Within these countries, only the years in which HepB and Hib were used were included in the analysis. For both HepB and Hib models, relative importance of low-income countries declined compared with the DTP model. The Hib sample becomes predominantly high-income and upper middle-income countries. In terms of geographical locations, more than half of the Hib vaccine-using countries in the data set were in the Americas and Western Pacific. Eastern Mediterranean accounted for about one-third of the countries in the sample.

Characteristics of wP-pentavalent vaccine-using countries included in the empirical model for the estimation of coverage impact on HepB and Hib vaccines

Using the observations as described in tables 1 and 2 , mixed-effect regression models as well as logistic models were estimated for the pooled cross-section and time series data. Table 3 reports the results for DTP. The effect of introduction of combination vaccines is shown by the shifter variable, the dummy for post-pentavalent introduction years. Different combinations of proxy variables (coverage of BCG alone, first dose of MCV (MCV1) alone and both BCG and MCV1) were evaluated as a mechanism for capturing changes in the immunisation programmes or longer-term changes in access and vaccine knowledge. Model selection using cAIC suggests that the inclusion of both the proxy coverage variables performed better than other alternatives.

Estimated effect of wP-pentavalent vaccine introduction on third dose of DTP (DTP3) coverage rates

Table 3 indicates that the introduction of wP-pentavalent vaccines increased the DTP3 coverage by about 3 percentage points (95% CI 2.45% to 3.61%). Therefore, introduction of pentavalent vaccines had statistically significant impact on vaccine coverage rates of DTP3, although the incremental effects were quite small but still important because the coverage of DTP appears to have stalled in recent years. To examine how well the empirical model predicts the coverage of DTP3 in countries, figure 1 shows the estimated and observed coverage rates by year. Note that the model predicts the actual coverage of DTP3 very well. The corresponding scatter plot of observed versus predicted is presented in online supplemental figure S2 .

Table 4 reports the results for HepB3 and Hib3 coverage rates and the incremental effect of introducing the combination vaccines. The post-pentavalent year dummy indicates that the incremental effect of the combination vaccines was to increase coverage of HepB3 by 10.1 percentage points (95% CI 8.41% to 11.71%) and the coverage of Hib3 by 9.9 percentage points (95% CI 7.08% to 12.71%). The increase in coverage was not due to the introduction of two new antigens in the schedule (HepB and Hib) but to its inclusion as part of the pentavalent vaccine. The figures corresponding to observed versus predicted based on annual average and for each data point are presented in online supplemental figures S3−S6 .

Estimated effect of wP-pentavalent vaccine introduction on HepB3 and Hib3 coverage rates

This study examined the effect of combination vaccines on childhood vaccine coverage rates from the global perspective, that is, considering all countries where wP-pentavalent vaccines were introduced (subject to availability of required data). To our knowledge, this is the first study that has conducted such an analysis at the global level.

The results imply that the introduction of pentavalent vaccines was associated with increased coverage of DTP3, HepB3 and Hib3. The DTP vaccines were introduced in the immunisation programmes in 1970s and it reached a relatively high coverage rate by 2000. Since then, worldwide coverage of DTP3 has stagnated. The positive impact of pentavalent introduction on DTP3 coverage suggests that combination vaccines may have helped in improving DTP3 coverage although other variables such as the strengthening of health systems may have also played an important role. Our analyses found that the introduction of pentavalent vaccines was associated with increased coverage of DTP3 by about 3 percentage points over and above the coverage increase of other vaccines not delivered at the same time as the DTP doses in the schedule. Increased coverage of the ‘proxy’ vaccines should reflect improvements in immunisation infrastructure, economic growth, enhanced access and improved vaccination-related knowledge of the population across countries and over the years. Although the increase in coverage of DTP3 is quite small in quantitative terms, it is still significant considering that global annual increase in DTP3 coverage of 0.9% (varying from 0.1% to 1.8% over the years by WHO regions) for the years 2000 and 2009. 37 Despite this modest effect of combination vaccines on DTP3 coverage, it will still be helpful in reaching the target coverage rate of 90%. Only about 66% of countries have been successful in achieving the target by 2018, 38 implying that introduction of combination vaccines may be considered as a potential strategy in achieving and sustaining the target coverage rates for major childhood vaccines.

The estimates of coverage increase of combination vaccines on new and underused vaccines are quite large. After controlling for coverage due to the introduction of new antigens through pentavalent vaccines, the combination vaccines itself helped improve the coverage rates of HepB3 and Hib3 by about 10 percentage points. Immunising against HepB and Hib prior to the introduction of pentavalent vaccines, in most cases, required separate injections in addition to DTP and IPV injections, and introduction of these new shots may have discouraged increased coverage. 39 40 With the introduction of pentavalent, these antigens could be delivered through a single shot.

The results agree with earlier studies that found positive effect of combination vaccines at country and region level and it implies that the positive incremental coverage effects may be valid at the global level as well. Higher coverage of vaccines due to the introduction of combination vaccines may be explained by the lowering (or not increasing) of the number of injections required in a single visit, higher number of antigens delivered and simplification of vaccination schedule by removing the complexity of dealing with multiple vaccines and multiple shots at the same time. Administering multiple shots during the same visit may also increase programmatic errors (maladministration, delayed administration, etc) as has been reported elsewhere. 14 For antigens being used for many years prior to the introduction of combination vaccines, the effect on coverage is modest but still significant. Currently, there are various hexavalent wP (DTwP–IPV–HepB–Hib) vaccines being developed which will include IPV in addition to the existing antigens in the pentavalent. 20–23 This aligns well with the WHO recommendation of including at least one dose of IPV worldwide. The empirical results of this research imply that the introduction of wP-hexavalent vaccine will likely improve the coverage of IPV compared with IPV as a standalone. Such combination vaccines will also help sustain the high coverage of polio vaccination in the longer run worldwide.

The study has various limitations. Although the data quality used in the analysis is presumed to be good, there are still few missing data on vaccine coverage. The number of missing values, however, is not large enough to create estimation problem. For this study, information on the year of introduction of wP-pentavalent vaccines was collected from various sources including Gavi; but for a limited number of countries, the year of introduction of pentavalent vaccines was found to be inconsistent with the vaccine coverage data on HepB and Hib. For our analysis, we have used WHO/UNICEF-reported coverage rate to redefine the year of introduction of pentavalent for countries that did not use HepB and/or Hib prior to pentavalent. Despite this, it is still possible that the year of introduction of pentavalent vaccines may not be correct for a small number of countries. In this paper, the conclusions are based on the results of the linear regression model although some authors prefer to use logistic regression when the continuous dependent variable is bounded in between 0 and 100. The case against linear models in such situations is not as strong as often assumed. 41 For comparative purposes, the logistic model was also run and the results are presented in online supplemental table S1, figures S7 and S8 . In the linear model, only about 3% of predicted values fell beyond the range (0–100) and the measure of ‘fit’ of the linear model was better than the logistic model (measured by RMSE). In any case, logistic model shows very similar results as the linear model in terms of effect of introduction of pentavalent vaccine on coverage rates of DTP3, HepB3 and Hib3. Interpreting the coefficients of linear model is also easier than interpreting logistic function coefficients. The fourth limitation is the ‘reduced’ number of sample countries and years in the data set for the estimation of HepB and Hib coverage equations. The reduced sample size lowered the relative importance of low-income countries in the data set. The HepB coverage model was based on 67 countries while the Hib coverage model had only 17 countries. If the number and country characteristics create any bias in the empirical estimation, the bias should be lower for HepB. The estimates suggest that the incremental coverage effect of both HepB and Hib was probably about 10 percentage points suggesting that the potential bias, if any, is likely to be very small. Another limitation of the study is related to Gavi support to countries. Even though Gavi funding introduced pentavalent vaccine in many of the countries in the sample, the assistance Gavi provided went beyond vaccine procurement and enhanced vaccine infrastructure and delivery. If these structural changes were more specific to pentavalent vaccine delivery, a part of coverage increase could be attributed to Gavi support, A final limitation is that this study could not include the effect of shift from tetravalent (DTwP–Hib or DTwP–HepB) vaccines to pentavalent due to lack of relevant information.

In conclusion, the empirical estimates suggested that combination vaccines may have helped in increasing the coverage rates of existing antigens in the national immunisation programmes and the effects are larger for relatively new vaccines (eg, HepB and Hib) than the vaccines that have been in place for many years (eg, DTP). Even though DTP3 achieved a relatively high coverage rate prior to the introduction of pentavalent, the combination vaccines appear to have improved global coverage by about 3 percentage points. The results imply that for achieving a high coverage rate of vaccines, policymakers should emphasise inclusion of vaccines in a combination rather than introducing the vaccines in standalone format. Introduction of combination vaccines can potentially generate other positive outcomes not considered here in this study. Future research should try to estimate the effects of combination vaccines in reducing intracountry inequality in vaccine coverage as well as timeliness of vaccine administration.

Ethics statements

Patient consent for publication.

Not required.

Ethics approval

Results presented in this manuscript are based on a secondary analysis of aggregated data available in the public domain. The implementation of this study did not require specific ethics approval.

Acknowledgments

We thank Carole Doudet and Marsha Ginson for their contributions to the conception of the study and data gathering. We thank Roopsha Brahma, for editorial assistance and manuscript coordination on behalf of Sanofi Pasteur. We thank Rama Mylapuram and Saili Dharadhar for providing editorial support for this manuscript.

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• ↵ A phase-I clinical study to assess the safety of biological ES liquid DTwP-rHepB-Hib-IPV vaccine in 16 to 24 months old healthy children. CTRI number: CTRI/2019/01/016891 . Available: ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=30093&EncHid=&userName= [Accessed 25 June 2020 ].
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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

Twitter @juancamilov

Contributors MMK and LC contributed to the conceptualisation of the paper. MMK, JCV-Z and LC contributed to the empirical methodology development, formal analysis, drafting, reviewing and editing the paper. MMK, JCV-Z and LC are responsible for the conduct of the study, had access to the data, reviewed the manuscript and had responsibility for the decision to submit for publication.

Funding This study was funded by Sanofi Pasteur (award/grant number: not applicable).

Competing interests MMK worked on the study as a paid consultant of Sanofi Pasteur. LC and JCV-Z are employees of Sanofi Pasteur and may hold shares and/or stock options in the company.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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• Infect Dis Ther
• v.11(3); 2022 Jun

Rationale for the Development of a Pentavalent Meningococcal Vaccine: A US-Focused Review

Gary s. marshall.

1 Division of Pediatric Infectious Diseases, Norton Children’s and University of Louisville School of Medicine, 571 S. Floyd St, Suite 321, Louisville, KY 40202 USA

Jaime Fergie

2 Driscoll Children’s Hospital, Corpus Christi, TX USA

Jessica Presa

3 Vaccines Medical Development & Scientific/Clinical Affairs, Pfizer Inc, Collegeville, PA USA

Paula Peyrani

Associated data.

Data sharing is not applicable to this article because no datasets were generated or analyzed during the current study.

While invasive meningococcal disease (IMD) is uncommon, it can result in serious sequelae and even death. In 2018 in the United States, the incidence of IMD per 100,000 people was 0.03 among adolescents 11−15 years of age, 0.10 among persons 16−23 years of age, and 0.83 among infants < 1 year of age. Serogroup B accounted for 86%, 62%, and 66% of cases, respectively, in those age groups. Currently, routine meningococcal vaccination covering serogroups ACWY (MenACWY) is recommended in the United States for all adolescents at 11−12 years of age, with a booster dose at 16 years of age, whereas a meningococcal serogroup B (MenB) vaccine series is recommended for persons 16−23 years of age under the shared clinical decision-making paradigm. The MenACWY vaccination program in adolescents has been successful in reducing disease burden, but does not prevent disease caused by serogroup B, which accounts for more than half of IMD cases. There are currently no approved vaccines that cover all of the most common disease-causing meningococcal serogroups, which are A, B, C, W, and Y. A pentavalent MenABCWY vaccine that is constituted from 2 licensed meningococcal vaccines—MenB-FHbp and MenACWY-TT—is being investigated in healthy persons ≥ 10–25 years of age. The addition of a MenABCWY vaccine is the next natural step in the incremental meningococcal immunization program in the United States to improve protection against the most common serogroup causing IMD, with no increase in the number of immunizations needed. With high uptake, routine use of MenABCWY could reduce IMD cases and associated mortality, the rate of long-term physical and psychosocial sequelae in survivors, and costs associated with controlling outbreaks, particularly on college campuses. A MenABCWY vaccine would also reduce the number of injections required for adolescents, potentially improving compliance.

Key Summary Points

Introduction

Neisseria meningitidis is an obligate human pathogen that causes endemic and epidemic disease, including invasive meningococcal disease (IMD) [ 1 ]. Case fatality rates (CFRs) can range from 10% to 15%, and up to 20% of individuals develop long-term sequelae, including limb amputation and neurologic deficits [ 1 – 3 ].

The occurrence of IMD varies according to age, underlying conditions, and geographic area, and is unpredictable because of fluctuations over time and differences based on serogroup [ 4 – 6 ]. In the United States, infants and young children are at greatest risk of IMD, with another incidence peak occurring in adolescents and young adults [ 7 ]. Serogroup B causes a high proportion of cases in many parts of the Americas, Australasia, Europe, and North Africa, and serogroup C predominates in some regions of South America, Asia, and Africa [ 8 ]. After near-eradication of serogroup A IMD in the African meningitis belt, cases caused by serogroup C are expanding, furthering the need for multivalent vaccination [ 5 ]. Although relatively uncommon compared with other serogroups, serogroup X meningococci are responsible for outbreaks and endemic disease in parts of sub-Saharan Africa [ 5 , 9 ]. Because nearly all IMD cases are caused by serogroups A, B, C, W, and Y [ 5 ], comprehensive protection against IMD requires vaccination against all 5 serogroups.

Several monovalent and polyvalent meningococcal vaccines are currently available (Table ​ (Table1). 1 ). Quadrivalent meningococcal conjugate (MenACWY) vaccines include capsular polysaccharides from serogroups A, C, W, and Y, individually conjugated to carrier proteins [ 10 – 13 ]. Because the serogroup B capsular polysaccharide is poorly immunogenic [ 14 ], vaccines based on cell surface-expressed proteins were developed and licensed for use against serogroup B disease [ 15 – 17 ]. There are currently no approved meningococcal vaccines that cover all 5 common disease-causing serogroups, although such vaccines are undergoing clinical investigation.

Currently available meningococcal vaccines

fHbp factor H binding protein, NadA neisserial adhesin A, NHBA neisserial heparin binding antigen

a Not currently licensed in the United States

This review considers the universal need for a pentavalent meningococcal vaccine covering serogroups A, B, C, W, and Y (MenABCWY), and focuses on data and recommendations from the United States for adolescents and infants, as well as on the epidemiology and high burden of meningococcal disease in these age groups. Progress towards developing pentavalent vaccines is ongoing, and this review is focused on the rationale for a MenABCWY meningococcal vaccine, which is constituted from 2 licensed meningococcal vaccines [MenB-FHbp (Trumenba ® ; Pfizer, Philadelphia, PA, USA) and MenACWY-TT (Nimenrix ® ; Pfizer Europe, Brussels, Belgium)]. This article is based on previously conducted studies and does not contain any new studies with human participants or animals.

Meningococcal Disease in Adolescents And Young Adults

Epidemiology and burden of disease in the united states.

Adolescents and young adults are at increased risk of IMD. In 2018, the incidence was 0.13 per 100,000 among adolescents and young adults 11−23 years of age (Fig.  1 a) [ 7 ]. While the incidence has generally decreased since 2015 (with a peak occurring in 2016), the burden of disease among young adults continues to be higher than in any other age group except for infants. Notably, serogroup B accounted for 66% of all cases of IMD in 2018 among adolescents and young adults (i.e., 86% and 62% of all cases among individuals 11−15 years of age and 16−23 years of age, respectively) (Fig.  1 b) [ 7 ]. In comparison, serogroup C, W, and Y cases collectively accounted for 10% of cases in those 11–25 years of age, and the incidence for these disease-causing serogroups has generally been stable since 2015 [ 7 , 18 – 20 ]. Serogroup A caused no IMD in the United States, and unknown or nongroupable IMD accounted for 13%–24% of cases in adolescents and young adults in the period 2015−2018 [ 7 , 18 – 20 ].

Incidence ( a ) and cases ( b ) of meningococcal disease in the United States in adolescents and young adults (2015-2018) [ 7 , 18 – 20 ]. "Other" includes nongroupable cases

No IMD-associated deaths were reported in adolescents or young adults 11−23 years of age in 2018 (Table ​ (Table2) 2 ) [ 7 ]. However, from 2015  to  2017, the CFR ranged from 12.5  to  25.0% and from 4.5 to 17.4% in those 11−15 and 16−23 years of age, respectively [ 18 – 20 ].

Case fatality rates in infants and adolescents and young adults in the United States (2015–2018) [ 7 , 18 – 20 ]

Nasopharyngeal carriage of the bacterium is a prerequisite for the development of IMD [ 1 ]. Thus, it is not surprising that carriage is most common among adolescents and young adults, peaking at about 24% at 19 years of age among countries in which serogroup B and C disease dominates [ 21 ], although most carriage strains do not cause invasive disease [ 22 ]. Carriage rates in institutional settings, such as college dormitories, can be much higher, exceeding 50% in historical reports from UK universities without meningococcal vaccine programs in place at the time [ 23 , 24 ]. Age-typical behaviors, such as smoking, having close or prolonged contact (e.g., through kissing), or living in close quarters (e.g., dormitories), leads to transmission from carriers to others, who may then develop disease [ 25 ]. Disease develops suddenly and progresses rapidly, and the initial symptoms can be nonspecific, together contributing to the high mortality rate. Therefore, a vaccination-based approach to prevention is justified [ 1 , 25 ].

College attendance is a risk factor of IMD; from 2015  to  2017, the incidence of IMD was more than five-fold higher among 18- to 24-year-olds attending college compared with those not attending (0.22 vs. 0.04 cases per 100,000) [ 26 ]. Adolescents and young adults are also at risk of IMD because of college outbreaks [ 27 ]. Between 1994 and 2002, 57% of organization-based outbreaks (i.e., occurring in individuals with a common affiliation but with no known close contact with each other) of meningococcal disease in the United States were caused by serogroup C, with the remaining attributed to serogroups B (25%) and Y (18%); notably, these data predate the availability of routine MenACWY vaccine programs that began in 2005 [ 28 , 29 ]. Between 2011 and 2019, the epidemiology of college outbreaks shifted, with all 14 college outbreaks being caused by serogroup B, including 50 cases, 2 deaths, an outbreak duration of a few weeks to more than 1 year, and a total at-risk population of more than 250,000 individuals [ 27 ].

Adolescents and young adults who have had IMD can experience high rates of long-term detrimental physical and psychosocial sequelae [ 3 , 30 ]. In a matched-cohort study, case subjects who had IMD between 15 and 19 years of age had poorer mental health, social support, educational outcomes, and quality of life compared with matched control subjects [ 30 ]. Specifically, 58% of those who had IMD experienced sequelae at 18−36 months after IMD, which was most commonly skin scarring (18%), vertigo (17%), mobility and speech problems (13% each), and hearing deficits (12%). A considerable percentage of those who had IMD also experienced effects on their daily life, with about half reporting effects on their leisure activities, physical ability, academic achievement, and home life, and with more than 40% noting that their friendships and vocational choices were affected. Serogroup B disease in children and adolescents caused significantly more disabilities in a population-based case–control study from the United Kingdom compared with matched controls [ 3 ]. These disabilities included major physical or neurologic disabilities, such as limb amputations, very low intelligence quotient (IQ), seizures, and hearing loss in approximately 10% of children, as well as minor deficits (e.g., psychological disorders, borderline IQ, digit loss, minor hearing loss, or communication deficits) in more than one-third of patients at a median of 3.75 years after disease.

Therefore, although the incidence of meningococcal disease is low, prevention of meningococcal disease among adolescents and young adults is important because of the devastating effects, including mortality and long-term sequelae, and the potential for outbreaks.

Vaccine Recommendations and Uptake in the United States

The US Advisory Committee on Immunization Practices (ACIP) recommends routine MenACWY vaccination for all adolescents at 11−12 years of age, with a booster dose at 16 years of age [ 31 ]. ACIP also recommends a meningococcal serogroup B (MenB) vaccine series for persons 16−23 years of age (preferred age of 16−18 years) under the shared clinical decision-making (SCDM) paradigm, which calls for a discussion between provider and patient about risks and benefits, without a default position in terms of whether vaccination should occur [ 32 – 34 ]. The decision to recommend SCDM (as opposed to routine use) was based on the overall low incidence of serogroup B disease, limited data on duration of protection and effectiveness, seriousness of disease, and the availability of licensed vaccines [ 34 ]. However, this recommendation may be in part responsible for the low uptake of the MenB vaccines [ 35 ].

The MenACWY vaccination program was associated with a reduced incidence of disease due to serogroups C, W, and Y in adolescents and young adults from 2006  to  2017, and an estimated 222 cases were averted in persons 11−22 years of age [ 36 ]. There is currently high uptake for the first dose of MenACWY by US adolescents (87% in 2018), which may partially be due to state mandates requiring vaccination for school entry [ 37 , 38 ]. However, uptake of the second dose is lower (51% in 2018) [ 37 ]. MenB vaccines have a low uptake (17% of adolescents in 2018 received ≥ 1 dose); it is not clear to what extent this is due to patient’s unwillingness to be vaccinated or the fact that SCDM conversations may not be taking place [ 37 , 39 – 41 ]. In either case, these data suggest that many adolescents and young adults are not fully protected.

Meningococcal Disease In Infants

The greatest burden of meningococcal disease is in infants < 1 year of age [ 7 ]. In 2018, the incidence of IMD in infants was 0.83 per 100,000 (Fig.  2 a) compared with 0.10 per 100,000 in the general population. Infants 2−5 months of age appear to be at highest risk, although data are limited [ 6 , 42 – 45 ]. Approximately 66% of cases in infants are caused by serogroup B, with serogroups C, W, and Y accounting for 28% of cases (Fig.  2 b) [ 7 ]. While the incidence of meningococcal disease overall and for serogroup B disease has decreased steadily from 2015  to  2017, an increase in total cases in infants was noted in 2018, which was predominantly attributed to serogroup B and to a lesser extent serogroup C disease [ 7 , 18 – 20 ]. As with adolescents, serogroup A caused no IMD in the United States in infants in the period 2015−2018 [ 7 , 18 – 20 ]. Over the same period, nongroupable and unknown accounted for 2%–24% of cases in infants.

Incidence ( a ) and cases ( b ) of meningococcal disease in the United States in infants (2015–2018) [ 7 , 18 – 20 ]. "Other" includes nongroupable cases

From 2015  to  2018, CFR in infants was 5.4%−12.9% (Table ​ (Table2) 2 ) [ 7 , 18 – 20 ]. Infants may be more likely to have sequelae and have more severe sequelae than older patients who had IMD [ 44 , 46 ]. For instance, hearing loss in infants with meningitis (19%) was more common than among adolescent or adult cases (12% and 8%, respectively). Neurologic complications in young infants, including hearing loss, are of concern because they may lead to developmental delay and may necessitate surgery [ 47 ].

While other risk factors of IMD in the general population are also thought to be applicable to infants, factors specifically in this population have not been well elucidated, although an association with increased IMD risk in infants and low birth weight, cigarette smoke exposure, and lower socioeconomic status is reported [ 42 , 48 ]. Catabolism of transplacentally acquired antibodies may also increase the risk of disease in infants [ 6 ]. Infants acquire meningococcus from colonized adolescents and adults in their environment, and they are more susceptible to infection because of immunologic immaturity [ 6 , 42 ].

Vaccine Recommendations in the United States

MenACWY vaccination is not routinely recommended by the ACIP for children 2 months to 10 years of age unless they have a high risk condition (e.g., HIV infection, anatomic asplenia, complement component deficiency, exposure in an outbreak, travel to or living in a country in which meningococcal disease is hyperendemic or epidemic) [ 49 ]. In recommending against routine vaccination in this age group, the ACIP cited the low burden of both IMD and cases that are preventable with MenACWY vaccines, which thereby was projected to limit the potential impact of a routine infant meningococcal vaccination program [ 42 ]. Of note, MenB vaccination of infants is not currently recommended [ 49 ] because no MenB vaccines are licensed in the United States for this age group [ 50 , 51 ].

Development of a Pentavalent Meningococcal Vaccine

An investigational pentavalent MenABCWY vaccine is being developed, which is constituted from 2 licensed meningococcal vaccines: MenB-FHbp and MenACWY-TT. MenB-FHbp is currently licensed in the United States for administration on a 2-dose (months 0 and 6) schedule in individuals 10−25 years of age, and is supported by a clinical development program involving more than 20,000 adolescents and young adults [ 51 , 52 ]. During an outbreak, a 3-dose schedule (months 0, 1−2, and 6) is recommended [ 53 ]. MenACWY-TT is a quadrivalent conjugate vaccine that uses tetanus toxoid as the carrier protein; it is licensed in the European Union and several other countries (but not the United States) for vaccination beginning at 6 weeks of age [ 13 , 54 ]. A 2-dose series (given 2 months apart) is administered from 6 weeks to < 6 months of age, or a single dose from 6 to 12 months of age, with a booster dose administered at 12 months of age (> 2 months after the previous dose) [ 13 ]. The clinical development of MenACWY-TT includes several phase 2 and 3 studies evaluating the immunogenicity and safety of primary vaccination in more than 2000 adolescents and young adults, as well as antibody persistence through 10 years after primary and booster dosing [ 54 , 55 ]. Clinical development also includes several phase 3 studies in more than 8000 infants and children 6 weeks to 10 years old [ 56 ].

The MenABCWY vaccine is being investigated in an ongoing phase 2/3 study in healthy adolescents and young adults 10−25 years of age, including both MenACWY vaccine-naive and -experienced subjects (NCT03135834) [ 57 ]. After administration of a 2-dose schedule given at months 0 and 6 (control subjects received MenB-FHbp at months 0 and 6 and MenACWY-CRM [Menveo ® ; GSK Vaccines, Sovicille, Italy] at month 0), immune responses to MenABCWY were robust and noninferior to MenB-FHbp and MenACWY-CRM at 1 month after dose 2, regardless of prior MenACWY vaccine exposure [ 57 ]. MenABCWY was also well tolerated with an acceptable safety profile [ 57 ]. Other ongoing clinical studies of the MenABCWY vaccine include phase 2 studies in healthy infants (NCT04645966) and adolescents (NCT04440176), and a phase 3 study in adolescents and young adults (NCT04440163; Table ​ Table3 3 ).

Ongoing clinical studies of the MenABCWY vaccine

Data are from ClinicalTrials.gov and are current as of July 27, 2021. Another MenABCWY vaccine is in development, but this review is focused on a pentavalent vaccine that is constituted from 2 licensed meningococcal vaccines (MenB-FHbp and MenACWY-TT)

Using the current US schedule (i.e., MenACWY vaccine given at 11 and 16 years of age) and assuming current rates of vaccination uptake for MenACWY and MenB vaccines, a population-based dynamic model simulating transmission of meningococcal disease in the United States found that vaccination with 2 doses of each vaccine (total of 4 injections between 11 and 16 years of age) has the potential to avert 165 cases of IMD over a 10-year period compared with no vaccination [ 58 ]. The same model estimated that a MenABCWY vaccine has the potential to prevent up to 256 cases of IMD in this population compared with no vaccine; the higher number of cases averted with the MenABCWY vaccine was predominantly attributed to the prevention of more serogroup B cases.

Considerations for Use of a Pentavalent Meningococcal Vaccination

Several factors would need to be weighed in considering recommendations for use of a MenABCWY vaccine in the general population.

Fatality Rate and Serious Sequelae

The public health threat represented by IMD is relatively low in the context of other current public health challenges, such as the coronavirus disease 2019 (COVID-19) pandemic, the opioid crisis, the decrease in preventive healthcare visits after 15 years of age, and poor uptake of the human papillomavirus vaccine [ 7 , 59 , 60 ]. However, as described previously, with the existing routine recommendations for MenACWY vaccination of adolescents in the United States, a large proportion of disease continues to occur, including in the age-based populations at greatest risk (i.e., infants and adolescents/young adults), which is mostly attributed to serogroup B and to a lesser extent serogroup C disease (Fig.  1 ) [ 7 ]. Thus, replacing MenACWY vaccine with a pentavalent MenABCWY vaccine would reduce disease burden and simplify the current vaccination schedule, and in many ways represents the next natural step in the evolution of the US meningococcal vaccination program. In addition, among vaccine-preventable diseases, meningitis has one of the highest fatality rates, and the burden is persistently high and lagging behind other vaccine-preventable diseases [ 61 ]. For adolescents and young adults, the CFR for IMD from 2015  to  2017 was exceptionally high (e.g., a CFR of 17.4%−25.0% in 2015) [ 7 , 18 – 20 ]. Any death, including preventable ones occurring in childhood or young adulthood, is devastating for families, loved ones, and the community, and the mortality risk of a vaccine-preventable disease should be a consideration in formulating recommendations for vaccination.

As described previously, patients who have IMD in childhood can also experience high rates of long-term effects, including detrimental physical and psychosocial sequelae that can linger into adulthood [ 3 , 30 , 62 ]. These can lead to adverse quality of life and psychosocial effects for both the children and their families [ 46 , 63 , 64 ]. Of note, the paucity of data regarding long-term outcomes for childhood survivors of IMD, particularly infants, emphasizes the need for further study, including population-based investigations.

Cost of IMD

A large proportion of IMD cases among college students occurs in the context of campus outbreaks [ 27 ]. Controlling IMD outbreaks requires coordination among numerous parties and significant human and capital resources [ 65 ]. In the absence of proactive vaccination programs, mitigating the extent of the outbreak is dependent on the ability of reactive vaccination strategies to quickly interrupt carriage and transmission. Responses to college outbreaks are also associated with high financial costs. For instance, the total cost of 2 serogroup B college outbreaks occurring in Oregon and Rhode Island was US$0.589−1.696 million with the cost per student vaccinated of US$636−2333 [ 27 ].

Traditional cost–benefit analyses may be difficult to apply to vaccination against IMD because of the unpredictable nature of IMD and the variability in the estimations of indirect disease costs (e.g., premature death, additional education, welfare needs) and vaccination benefits [ 66 ]. Of relevance to the epidemiologic situation in the United States, the quality-adjusted life-year thresholds for MenB vaccines have been outside the accepted willingness-to-pay range; however, the methodology used to assess cost effectiveness can vary and may not fully measure vaccine impact [ 66 ]. Incorporation of a MenABCWY vaccine into the recommended vaccination schedule would prevent disease due to serogroup B and reduce costs associated with individual and outbreak response.

Challenges with Vaccination

Importantly, meningococcal vaccination programs have resulted in disease reductions, emphasizing the benefits of such public health measures. For instance, countries that included routine use of the serogroup C conjugate vaccine in the routine infant vaccination program experienced dramatic decreases in IMD among infants, as well as in other age groups who were not directly vaccinated [ 67 – 70 ]. In the Netherlands, after the introduction of a meningococcal serogroup C vaccination program in individuals 1−18 years of age in 2002, the number of disease cases due to serogroup C rapidly decreased across all age groups [ 70 ]. Within 2 years of the introduction of routine MenACWY in the Netherlands in 2018, there was a reduction in the incidence of IMD of 85% in all vaccine-eligible ages, mainly driven by a reduction in serogroup W disease [ 13 ]. In addition, 3 years after MenB-4C was included in the UK infant immunization program, a 75% decrease in the incidence of serogroup B disease was reported among all children who were eligible for vaccination [ 71 ]. Importantly, while large observational studies have shown vaccination against serogroups A and C can affect meningococcal carriage, this effect of MenB vaccination has not been shown in adolescents with moderate-to-high vaccine uptake [ 72 , 73 ]. Therefore, direct vaccination of at-risk populations will be required to reduce serogroup B disease.

To achieve these public health benefits of meningococcal vaccination, it is necessary that there be large uptake of a vaccine for the currently relevant disease-causing serogroup(s). However, challenges exist in achieving these goals.

Dynamic Nature of Meningococcal Disease Epidemiology

The variable epidemiology of IMD, including temporal fluctuations in the predominant disease-causing serogroup, can lead to challenges in ensuring that at-risk populations are appropriately protected. To address these challenges, several countries outside the United States have amended vaccine recommendations as the incidence of IMD caused by specific serogroups has changed [ 74 – 76 ]. Serogroup W cases have been associated with a hypervirulent ST-11 strain and an emergent ST-9316 strain predominantly affecting children younger than 4 years [ 74 , 77 – 80 ]. A proportion of these serogroup W cases has presented with atypical clinical features, including septic arthritis, gastrointestinal symptoms, and severe respiratory tract infections, such as pneumonia, epiglottitis, and supraglottitis [ 74 , 81 ]. The serogroup Y cases have varied regarding the most affected age group, and commonly manifest as septicemia and with decreased penicillin susceptibility [ 75 , 76 ]. Importantly, several countries worldwide have introduced MenACWY vaccination to their immunization programs in response to this changing epidemiology [ 82 ], emphasizing that a single vaccine that provides protection against the 5 predominant disease-causing serogroups could best address the variable epidemiology of IMD for at-risk populations.

Challenges with Vaccinating Infants and Adolescents

The infant vaccination schedule is already crowded; incorporating optimal protection against IMD using separate MenACWY and MenB vaccines would add as many as 8 injections to the first year of life [ 11 , 83 ], which may lead to decreased compliance [ 84 ]. Combination vaccines are generally preferred by ACIP because they reduce the number of injections that are required and improve vaccine coverage rates, among other benefits [ 85 ]. The availability of a MenABCWY vaccine may therefore offer the possibility of more efficiently vaccinating infants against the most predominant disease-causing serogroups and with a minimal number of doses. The same arguments could be made in limiting the number of injections for other age groups.

The uptake of meningococcal vaccines among adolescents can also be challenging [ 86 ]. Patient-associated factors among adolescents that could account, at least in part, for diminished vaccine uptake include less healthcare utilization compared with younger individuals and missed opportunities for vaccination (i.e., a healthcare visit in which vaccines could have been administered but were not). Other provider-/practice- and policy-related factors that are suggested to affect vaccine uptake among adolescents include competing demands among healthcare providers to address important topics at adolescent clinic visits, the lack of school entry requirements for vaccinations, and the ability to be vaccinated without parental consent [ 86 ].

Besides the availability of safe and efficacious vaccines, successful pediatric vaccination programs require sufficient parental awareness, provider knowledge, and equitable access [ 35 ]. However, notable challenges have been found in this regard. For instance, a US survey of healthcare providers’ understanding of ACIP meningococcal recommendations found a lack of understanding of the shared decision-making recommendations [ 40 ]. In addition, parents are often unaware of MenB vaccines, and racial and socioeconomic inequities exist in patient access to these vaccines [ 35 ].

Despite these challenges, the relative success of the existing MenACWY vaccination program presents an opportunity to build on the existing framework to cover all serogroups with a MenABCWY vaccine [ 87 ]. Given the persistent and dynamic nature of IMD [ 88 ], it is not likely that the current recommendations for MenACWY vaccination will be removed. Thus, providing additional coverage of serogroup B with a MenABCWY vaccine would further reduce disease incidence regardless of potential serogroup replacement in the future and the costs associated with outbreak response.

Although rare, IMD can have devastating clinical consequences for individuals and cause disruptive and costly outbreaks. The universal MenACWY vaccination program in US adolescents has been successful in reducing disease burden, but is incomplete in the sense that less than half of the incident disease is prevented. A MenABCWY vaccine would cover serogroup B disease and could help close this gap. Availability of such a vaccine would warrant serious consideration for addition to the routine immunization schedule, given the higher incidence of disease in adolescents and infants and the potential for life-long sequelae. Traditional cost–benefit analyses may underestimate the human impact that such a program might have.

Acknowledgements

This work was funded by Pfizer Inc. The sponsor is also funding the journal’s Rapid Service Fee.

Medical Writing and Editorial Assistance

Editorial/medical writing support was provided by Tricia Newell, PhD, and Allison Gillies, PhD, of ICON (Blue Bell, PA), and was funded by Pfizer Inc.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contributions

Conception and design: Gary S. Marshall; Jaime Fergie; Jessica Presa; Paula Peyrani. Data collection: Not applicable. Statistical analysis: Not applicable. Drafting and revising for intellectual content: Gary S. Marshall; Jaime Fergie; Jessica Presa; Paula Peyrani. Agreed to be accountable for the integrity of the work: Gary S. Marshall; Jaime Fergie; Jessica Presa; Paula Peyrani.

Disclosures

GSM has been an investigator on clinical trials and participated in advisory boards for GlaxoSmithKline, Merck, Novartis, Pfizer, Sanofi Pasteur, and Seqirus and is a speaker for Pfizer and Sanofi. JF is a speaker for Pfizer, Merck, AstraZeneca, and Sanofi; is a consultant/advisory board member for Pfizer, Merck, Sanofi, Moderna, Novavax, and Sobi; and is principal investigator or investigator for Pfizer, AstraZeneca, and Merck trials. JP and PP are employees of Pfizer Inc and may hold stock or stock options.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals.

Data Availability

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Gary S. Marshall, Email: [email protected] .

Jaime Fergie, Email: [email protected] .

Jessica Presa, Email: [email protected] .

Paula Peyrani, Email: [email protected] .

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Exploring the Mechanisms and Therapeutic Approaches of Mitochondrial Dysfunction in Alzheimer’s Disease: An Educational Literature Review

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• Mostafa Hossam El Din Moawad 1 , 2 ,
• Ibrahim Serag 3 ,
• Ibraheem M. Alkhawaldeh 4 ,
• Abdallah Abbas 5 ,
• Abdulrahman Sharaf 6 ,
• Sumaya Alsalah 7 ,
• Mohammed Ahmed Sadeq 8 ,
• Mahmoud Mohamed Mohamed Shalaby 9 ,
• Mahmoud Tarek Hefnawy 10 ,
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Alzheimer’s disease (AD) presents a significant challenge to global health. It is characterized by progressive cognitive deterioration and increased rates of morbidity and mortality among older adults. Among the various pathophysiologies of AD, mitochondrial dysfunction, encompassing conditions such as increased reactive oxygen production, dysregulated calcium homeostasis, and impaired mitochondrial dynamics, plays a pivotal role. This review comprehensively investigates the mechanisms of mitochondrial dysfunction in AD, focusing on aspects such as glucose metabolism impairment, mitochondrial bioenergetics, calcium signaling, protein tau and amyloid-beta-associated synapse dysfunction, mitophagy, aging, inflammation, mitochondrial DNA, mitochondria-localized microRNAs, genetics, hormones, and the electron transport chain and Krebs cycle. While lecanemab is the only FDA-approved medication to treat AD, we explore various therapeutic modalities for mitigating mitochondrial dysfunction in AD, including antioxidant drugs, antidiabetic agents, acetylcholinesterase inhibitors (FDA-approved to manage symptoms), nutritional supplements, natural products, phenylpropanoids, vaccines, exercise, and other potential treatments.

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Introduction

Alzheimer’s disease (AD) is the leading cause of dementia and presents a substantial challenge to healthcare systems worldwide [ 1 , 2 ]. It is distinguished by a gradual deterioration in cognitive function, leading to impairment in daily activities and a rise in morbidity and mortality among older people [ 1 , 2 ]. FDA-approved AD medications encompass both symptom management and disease treatment. Symptom management drugs include brexpiprazole, donepezil, galantamine, memantine, a combination of memantine and donepezil, and rivastigmine [ 3 ]. For disease treatment, lecanemab, a disease-modifying immunotherapy, is used. It treats mild cognitive impairment or mild AD by removing abnormal beta-amyloid to help reduce the number of plaques in the brain [ 3 , 4 ].

The pathophysiology of AD is complex and involves multiple factors [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Mitochondria, essential for cellular energy metabolism, can impair neuronal function when dysfunctional [ 8 , 13 ]. Synapses, the connections between neurons, are critical for communication and signal transmission in the brain. Several mechanisms contribute to synapse dysfunction in AD, including amyloid beta peptide (Aβ) and tau protein [ 14 ], synaptic pruning [ 15 , 16 ], inflammatory processes [ 17 ], mitochondrial dysfunction, and cholinergic signaling, particularly acetylcholinesterase [ 18 , 19 , 20 , 21 ] (Fig.  1 ).

Synaptic mechanisms in Alzheimer’s disease (AD). A AD is characterized by the accumulation of tau protein tangles and amyloid beta (Aβ) plaques in the brain, disrupting synapses’ normal functioning. The regular operation of synapses is compromised due to the interference of oligomers with neurotransmitter action. Microtubules, which are essential for maintaining the structure and function of synapses, are adversely affected by tau protein tangles that disrupt their typical structure and function [ 14 ]; B synaptic pruning is a process through which the brain eliminates redundant or underused synapses. This process is essential for the normal functioning of the brain. However, it may be implicated in AD. In AD, synaptic pruning is excessively activated, leading to a reduction in functional synapses. Consequently, the brain ends up with fewer synapses, which could contribute to the cognitive decline associated with AD [ 15 , 16 ]; C microglia, the brain’s immune cells, can become activated due to persistent inflammation. While microglia are necessary for removing Aβ plaques, they may also contribute to synaptic dysfunction. The pro-inflammatory cytokines secreted by activated microglia can impair synaptic function. Additionally, the activation of astrocytes, another type of brain cell, can release inflammatory substances that exacerbate synaptic dysfunction [ 17 ]; D the onset of AD has been linked to mitochondrial dysfunction. When mitochondria fail, they produce reactive oxygen compounds that can disrupt proteins, lipids, and DNA. This oxidative stress may play a role in the loss of functional connections, a characteristic feature of AD [ 13 ], and ( E ) neurotransmitters are chemical messengers essential for transmitting signals between neurons. AD is characterized by decreased neurotransmitters, such as acetylcholine, which plays a crucial role in memory and learning. The dysfunction of synapses caused by this neurotransmitter deficiency may contribute to the cognitive decline associated with AD [ 18 ]

Research suggests that mitochondrial dysfunction plays a central role in the progression of AD [ 22 , 23 ]. This literature review aims to highlight and provide up-to-date information on the mechanism of mitochondrial dysfunction and the therapeutic modalities for mitigating mitochondrial dysfunction in AD.

Mechanism of Mitochondrial Dysfunction in Alzheimer’s Disease

Glucose metabolism impairment and ad.

Despite accounting for only 2% of body weight, the brain consumes 25% of the body’s oxygen and 25% of its glucose. These demonstrated how vulnerable our brains are to energy metabolism abnormalities, to the point that a minor change in energy metabolism is significantly associated with a disturbance in the functioning of the nervous system. Impaired energy metabolism is one of the early and most persistent symptoms of AD [ 24 ]. The primary necessary substrate for the adult human brain and its cerebral endothelial cells is glucose [ 25 ]. A 55-kDa isoform of glucose transporter 1 (GLUT1) imports glucose into cerebral endothelial cells [ 26 ]. After that, glucose travels through glycolysis, followed by the pentose-phosphate route, lactate fermentation, or mitochondrial metabolism [ 25 ].

A growing amount of data points to decreased glucose consumption as an early and persistent characteristic of AD, occurring up to decades before the disease’s onset [ 27 , 28 , 29 , 30 ]. When comparing AD brains (especially the hippocampus and cortex) to individuals without dementia, fluoro-2 deoxyglucose positron-emission tomography (FDG-PET) was used to discover a greater decline in glucose consumption. Furthermore, in the early stages of AD, the posterior cingulate cortex was shown to be the most metabolically damaged of all brain areas [ 27 ]. Moreover, people with moderate cognitive decline, a prodromal phase of AD, show glucose hypometabolism but to a lower extent in terms of quantity or geographic distribution. This suggests low glucose metabolism affected the disease’s onset [ 29 ]. Apolipoprotein E (ApoE ε4) allele is recognized as a risk factor for AD and moderate cognitive decline. Indeed, it is frequently mentioned as the primary genetic factor of AD [ 31 , 32 , 33 , 34 , 35 , 36 ]. In their 84-month longitudinal FDG PET investigation, Paranjpe et al. [ 31 ] showed that patients with moderate cognitive decline had an ApoE ε4-associated brain region-specific glucose metabolism pattern. Decades before dementia may manifest, in their 20 s, young persons with the ApoE ε4 gene were found to have glucose hypometabolism in the brain regions that are susceptible to it [ 37 ].

Furthermore, in patients with AD, the amount and geography of glucose underutilization reflected the distribution of diminished synaptic function and density in distinct brain areas, coinciding with the severity of symptoms [ 38 , 39 ]. These days, cerebral glucose hypometabolism is recognized as a characteristic of the illness, and measuring it with FDG-PET is turning it into a biomarker for early AD identification and entirely accurate and sensitive moderate cognitive decline to AD conversion prediction [ 40 , 41 ].

The relationship between amyloid plaque formation and glucose low metabolism has been examined using amyloid PET biomarkers and FDG PET. Longitudinal A depositions (the predominant type of amyloid) were found in practically every cortical area in carriers of autosomal-dominate AD mutations 15–25 years before the expected age of beginning, which appeared before glucose hypometabolism in specific cortical regions approximately 5–10 years later. In these circumstances, glucose underutilization may arise due to A depositions in AD development [ 30 , 42 , 43 ]. Diminished local glucose consumption was linked to worldwide amyloidosis. Comparing the same patients revealed weak correlations between regional amyloid pathology and regional glucose hypometabolism (just one location out of 404 showed a negative correlation between glucose metabolism and amyloid plaque deposition) [ 44 ]. These findings might imply that glucose underutilization is vital in defining the clinical manifestations of the illness, even if it happens incidentally in autosomal-dominate AD carriers. Given this, as well as the recurrent failures of A-centered clinical studies, one may argue that it is too late to target A in AD or even those with moderate cognitive decline after years of amyloid pathology launching deadly cascades of events. Impaired energy metabolism, on the other hand, may afford a wider window for therapeutic intervention [ 24 ].

Mitochondrial Bioenergetics in AD

Several studies have identified abnormalities in mitochondrial-related metabolic processes associated with AD through gene expression analyses, providing compelling evidence of dysfunctional mitochondrial bioenergetics in patients with AD [ 45 , 46 , 47 , 48 , 49 ]. Liang et al. [ 46 ] conducted a genome-wide transcriptome study using postmortem brains of patients with AD and controls from various brain regions, focusing on the activity of 80 metabolically relevant nuclear genes in non-tangle-bearing neurons obtained through laser-capture microdissection. Their findings revealed a significant decrease in the expression of nuclear genes encoding components of the mitochondrial electron transport chain in patients with AD’s posterior cingulate cortex, hippocampus CA1, and middle temporal gyrus, with reductions of 70%, 65%, and 61%, respectively. In contrast, the visual cortex exhibited only a 16% decrease in expression, indicating relative protection from metabolic deficits in aging and AD [ 47 , 48 ].

Another study utilized postmortem human hippocampus tissues to analyze the expression of mRNA transcripts involved in glucose metabolism in patients with AD, revealing substantial downregulation of 15 out of 51 members associated with pathways related to oxidative phosphorylation (OXPHOS), glycolysis, and the TCA cycle [ 49 ]. Mastroeni et al. [ 45 ] investigated hippocampal specimens from healthy controls, individuals with amnestic mild cognitive impairment, and AD cases, confirming a significant reduction in OXPHOS genes in AD, particularly those expressed by the nucleus. Interestingly, individuals with mild cognitive impairment exhibited higher levels of these genes compared to both patients with AD and healthy controls.

Mitochondria and Calcium Signaling

The active transport of calcium ions (Ca 2+ ), triggered by the action potential, is essential for neuronal development and function [ 50 ]. It functions as a messenger, activating the calcium channel to transfer depolarization calcium ions to the neuron’s presynaptic end. This releases neurotransmitters via exocytosis, which gives the postsynaptic neuron the action potential [ 51 , 52 ]. The presynaptic zone has an increase in calcium concentrations due to this mechanism [ 51 ]. Calcium homeostasis is one of the most critical functions performed by mitochondria and the endoplasmic reticulum [ 53 , 54 ]. It reduces calcium concentrations by transferring calcium ions out of the mitochondria and into the matrix via the voltage-dependent anion-selective channel 1 (VDAC1) on the outer membrane, the Na + -dependent mitochondrial calcium efflux transporter (NCLX), and the mitochondrion calcium uniporter (MCU) on the inner membrane of the mitochondria [ 55 , 56 , 57 , 58 ]. When the mitochondria are overloaded with calcium ions, the inner membrane’s permeability of mitochondria transition pores (mPTPs) opens, releasing cytochrome c from the cells and triggering caspases in the cytoplasm, triggering apoptosis [ 59 ] (Fig.  2 ). Aβ plaque accumulation in synaptic mitochondria plays a significant role in calcium dyshomeostasis in AD [ 59 ].

Illustration of calcium ions (Ca2 +) signaling in mitochondrial dysfunction-associated neuronal apoptosis in Alzheimer’s disease (AD). The buildup of Aβ in cortical neurons is associated with releasing calcium from the endoplasmic reticulum, leading to increased cytosolic calcium ion levels and enhanced mitochondrial calcium absorption. Mitochondria and the endoplasmic reticulum play a crucial role in maintaining calcium homeostasis by transferring calcium ions out of the mitochondria and into the matrix via various channels and transporters [voltage-dependent anion-selective channel 1 (VDAC1); the Na + -dependent mitochondrial calcium efflux transporter (NCLX), and the mitochondrion calcium uniporter (MCU)]. Overloading mitochondria with calcium ions triggers the opening of mitochondrial transition pores (mPTPs), releasing cytochrome c, activating caspase activation, and initiating apoptosis [ 50 , 51 , 52 , 53 , 54 , 59 ]

Furthermore, it is hypothesized that the accumulation of Aβ in cortical neurons instigates calcium release from the endoplasmic reticulum. This event elevates the levels of cytosolic calcium ions, thereby prompting mitochondria to absorb more calcium [ 60 , 61 ]. The subsequent rupture of the mitochondrial membrane can be attributed to the high calcium concentrations within the mitochondria. This phenomenon can be elucidated by activating pro-apoptotic proteins, opening mPTPs, and augmentation in ROS [ 59 ]. Notably, this dysregulation of calcium at the mitochondrial level has been observed in the brains of patients diagnosed with AD [ 62 , 63 ].

Aβ, Protein Tau, and Associated Synapse Dysfunction

An accumulation has been associated with synaptic dysfunction and neurotoxicity. It obstructs anterograde mitochondrial transport to the synapses, neurotransmitter release, and synaptic vehicle renewal [ 64 , 65 , 66 , 67 , 68 ]. Furthermore, it was demonstrated that Aβ promoted and inhibited long-term depression and N-metylo-D-asparaginowy (NMDA)-dependent long-term potentiation in synaptic connections [ 69 , 70 ]. In a similar vein, tau has been linked to synaptic impairment in patients with AD. Through its interaction with Synaptogyrin-3, it was discovered to limit synaptic vesicles’ mobility and diminish neurotransmitters’ release from vesicles [ 64 , 71 , 72 ]. Furthermore, tau has been linked to reduced mitochondrial axonal transport movement by interfering with microtubules, which in turn interferes with dynein and kinesin binding, diminishing neurotransmission [ 73 , 74 ]. Interestingly, increased synaptic activity has been linked to increased tau diffusion to synapses, exacerbating synaptic dysfunction [ 75 ]. It was discovered that interactions between dynamin-related protein 1 (Drp1) and a rise in hyperphosphorylated tau mitochondrial fission, which in turn reduces the amount of functional mitochondria present in the synapse [ 11 ]. Memory impairment and cognitive impairment caused by AD are triggered by slower and disrupted neurotransmission as a result of progressive synaptic dysfunction. Individuals with AD experience dementia, and the condition proceeds as a result of synaptic degradation and subsequent neuronal death in their brains [ 76 ].

Mitophagy and Autophagy

Mitophagy is a particular type of autophagy through which mitochondria are attacked and degraded. These cellular processes play a crucial role in energy conservation, cellular destruction, and preventing the accumulation of damaged organic molecules [ 77 ]. Many studies revealed that mitophagy processes are deformed in AD [ 78 , 79 , 80 , 81 ].

Most studies report the Pink–Parkin mitophagy pathway; however, cardiolipin-induced mitophagy has been reported in mouse models with AD [ 82 ]. Mitophagy markers increase with the disease progression, as reported in postmortem brain tissue and animal models. Yet, the cytosolic Parkin concentration is decreased, reducing its availability for mitophagy [ 83 ]. The cause of the accumulated mitochondria that are targeted for mitophagy is unclear. However, some studies reported that cells with presenilin-1 (PSEN1) mutations [ 84 ] or cells expressing the apoE4 gene [ 85 ] exhibit lysosomal dysfunction.

It is unknown what is generating the increased recruiting of Parkin to mitochondria; it might be due to mitochondrial membrane potential depolarization, which is produced by amyloid interlinkage with mitochondria. Furthermore, amyloid contributes to ROS generation, signaling mitophagy’s start by boosting Parkin accumulation [ 77 ]. However, studies using animal and cell models have demonstrated that tau can either boost the recruitment of Parkin to mitochondria [ 79 ] or prevent its movement from the cytoplasm [ 80 , 81 ].

The preparedness of a mitochondrion for mitophagy can be influenced by several factors, including the formation of ROS and its breakdown of mitochondrial membrane potential. The permeability of the mPTP is a transmembrane protein found in the inner mitochondrial layer that is critical in determining the degree of cellular death and mitophagy [ 86 ]. It has been reported that the mPTP function may be disturbed in AD, as a study showed a further constant activation of the pore in cells compared to healthy controls [ 87 ].

Because of accumulating damage and limited self-repair, old age is a substantial contributory factor for many neurodegenerative illnesses. As we age, our mitochondria’s shape and function alter substantially. Several studies, for example, found age-related changes in the structure of mitochondrial membranes, including the loss of cristae and inner membrane vesicles. Apoptogens are released into the cytoplasm because of the outer membrane breach caused by the division of adenosine triphosphate (ATP) synthase dimers into monomers. Furthermore, vesiculations of the membrane’s inner layer and the breaking of ATP synthase dimers cause a considerable decrease in ATP [ 88 ].

According to research, age-related synaptic mitochondria aggregation disrupts synaptic activities such as ATP synthesis and calcium equilibrium, which are required for efficient depolarization-evoked neurotransmitter vesicle formation and plasticity. As a result, cognitive function and memory are impaired. Nonsynaptic mitochondria are less sensitive to age-dependent alterations and the accumulation of A aggregates [ 89 , 90 ].

Aging is the leading risk factor for the beginning of sporadic AD; prevalence increases with age, from 2% in those 65–69 to 25% in those 90 + [ 91 ]. Numerous cohort studies indicate that age must be considered when evaluating AD treatments’ safety and possible efficacy [ 92 ]. The accumulation of free radicals may accelerate aging in addition to metabolic decline.

Oxidative damage to mitochondrial macromolecules, especially mtDNA, would be most severe as mitochondria are the cell’s primary source of free radical production [ 93 ]. Reduced activity of antioxidant enzymes such as glutathione reductase, catalase, superoxide dismutase, and glutathione peroxidase is also associated with chronic free radical accumulation in the AD brain [ 94 , 95 ].

Moreover, reports indicate that a decline in proteasome activity brought on by aging may facilitate the deposition of Aβ and tau [ 96 , 97 ]. Consequently, these aging-related mechanisms establish an endless loop that leads to advanced mitochondrial dysfunction as well as the buildup of Aβ and tau, the two main pathogenic characteristics of AD.

Inflammation

Pathogen-associated molecular patterns (PAMPs) originate from pathogens or exogenous ligands, while damage-associated molecular patterns (DAMPs) are endogenously produced molecules released into the extracellular environment following tissue damage. Pattern recognition receptors identify PAMPs and DAMPs, subsequently triggering intracellular signal transduction pathways that enhance innate immune responses. Due to the similarities between mitochondria and bacteria, when mitochondrial material escapes into the cytosol or extracellular environment, it activates pattern recognition receptors signaling by serving as a PAMP or DAMP [ 98 ]. As a result, mitochondria control the signals that cause inflammation.

DAMPs and PAMPs in the central nervous system induce pro-inflammatory immune responses in glial cells, resulting in chronic neuroinflammation and speeding up the etiology of neurodegenerative diseases such as AD [ 99 , 100 ]. There is evidence that mtDNA causes in vivo neuroinflammation, as when mtDNA or mitochondrial lysates are injected into the hippocampus dentate gyri, pro-inflammatory signaling is triggered [ 101 ].

The introduction of mitochondria or mtDNA into the hippocampus area phosphorylates NF-B, increases TNF mRNA synthesis, and lowers myeloid cells 2 (TREM2) expression, all of which are markers of AD pathogenesis [ 102 , 103 ] and are included in phagocytic and anti-inflammatory pathways [ 104 , 105 ]. Notably, mitochondrial lysates likewise increase endogenous APP and Aβ [ 101 ].

Mitochondrial DNA (mtDNA)

mtDNA is susceptible to oxidative damage due to its proximity to generating ROS, the absence of protective histones, and limited repair mechanisms [ 106 ]. In the brains of patients with AD, mtDNA exhibits approximately ten times more oxidized bases and three times more oxidative damage than nuclear DNA, potentially leading to mutations impairing mitochondrial function, cell death, and disease progression [ 107 ]. Mutations in mtDNA have been associated with cognitive impairments and are implicated in the onset of AD [ 106 ]. Specific maternally inherited genetic changes, known as mtDNA single nucleotide polymorphisms and haplogroups, have been linked to an increased risk of AD [ 108 , 109 , 110 ]. Notably, mtDNA accumulates mutations during aging, the primary risk factor for AD [ 111 ]. Furthermore, alterations in mtDNA, such as elevated 5-methylcytosine levels in the D-loop region in AD pathology brain samples with and reduced D-loop region methylation in peripheral blood mtDNA from patients with late-onset AD, can impact mtDNA transcription and function [ 112 , 113 ].

ROS or the autophagic/lysosomal system may release mtDNA, initiating or exacerbating AD development by triggering a pro-inflammatory response. While this phenomenon has been observed in other conditions, such as cardiomyopathy and systemic inflammation, the specific mechanisms underlying the effects of released mtDNA in AD remain unclear and require additional investigation [ 114 ].

Mitochondria-Localized microRNAs (mitomiRs)

The pathogenesis of AD has been linked to mitochondrial miRNAs, which play a crucial role in regulating mitochondrial function. Dysfunctional miRNAs in neurons, often due to oxidative stress, can lead to increased production of ROS by mitochondria [ 115 ]. Specific mitochondrial miRNAs, such as miR-98 and miR-15b, have been shown to support redox balance, while miR-204 and miR-34a have been found to elevate ROS generation and impede the activity of antioxidant enzymes [ 116 , 117 , 118 , 119 ]. Dysregulation of these miRNAs can lead to neuronal death due to heightened oxidative stress in AD, while reduced levels of miR-98 and miR-15b can increase ROS production and oxidative damage. The transmission of synaptic information and plasticity heavily relies on mitochondrial function. Specific mitochondrial miRNAs, including miR-484, miR-132, and miR-212, have been demonstrated to enhance neurotransmission [ 120 , 121 ].

Additionally, miR-218 has been identified as playing a role in protecting neurons from toxins and metallic ions that can induce synaptic toxicity [ 122 ]. The dysregulation of miRNAs involved in synaptic plasticity, such as miR-132 and miR-484, is likely to contribute to the observed synaptic dysfunction in AD [ 117 , 121 ]. Programmed cell death, or apoptosis, is a fundamental mechanism for regulating the survival and death of neurons, particularly in the context of AD. Dysregulation of mitochondrial miRNAs implicated in apoptosis, such as miR-7, miR-98, and miR-30, has been observed, potentially leading to increased apoptosis and neuronal death [ 118 , 123 , 124 ]. Extensive neuronal death disrupts pathways associated with learning and memory, further exacerbating the cognitive deficits seen in AD [ 125 ]. Therefore, the dysregulation of mitochondrial miRNAs in AD will likely contribute to various aspects of the condition, including oxidative damage, synaptic dysfunction, and neuronal death. Overall, research on mitochondrial miRNAs and their role in neurodegenerative diseases holds promise for developing novel diagnostic and therapeutic approaches for AD and other neurodegenerative disorders (Fig.  3 ).

The role of mitochondrial miRNAs in the pathogenesis of Alzheimer’s disease (AD). Dysregulation of specific miRNAs, often due to oxidative stress, can lead to increased production of ROS and neuronal death. Specific miRNAs, such as miR-98 and miR-15b, support redox balance, while others, like miR-204 and miR-34a, elevate ROS generation. The figure also highlights the role of miRNAs in synaptic information transmission and plasticity, with miR-484, miR-132, and miR-212 enhancing neurotransmission. Dysregulation of these miRNAs can contribute to synaptic dysfunction in AD. The figure further depicts the role of miRNAs in apoptosis, a mechanism regulating neuronal survival and death. Dysregulation of miRNAs implicated in apoptosis, such as miR-7, miR-98, and miR-30, can lead to increased apoptosis and neuronal death, disrupting learning and memory pathways [ 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 ]

Genetic variations in mitochondrial regulatory pathways can lead to a gradual decline, ultimately resulting in compromised mitochondrial integrity and mtDNA damage, leading to mtDNA alteration dysfunction and disease [ 126 ]. Genetics can influence mitochondrial dysfunction and increase the risk of developing AD through various mechanisms. Aberrations in genes responsible for encoding mitochondrial proteins can disrupt mitochondrial function, resulting in the accumulation of oxidative damage and a decrease in energy production. Some of these mutations are associated with the production and metabolism of Aβ, which are known to aggregate in the brains of individuals with AD. Early-onset, autosomal dominant familial AD has been linked to mutations in the amyloid precursor protein (APP), PSEN1, and PSEN2 genes, typically manifesting in the fifth or sixth decade of life [ 126 ]. However, exceptions exist, and generally, if an individual develops AD after the age of 60 and does not have a parent who was affected by the disease before the age of 60, genetic testing is unlikely to reveal an autosomal dominant mutation in the APP, PS1, or PS2 genes. Individuals who develop sporadic AD at a younger age are thought to have a higher genetic predisposition for the disease. The presence of the APOE4 allele is frequently observed in these patients, indicating that APOE4 may be a risk factor for the early onset of AD in individuals carrying this allele [ 127 ].

Several studies have indicated sex-specific differences in mitochondrial dysfunction in the brain and that age-related declines in sex hormone levels may play a role in such dysfunction due to the critical regulatory role of hormones in mitochondrial activity [ 128 ]. Moreover, research has shown that ovulation significantly reduces mitochondrial respiration, suggesting that female sex hormones like progesterone and estrogen have a more pronounced impact on mitochondrial activity than testosterone [ 129 ]. Estradiol, the primary estrogen in humans, has been found to enhance OXPHOS activity, reduce the generation of ROS, and preserve mitochondrial membrane potential [ 130 ]. A postmenopausal mouse model investigation revealed that cognitive decline associated with estrogen deficiency coincides with abnormal mitochondrial biogenesis, disrupted mitochondrial dynamics, reduced mitophagy, and mitochondrial dysfunction [ 131 ]. Similarly, progesterone has been shown to decrease oxidative stress and increase mitochondrial energy production [ 132 ]. Additionally, studies have suggested that testosterone deficiency may potentially impair brain substantia nigra mitochondria by increasing oxidative stress and reducing the activity of complex I, underscoring the potential influence of testosterone on mitochondrial dysfunction in the brain [ 133 ]. Furthermore, it has been proposed that the age-related decline in sexual steroid production could contribute to the deterioration of brain mitochondria [ 128 ].

Electron Transport Chain and Krebs Cycle

Numerous studies have highlighted alterations in the electron transport chain (ETC) and tricarboxylic acid (TCA) cycle, the two paramount metabolic pathways within mitochondria. Researchers have reported a decrease of 30–40% in the activity of complex IV [ 134 , 135 , 136 , 137 ] and alpha-ketoglutarate dehydrogenase (aKGDH) [ 138 , 139 , 140 ], both crucial components of these metabolic pathways. Recent studies on human donor livers have provided evidence that the activity of the mitochondrial respiratory chain (complexes I, II, III, IV) and Krebs cycle enzymes (aconitase, citrate synthase) does not significantly differ before and after a 4-h preservation period across all study groups ( p  > 0.05) [ 141 ]. Interestingly, low-risk livers that were clinically viable ( n  = 8) exhibited lower activities of complexes II–III following 4-h perfusion compared to high-risk livers (73 nmol/mg/min vs. 113 nmol/mg/min, p  = 0.01). Applying actively oxygenated and air-equilibrated end-ischemic hypothermic machine perfusion (HMP) did not induce oxidative damage to aconitase, and the integrity of the respiratory chain complexes was maintained. This suggests that mitochondria likely adapt their respiratory function in response to varying oxygen levels in the perfusate during end-ischemic HMP. Given these findings, the activities of complexes II–III warrant further investigation as potential biomarkers for viability [ 141 ].

A more exhaustive screening of the activities of TCA cycle enzymes in AD [ 142 ] revealed a heterogeneous response: some enzymes exhibited decreased activity (e.g., pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, isocitrate dehydrogenase), others showed increased activity (e.g., succinate dehydrogenase and malate dehydrogenase), while the activity of the remaining four enzymes remained unchanged (e.g., aconitase). These alterations are presumed to result in a decline in succinyl-CoA, an intermediate of the TCA cycle produced by alpha-ketoglutarate dehydrogenase and utilized in the subsequent reactions catalyzed by succinate dehydrogenase and malate dehydrogenase. Succinyl-CoA serves as a precursor for heme synthesis [ 143 , 144 ]; thus, a decrease in succinyl-CoA levels would be expected to lead to a decline in heme production [ 145 , 146 ].

Therapeutic Modalities for Mitigating Mitochondrial Dysfunction in Alzheimer’s Disease

Numerous studies have connected mitochondrial dysfunction to the etiology of AD, involving oxidative stress, faulty electron transport chain, mtDNA damage, and improper mitochondrial dysfunction (Fig.  4 ). The following section highlights potential therapeutics for AD in preclinical (catalase, N-acetylcysteine, Coenzyme Q10, melatonin, exenatide, metformin, carnosine, clove, berberine, ligstroside and oleuroside, Egb761, quercetin, dihydroxyflavone, nilotinib, rapamycin, resveratrol, Aβ3-10-KLH vaccine, and olesoxime), and clinical models (vitamin C and E, alfa-lipoic acid, thiazolidinediones, curcumin, lithium, and small peptide SS-31). Table 1 summarizes the mechanisms of proposed therapeutic modalities [ 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 147 , 148 , 149 , 150 , 151 , 152 , 153 ].

Summary of therapeutic modalities for mitigating mitochondrial dysfunction in Alzheimer’s disease. Preclinical models (catalase, N-acetylcysteine, Coenzyme Q10, melatonin, exenatide, metformin, carnosine, clove, berberine, ligstroside, and oleuroside, Egb761, quercetin, dihydroxyflavone, nilotinib, rapamycin, resveratrol, Aβ3-10-KLH vaccine and olesoxime), and clinical models (vitamin C and E, alfa-lipoic acid, thiazolidinediones, curcumin, lithium and small peptide SS-31)

Antioxidant Drugs

Vitamin c, e.

Exogenous antioxidants, such as vitamins C and E, which can reduce ROS-induced damage, are one strategy to enhance mitochondrial function and halt disease development (Fig.  5 ). Unfortunately, clinical trials have not proved these antioxidants’ usefulness since they cannot localize into mitochondria or cross the blood–brain barrier. Researchers added a novel group of naturally occurring antioxidants termed triphenylphosphonium to the mix to circumvent this barrier. This lipophilic cation boosts the efficiency of antioxidants in restoring mitochondrial health due to its capacity to localize to the negatively charged mitochondrial membrane. One example is MitoVitE, a vitamin E molecule connected to a triphenylphosphonium cation. This enables its rapid uptake into mitochondria, and it has been found to reduce mitochondrial damage induced by oxidative stress and protect against loss of mitochondrial membrane potential in rats [ 154 ]. On the other hand, individuals with AD who participated in a 1-year open clinical study received daily supplements containing 1000 mg of vitamin C and 400 IU of vitamin E. Antioxidant vitamins in cerebral fluid increased due to the treatment. However, the progression of AD was not significantly affected [ 155 ]. Furthermore, a meta-analysis of vitamin C, E, and carotene levels found that in patients with AD, vitamin E levels were considerably lower than in the control group; however, little difference was seen for vitamin C or carotene [ 156 ]. These findings suggest that increasing the intake of vitamin E–rich foods may be beneficial in preventing AD.

Reactive oxygen species (ROS)-induced mitochondrial abnormalities in Alzheimer’s disease (AD). The overproduction of ROS or an impaired antioxidant system can shift the cellular redox balance towards oxidative imbalance. ROS, generated during cellular respiration, can harm mitochondria and neuronal function. An increase in ROS can lead to a reduction in mitochondrial membrane potential (ΔΨm) and ATP generation, negatively impacting mitochondrial energy stores, disrupting energy metabolism, and compromising dynamics and mitophagy. Furthermore, ROS can increase caspase activity, initiating apoptosis. Overproduction of ROS can also inhibit phosphatase 2A (PP2A), which activates glycogen synthase kinase (GSK) 3β, leading to tau hyperphosphorylation and the accumulation of neurofibrillary tangles [ 157 ]

Catalase is an enzyme that aids in breaking hydrogen peroxide, a poisonous byproduct of cellular metabolism linked to mitochondrial malfunction and AD pathology. A study discovered that the mitochondria-targeted antioxidant catalase can prevent aberrant APP processing, lower A levels, and increase A-degrading enzymes in AD mice, showing its promise as a treatment strategy [ 158 ].

N-acetyl cysteine

N-acetyl cysteine is the primary source of glutathione, an antioxidant vital in avoiding oxidative stress and mitochondrial dysfunction. According to research on an AD animal model, N-acetyl cysteine treatment improved Aβ-induced abnormalities in mitochondria and synaptic degeneration, reduced oxidative stress, and increased mitochondrial function [ 159 ]. However, more investigation is needed to determine the ideal dosage and length of N-acetyl cysteine therapy to address mitochondrial dysfunction in patients with AD.

Coenzyme Q10 (CoQ10)

AD and other neurodegenerative illnesses may benefit from Coenzyme Q10 (CoQ10) as a treatment [ 160 ]. Although CoQ10 may have neuroprotective properties, research on in vitro and animal models has shown conflicting findings in AD clinical trials [ 160 ]. Patients with AD exhibited equivalent serum/plasma CoQ10 levels to controls, according to a comprehensive review and meta-analysis of studies evaluating tissue CoQ10 levels in patients with dementia and controls [ 161 ]. Human investigations have produced conflicting outcomes, although CoQ10 has demonstrated significant neuroprotective effects in laboratory models of AD and other dementias [ 161 ].

Alpha-lipoic Acid

Alpha-lipoic acid has been shown to have various beneficial effects on pathogenic pathways of dementia, including reducing oxidative stress, inflammation, and mitochondrial dysfunction [ 162 ]. A study investigated the impact of alpha-lipoic acid treatment (600 mg/day) on cognitive performance in patients with AD with and without diabetes mellitus and found that alpha-lipoic acid therapy may be effective in slowing cognitive decline in patients with AD with insulin resistance [ 163 ]. Furthermore, a review article suggests that alpha-lipoic acid may have potential therapeutic benefits in preventing several diseases, including AD, due to its antioxidant and anti-inflammatory properties [ 164 ].

Melatonin’s antioxidant properties and sleep–wake cycle modulation are only two of its numerous roles. Melatonin is widely known for protecting against aging, neurological ailments, and mitochondrial diseases. However, its effect on mitophagy in AD is unknown. An experiment on an AD-prone mouse model indicated that oral melatonin treatment increased mitophagy, restored mitochondrial function, decreased A pathology, and improved cognitive performance, hinting that it might be used as a therapeutic alternative for managing AD [ 165 ].

Antidiabetic Agents

Thiazolidinediones.

Thiazolidinediones are a family of insulin-sensitizing drugs that have been identified to have potential therapeutic benefits in treating AD due to their unique agonists of the gamma receptor for peroxisome proliferator (PPAR). They have also been proposed as innovative and potentially effective treatments for neurodegenerative illnesses. In preclinical studies, rosiglitazone treatment had positive effects. Rodent studies show that rosiglitazone reduces the quantity of phosphorylated tau protein, improves cognition, boosts mitochondria biogenesis, and lowers A burden [ 166 ]. Furthermore, in a Phase 2 human study, rosiglitazone-treated patients with AD (ApoE 4 non-carriers) displayed enhanced cognitive performance [ 167 ]. Advantages were not shown in later phase 3 trials [ 168 ].

GLP-1 agonists have been licensed to heal type 2 diabetes, including exenatide. It has also been postulated that these agents may have neuroprotective effects due to their impact on mitochondrial activity [ 169 ]. GLP-1 analogs have been shown to improve mitochondrial function by increasing OXPHOS activity, decreasing oxidative stress, increasing glucose uptake and utilization, and boosting mitochondrial biogenesis. Exenatide, a GLP-1 receptor agonist, has shown promise in lowering mitochondrial dysfunction and cognitive decline in 5xFAD transgenic mice, implying that it might one day be utilized to prevent mitochondrial damage in AD [ 170 ]. Furthermore, the research looked at the impact of subcutaneous liraglutide (25 nmol/kg/qd for 8 weeks) in 5 FAD mice and A-treated astrocytes. Liraglutide was discovered to increase neuronal support, reduce neuronal death, and alleviate mitochondrial dysfunction in the brain by activating the cyclic adenosine 3′,5′-monophosphate (cAMP)/phosphorylate protein kinase A (PKA) pathway. Furthermore, GLP-1 reduced mitochondrial fragmentation in A-treated astrocytes, enhanced mitochondrial failure, ROS excessive production, mitochondrial membrane potential collapse, and cell toxicity [ 171 ].

Metformin, a treatment for type 2 diabetes mellitus, has demonstrated potential in managing conditions such as AD [ 172 ]. Clinical studies have indicated that metformin is associated with enhanced cognitive function and a reduced risk of developing AD; however, these effects may be influenced by variables such as APOE-ε4 status and diabetes status [ 172 ]. Mechanistic investigations have revealed the impact of metformin on AD etiology and pathophysiology, encompassing neuronal loss, neural dysfunction, tau phosphorylation, Aβ deposition, chronic neuroinflammation, insulin resistance, altered glucose metabolism, and mitochondrial dysfunction [ 172 ]. Recent research suggests that metformin prevents mitochondrial-mediated apoptosis and diminishes the generation of ROS in mitochondrial respiratory-chain complex 1 [ 173 ]. Metformin has been shown to delay aging and mitigate the progression of aging-related diseases, including AD, by targeting critical aging-related events, such as mitochondrial dysfunction [ 174 ]. Furthermore, metformin activates SIRT1, AMPK, and Parkin while inhibiting complex 1 and mTOR activities, thereby inducing mitophagy [ 175 ]. Additionally, promising results of metformin have been observed in disease models, including increased lifespan in mice, reduced hyperphosphorylated τ in a diabetes mouse model, and reversal of AD features in APP/PS1 [ 176 ].

Acetylcholinesterase Inhibitors/NMDA-Receptor Antagonist

The only pharmacological treatments approved for AD are acetylcholinesterase inhibitors (ChEIs) and the NMDA receptor antagonist memantine [ 177 ]. Despite their seemingly modest benefits [ 178 , 179 ], a substantial body of evidence supports their efficacy in enhancing cognition and cost-effectiveness [ 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 ]. One of the earliest pathological findings in AD is the degeneration of basal forebrain cholinergic neurons, which precedes the onset of dementia [ 180 , 190 ]. The progression of AD correlates more closely with dysfunction in the cholinergic system than with the amyloid plaque load [ 191 ]. Furthermore, a reduction in the volume of the basal forebrain precedes changes in the volume of the hippocampus and predicts the cortical spread of AD pathology [ 192 ].

ChEIs function by maximizing the availability of endogenous acetylcholine in the brain [ 193 ]. However, few randomized clinical trials have investigated the efficacy of ChEIs in AD following 1 year of treatment [ 194 , 195 , 196 , 197 , 198 ] or have conducted patient follow-ups beyond this point [ 197 ]. Studies examining long-term cognitive decline are complicated due to high attrition rates and loss of follow-up [ 197 ]. Some follow-up studies of cohorts treated with ChEIs for Alzheimer’s dementia have demonstrated minor cognitive benefits at 2, 3, and over 10 years [ 199 , 200 , 201 ]. A positive short-term response to ChEIs can also delay admission to nursing homes [ 202 ].

Xu et al. [ 203 ] emphasized that ChEIs are associated with modest cognitive benefits that persist over time and with a reduced risk of mortality, which could be partially attributed to their cognitive effects. Among all ChEIs, only galantamine has demonstrated a significant reduction in the risk of progressing to severe dementia. Other studies have reported associations between the use of ChEIs and a decreased risk of myocardial infarction, stroke, and death in patients with AD [ 204 , 205 , 206 , 207 ].

Nutritional Supplements

AD is known by zinc (Zn 2+ ) dyshomeostasis with the pathological accumulation of Aβ and tau protein in the brain [ 208 ]. A study investigated the potential impact of carnosine, a dipeptide, on zinc (Zn 2+ ) chelation and AD-like cognitive deficits in 3xTg-AD mice [ 209 ]. The findings demonstrated that carnosine effectively chelates intracellular Zn 2+ and reduces intraneuronal Aβ deposition in the hippocampus. However, it was ineffective in addressing tau pathology in the brain [ 208 ]. The administration of carnosine at a concentration of 20 mM during acute and intense Zn 2+ rises allowed for examining its chelating properties [ 208 ]. The supplementation of carnosine exhibited a favorable trend towards improved cognitive performance in 3xTg-AD mice, as evidenced by the reduced latency to locate the platform [ 208 ]. The study suggests that carnosine may serve as a potential dietary supplement for mitigating intracellular Zn 2+ dyshomeostasis and intraneuronal Aβ deposition, which are significant contributors to the onset and progression of AD [ 208 ].

Natural Products

Syzygium aromaticum (clove).

Shekhar et al. [ 210 ] investigated the impact of Syzygium aromaticum (or clove) on sirtuin (SIRT1) and the oxidative balance in the context of Aβ-induced toxicity to determine whether clove could modulate the oxidative pathway. The findings revealed that clove exhibits anti-oxidative properties, which can scavenge ROS, activate SIRT1, and downregulate secretase levels [ 210 ]. These results suggest that clove may offer a holistic approach to treating neurodegenerative diseases, potentially leading to the development of innovative therapeutics for AD. Given its high oxygen radical absorbance capacity value and ability to balance Vata while stimulating nerves, clove may also serve as a potential anti-aging agent [ 211 ].

Chinese medicinal herbs, such as berberine, have a long history of use in treating various illnesses, including AD [ 212 ]. berberine has been associated with numerous neuroprotective benefits that may enhance the brain’s energy state in the early stages of AD [ 213 ]. A recent study revealed that berberine mitigates abnormalities in crucial energy and glutathione metabolism pathways in AD cells and modulates mitochondrial bioenergetics, slowing basal respiration and reducing the production of pro-inflammatory cytokines from activated microglial cells [ 214 ]. These findings suggest that berberine may benefit from disrupted metabolic pathways in the early stages of AD development [ 214 ]. Additionally, the study investigated the synergistic effects of berberine and pioglitazone, a PPAR agonist. It indicated that both drugs may have comparable potential benefits for AD, as they bind to the PPAR protein with similar affinities [ 214 ].

Ligstroside and Oleuroside

Two secoiridoids, ligstroside and oleuroside, are bioactive chemicals in olive oil [ 215 ], which may play an essential role in preventing AD due to their capacity to increase mitochondrial activity [ 216 ]. Grewal et al. studied the effects of two metabolites and ten distinct pure phenolic secoiridoids at deficient concentrations on mitochondrial activity in early AD cellular model SH-SY5Y-APP695 cells [ 149 ]. The studied secoiridoids markedly raised these cells’ baseline ATP levels. The compounds that significantly impacted ATP levels were ligstroside, oleacein, oleeuroside, and oleocanthal. They were also tested for their effects on mitochondrial respiration. The only substances that may increase the respiratory chain complexes’ capability were ligstroside and oleocanthal [ 149 ].

To investigate the underlying molecular mechanisms of these activities, qRT-PCR was utilized to assess the expression of genes associated with respiration, anti-oxidative ability, and mitochondrial biogenesis. Only ligstroside increased mRNA expression of complex I, GPx1, SIRT1, and CREB1 [ 149 ]. Additionally, oleocanthal, not ligstroside, reduced A 1–40 levels in SH-SY5Y-APP695 cells. To assess the in vivo effects of pure secoiridoid, the two most promising compounds, oleocanthal, and ligstroside, were tested in an aging mouse model [ 217 ]. Female NMRI mice were fed a diet supplemented with 50 mg/kg of ligstroside or oleocanthal for 6 months. Compared to aged control animals, mice administered with ligstroside exhibited significantly prolonged lifespan, improved spatial working memory, and restored brain ATP levels [ 149 ]. These findings indicate that pure ligstroside significantly enhances mitochondrial bioenergetics in early AD and brain aging models through pathways that may not affect A production. Furthermore, ligstroside enhances cognitive function and extends the lifespan of aged mice [ 149 ]. Therefore, ligstroside holds promise as a potential therapeutic agent for the prevention and treatment of AD.

Egb761 ( Ginkgo biloba Extract)

Flavonoids and terpenoids are among the bioactive substances found in EGb761, a standardized extract made from Ginkgo biloba leaves [ 218 ]. The possible therapeutic effects of EGb761 on brain function have been assessed in clinical studies; its impact on age-related dementias and AD has received particular attention [ 219 ].

In recent work, researchers used an in vitro cell culture model and an in vivo AD rat model to evaluate the regulation of A-induced necroptosis by EGb761 and associated roles in AD pathogenesis [ 150 ]. They showed that EGb761 may suppress the JNK signaling pathway in vitro and in vivo. This could explain why it may avoid A-induced tissue morphogenesis, cell death, and necroptosis in BV2 cells and enhance cognitive performance. These findings support the potential therapeutic effects of plant extracts like Egb761 in treating neurodegenerative illnesses like Alzheimer’s [ 150 ].

Randomized double-blind trials were carried out in the study, requiring a minimum of 22 weeks of treatment for EGb761 at a dose of 240 mg/day and 12 weeks for ChEIs or memantine [ 220 ]. The study assessed how Medicare enrollees with dementia or moderate cognitive impairment were managed clinically with amyloid PET imaging. This multisite longitudinal trial, called the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study, aimed to determine whether amyloid PET imaging was associated with changes in clinical care after that [ 220 , 221 ].

Phenylpropanoids

Phenylpropanoids are a class of natural chemicals found in plants with a wide range of biological actions [ 222 ]. Because of their anti-inflammatory, antioxidant, and neuroprotective qualities, they have been examined for their potential therapeutic implications in mitochondrial dysfunction associated with AD. Among the phenylpropanoids, quercetin and curcumin have been widely studied for their potential advantages in treating mitochondrial dysfunction in AD [ 223 ].

Quercetin, a naturally occurring flavonoid, has been demonstrated to have protective benefits in animal models of AD. It is being studied for its efficacy in treating mitochondrial dysfunction in AD [ 224 ]. Studies on the effect of quercetin on mitochondrial function have yielded promising results. Quercetin treatment boosted mitochondrial biogenesis, decreasing free radicals in neuronal SH-SY5Y cells [ 225 ]. Chronic oral quercetin therapy decreased -amyloidosis and tauopathy in a triple transgenic AD mouse model, leading to cognitive functional recovery [ 226 ]. A meta-analysis of 14 research found that quercetin had neuroprotective benefits in multiple AD models, including the potential to ameliorate mitochondrial abnormalities [ 224 ]. Moreover, a study exploring the effects of quercetin liposomes administered nasally demonstrated improved cognitive behavior and reduced oxidative stress markers in the hippocampus of an AD animal model [ 227 ].

Curcumin, a natural chemical found in turmeric, has received interest for its possible neuroprotective and cognitive-enhancing qualities in treating or preventing neurodegenerative illnesses such as AD [ 228 , 229 ]. Several studies have investigated curcumin’s potential in addressing mitochondrial dysfunction in AD. Notably, one study demonstrated curcumin’s ability to suppress Aβ-induced oxidative damage, improve memory impairment, and enhance microglial labeling near Aβ [ 229 ]. Additionally, a review article explored curcumin’s effects on cognition and proposed strategies to overcome current limitations and improve its efficacy [ 230 ]. Studies in vitro and in vivo have shown that curcumin can decrease Aβ production, inhibit Aβ aggregation, and promote Aβ clearance [ 231 ]. Its mechanism of action involves attenuating amyloid precursor protein maturation, suppressing beta-secretase 1 expression, and binding to Aβ peptides to prevent aggregation [ 232 ].

Additionally, curcumin activates the Wnt/β-catenin and PERK/eIF2/ATF4 pathways, leading to BACE-1 inhibition and accelerated Aβ clearance [ 233 ]. Moreover, a study discussed using curcumin nanoformulations as theranostic agents to optimize its pharmacokinetic properties alongside other bioactive compounds [ 234 ]. However, a systematic review evaluating the efficacy of curcumin in patients with AD, encompassing dosages ranging from 100 mg to 4 gm/day, indicated inconsistent results likely attributed to limitations such as small sample sizes and short study durations, underscoring the necessity for further research in this field [ 228 ].

The Aβ3-10-KLH vaccine has been developed as a potential treatment for AD by stimulating an immune response against Aβ [ 235 ]. This vaccine includes Aβ3-10, a fragment of the protein believed to be highly immunogenic. In a study on a mouse model of AD [ 151 ], the A3-10-KLH vaccination induced a high level of anti-A antibodies in mice, improving cognitive and learning abilities. The vaccination reduced A plaques and oligomers in the cortex and hippocampus of mice, which are areas of the brain most affected by AD [ 151 ]. Additionally, the vaccination inhibited neuron loss and apoptosis, which are significant pathogenic factors in AD. Moreover, the immunization increased the levels of Preps, a protein that may degrade A in brain mitochondria. Consequently, the A3-10-KLH vaccination shows promise as a therapy for AD, potentially enhancing cognitive performance while reducing pathogenic markers associated with the condition [ 151 ].

It has been proposed that physical activity may help enhance cognitive abilities among people with AD. According to a recent investigation conducted on APP/PS1 transgenic mice [ 236 ], high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) workouts were found to increase memory and exploratory behavior. In the Morris water maze test [ 237 ], both workouts increased navigation and swimming distance, with no significant difference between the two activities [ 236 ]. In the spatial probe test, both workouts enhanced the frequency of platform crossings and the percentage of platform quadrant distance, improving memory capacity. Furthermore, both workouts enhanced exploratory behavior in the open field test, as indicated by the number of probing, total time in the center region, and total distance in the central area. Body weight did not differ considerably across groups; however, the HIIT and MICT groups increased their exercise capacity significantly. These data demonstrate that independent of body weight, HIIT and MICT may improve cognitive performance in patients with AD [ 236 ].

Dihydroxyflavone

In a study using a rat model, it was observed that 7,8-dihydroxyflavone (7,8-DHF), a naturally occurring flavonoid present in certain plants, enhanced cognitive function and decreased neurodegeneration by mitigating oxidative stress, mitochondrial dysfunction, and insulin resistance. These findings suggest that 7,8-DHF holds promise as a potential therapeutic intervention for AD in humans. Additionally, the study demonstrated that 7,8-DHF restored cognitive impairment in a rat AD model by addressing oxidative imbalance and dysfunction of mitochondrial enzymes [ 238 ].

Rapamycin, a pharmacological agent, has emerged as a promising intervention for enhancing healthy aging and longevity in animals. Its potential use in treating mitochondrial disorders in AD has also been investigated. According to a study, rapamycin therapy increased mitochondrial activity and reduced oxidative stress in a mouse model of AD [ 239 ]. Another study revealed that even in the absence of detectable improvements in mitochondrial dysfunction, low-dose oral rapamycin was sufficient to prolong the lifespan of a mouse model with authentic mtDNA disease resulting from a mutation in the thymidine kinase 2 (TK2) [ 240 ].

Resveratrol

Grapes, apples, blueberries, plums, and peanuts produce natural non-flavonoid polyphenol resveratrol. It exists naturally as a phytoalexin [ 241 ]. Numerous bioactivities of resveratrol have been demonstrated, such as anti-aging, anti-inflammatory, cardiovascular protection, anti-cancer, anti-diabetes mellitus, anti-obesity, and neuroprotective properties [ 242 ]. In rats, resveratrol at doses of 20 and 40 mg/kg/day was beneficial in lowering the expression of pro-inflammatory markers and mitigating the memory and learning deficits caused by Aβ [ 243 ]. Rats with vascular dementia showed enhanced learning and memory when resveratrol (25 mg/kg) was given intragastrically daily. Moreover, it raised glutathione levels, superoxide dismutase activity, and malondialdehyde levels in vascular dementia-affected rats' hippocampal and cerebral cortex [ 244 ].

Lithium, a treatment for psychiatric illnesses, has been found to have the potential to treat neurodegenerative disorders, including AD, due to its neuroprotective and neurotrophic properties [ 245 ]. GSK-3β, a kinase protein implicated in multiple physiological processes related to neurodegeneration, is selectively inhibited by lithium. Its inhibitory action on GSK-3β has been demonstrated to lessen Aβ generation, stop tau phosphorylation, and make it easier to induce long-term potentiation in AD-affected mice [ 152 ]. Human studies have also shown a substantial positive correlation between long-term lithium medication and a lower incidence of dementia in elderly bipolar illness patients [ 246 ]. Additionally, long-term subtherapeutic lithium medication has raised levels of brain-derived neurotrophic factor, lowered AD-related CSF fluid biomarkers [ 247 ], and slowed the deterioration in cognitive and functional abilities in patients with amnestic mild cognitive impairment [ 248 ]. The neuroprotective mechanisms of lithium may also be related to its regulation of energy metabolism and mitochondrial efficiency, including the activation of the Wnt signaling pathway [ 249 ].

Small Peptide SS-31

SS-31, a mitochondrial peptide, has shown promise as a possible therapy for AD [ 250 ]. The peptide belongs to the Szeto-Schiller family of tiny cell-permeable peptides and binds to the inner mitochondrial membrane without requiring mitochondrial membrane potential or energy [ 251 ]. Elamipretide, MTP-131, and Bendavia are the brand names for these drugs. SS-31 is more effective than standard antioxidants like vitamin E [ 153 ]. It inhibits oxidative stress and restores normal mitochondrial function. Mitochondria oversee glucose homeostasis, and mitochondrial failure is linked to oxidative stress and malfunction. These have been connected to the development of metabolic and neurological diseases. The usage of MT-targeted drugs like SS-31 can aid in the reduction of oxidative stress and mitochondrial damage [ 251 ]. SS-31 has been found to have neuroprotective effects by protecting the synapses, reducing Aβ accumulation, and preventing mitochondrial dysfunction [ 250 ]. The peptide has shown promise in preclinical studies for treating AD, indicating its potential as a novel therapeutic agent.

Olesoxime (TRO19622) is a medication tested in AD animal models to see how it affects mitochondrial dysfunction and amyloid precursor protein processing [ 252 ]. TRO19622 was given to 3-month-old mice with AD-like features and wild-type mice for 15 weeks in research [ 148 ]. In dissociated brain cells and brain tissue homogenates, the drug’s effects on mitochondrial membrane potential, adenosine triphosphate levels, respiration, citrate synthase activity, Aβ levels, and malondialdehyde levels were studied. The results showed that TRO19622 alleviated mitochondrial dysfunction by increasing respiratory chain complex activity and reversing complex IV activity and mitochondrial membrane potential [ 148 ]. Furthermore, the medication protected dissociated brain cells against complex I activity inhibition. TRO19622, on the other hand, was shown to enhance the levels of A1-40 in the brains of mice and HEKsw cells. This study reveals that while TRO19622 may have mitochondrial advantages, the increased production of A1-40 may have negative consequences. More studies are needed to determine TRO19622’s potential as a feasible therapy for AD [ 148 ].

Future Research Directions and Potential Roadblocks

The development of therapeutic drugs that specifically target mitochondrial dysfunction is an increasing focus in AD management. An ideal drug may enhance mitochondrial function, reduce oxidative stress, and prevent neuronal death [ 157 , 253 ]. We have highlighted the latest scientific progress toward developing such medications in Table  2 . However, the development of formulations targeting mitochondria faces explicitly numerous challenges.

First, the precise mechanisms of action of these drugs are still not fully understood, and further research is needed to elucidate these mechanisms and optimize the efficacy of these drugs, particularly those with promising results in preclinical models such as CoQ10 [ 161 ], melatonin [ 165 ], olesoxime [ 148 ], SS-31 [ 250 , 251 ], lithium [ 152 , 245 , 248 , 249 ], vaccines [ 151 , 235 ], berberine, and pioglitazone [ 212 , 213 , 214 ].

Second, there is difficulty in diagnosing the extent of mitochondrial functioning and dysfunction and determining the drug dose required to produce the desired modulation in mitochondrial functioning [ 77 , 254 , 255 ]. Available AD diagnosis includes cognitive testing, imaging of Aβ and tau pathology in various brain parts, and cerebrospinal fluid assays [ 256 ]. However, these techniques have disadvantages, including limited availability, high cost, and invasive procedures employed with their results and integrity under question. Technological advancement has led to researchers speculating novel biomarkers involved in the disorder’s pathogenesis, such as 5-methylcytosine levels in patients with late-onset AD [ 112 , 113 ], complexes II–III in ETC, and Krebs cycle [ 141 ] and mtDNA [ 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 ]. Developing mitochondrial biomarkers could be an excellent approach, as mitochondrial functions are standard in various cell types and present in sporadic and familial AD. However, identifying common metabolic deficits in most AD patients is undoubtedly required before producing the mitochondrial function as a clinically useful biomarker.

Third, achieve tissue selectivity for the drug to reach mitochondria by penetrating the blood–brain barrier to minimize other side effects. Some proposed ways to attain this include selective activation of pro-drug by enzymes, combined delivery of more than one active compound targeting mitochondria that react with each other after reaching mitochondria, or radiotherapeutic approaches [ 255 , 257 , 258 ].

Understanding mitochondrial function in AD is challenging due to the complex nature of the mitochondrial network and its interactions with other cellular components. Some therapeutic modalities have shown promising results in preclinical models, including antioxidants, CoQ10, melatonin, olesoxime, small peptide SS-31, lithium, vaccines, berberine, and pioglitazone. However, it is crucial to acknowledge that current animal and human cell models do not fully replicate AD or the complexity of the human brain. Furthermore, AD’s varied potential causes and progression paths add another layer of complexity to the research. Future work should prioritize understanding the progression of AD and the mitochondria-associated biomarkers at each stage. This knowledge can then be used to develop formulations targeting these biomarkers in mitochondria while optimizing tissue selectivity. Meanwhile, it is essential to optimize the use of current FDA-approved medications to manage the symptoms of AD, tailoring them to the specific needs of patients.

Data Availability

No datasets were generated or analysed during the current study.

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Acknowledgements

Mohamed Abouzid is a participant of STER Internationalization of Doctoral Schools Program from NAWA Polish National Agency for Academic Exchange No. PPI/STE/2020/1/00014/DEC/02.

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Faculty of Pharmacy, Clinical Department, Alexandria Main University Hospital, Alexandria, Egypt

Mostafa Hossam El Din Moawad

Faculty of Medicine, Suez Canal University, Ismailia, Egypt

Faculty of Medicine, Mansoura University, Mansoura, Egypt

Ibrahim Serag

Faculty of Medicine, Mutah University, Al-Karak, Jordan

Ibraheem M. Alkhawaldeh

Faculty of Medicine, Al-Azhar University, Damietta, Egypt

Abdallah Abbas

Department of Clinical Pharmacy, Salmaniya Medical Complex, Government Hospital, Manama, Bahrain

Abdulrahman Sharaf

Ministry of Health, Primary Care, Governmental Health Centers, Manama, Bahrain

Sumaya Alsalah

Misr University for Science and Technology, 6th of October City, Egypt

Mohammed Ahmed Sadeq

Faculty of Medicine, Ain Shams University, Cairo, Egypt

Mahmoud Mohamed Mohamed Shalaby

Faculty of Medicine, Zagazig University, Zagazig, Egypt

Mahmoud Tarek Hefnawy

Department of Physical Pharmacy and Pharmacokinetics, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3 St., 60-806, Poznan, Poland

Mohamed Abouzid

Doctoral School, Poznan University of Medical Sciences, 60-812, Poznan, Poland

Department of Neurology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

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Conceptualization; writing—original draft; writing—review and editing: Mostafa Hossam El Din Moawad, Ibrahim Serag, Ibraheem M Alkhawaldeh, Abdallah Abbas, Abdulrahman Sharaf, Sumaya Alsalah, Mohammed Ahmed Sadeq, Mahmoud Mohamed Mohamed Shalaby, Mahmoud Tarek Hefnawy, Mostafa Meshref, and Mohamed Abouzid.

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Moawad, M.H.E.D., Serag, I., Alkhawaldeh, I.M. et al. Exploring the Mechanisms and Therapeutic Approaches of Mitochondrial Dysfunction in Alzheimer’s Disease: An Educational Literature Review. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04468-y

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Received : 30 January 2024

Accepted : 30 August 2024

Published : 10 September 2024

DOI : https://doi.org/10.1007/s12035-024-04468-y

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