Frequency of serious adverse events and death in 5-17 months children receiving RTS,S/AS01E vaccine - a systematic review and meta-analysis of RCTs.

Frequency of serious adverse events and death in 5-17 months children receiving RTS,S/AS01E vaccine - a systematic review and meta-analysis of RCTs. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Frequency of serious adverse events and death in 5-17 months children receiving RTS,S/AS01E vaccine - a systematic review and meta-analysis of RCTs. Alexis Zoa Bindzi, Rachi-metou Njemguie Linjouom, Martin Nyangono Ndongo, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3975532/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The RTS,S/AS01E vaccine has been authorized for use in children in sub-Saharan Africa from the age of 5 months. Nevertheless, there is a limited number of clinical studies documenting serious adverse events (SAEs) and their correlation with the vaccine. This systematic review and meta-analysis aimed to analyze and summarize the data published to date on the primary serious adverse events (SAEs) associated with the RTS,S/AS01E malaria vaccine in children aged 5–17 months. Methods The systematic review adhered to the PRISMA 2020 guidelines. An extensive search was conducted across multiple databases, including PubMed, Cochrane Library, Wiley Online Library, and Web of Science, without any restrictions on publication year and language. The final search of databases and registries was completed on January 23, 2024. Randomized clinical trials (RCTs) related to SAEs of RTS,S/AS01E in children aged 5–17 months, for 0, 1, 2-schedule, were included in the study. The primary outcomes focused on the proportions of SAEs and deaths in RTS,S/AS01E vaccine recipients. Pooled effect size estimates and their 95% confidence intervals were obtained through random-effect models meta-analysis. Publication bias among included studies was evaluated using the "risk of bias assessment" tool from the Cochrane systematic review. Outcomes were tested for significance using Z tests. Results This meta-analysis comprised 10 studies and 30,573 children (19,769 recipients of RTS,S/AS01E and 10,804 control recipients). The combined frequency of all SAEs was 17.6% (95% CI: [15.3, 20.2]) among RTS,S/AS01E recipients, which was significantly lower than the combined frequency of 22% (95% CI: [0.204, 0.237]) observed in the control group, with a combined risk ratio (RR) of 0.80 (95% CI: [0.72, 0.90], P = 0.0002). The combined frequency of all deaths was 1% (95% CI: [08, 1.2], P < 0.0001) among RTS,S/AS01E recipients, which was not significantly higher than the combined frequency of 0.7% (95% CI: [0.3, 1.7]) observed in the control group, with a combined RR of 1.04 (95% CI: [0.77, 1.41], P = 0.79. Throughout the follow-up period, the frequently reported SAEs were as follows: severe malaria (25.9% and 44.6%), pneumonia (31.5% and 27.5%), gastroenteritis (14.8% and 15.1%), anemia (16.7% and 19.4%), and febrile convulsions (26.5% and 23.3%) in the RTS,S/AS01E and control groups, respectively. The corresponding odds ratios (ORs) were as follows: severe malaria 0.47 (95% CI: [0.29, 0.76], P = 0.002), pneumonia 1.19 (95% CI: [0.98, 1.45], P = 0.07), gastroenteritis 0.99 (95% CI: [0.65, 152], P = 0.97), anemia 0.70 (95% CI: [0.33–1.47], P = 0.34), and febrile convulsions 1.26 (95% CI: [1.00, 1.59], P = 0.005). Conclusions The occurrence of major serious adverse events (SAEs) with the RTS vaccine is rare, and their frequency does not seem to differ from that in unvaccinated children. As a result, there were no significant major side effects associated with the vaccine. However, additional long-term data is required. Trial registration CRD42024321008 / PROSPERO. RTS S/AS01E serious adverse events clinical trials Africa meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Malaria represents a substantial global burden of infectious disease. The World Health Organization (WHO) documented over 249 million cases of malaria and 608,000 malaria-related fatalities in 2022 [ 1 ], with 76.8% of these deaths happening in children under 5 years of age. Among the four primary malaria-causing agents in humans, Plasmodium falciparum is the deadliest and accounts for the most prevalent infection in Africa [ 2 ]. Current malaria control measures, largely based on chemoprevention and vector control, have led to a modest reduction in the malaria death rate [ 3 ]. These measures are facing P. falciparum and Anopheles resistance. Resistance to artemisinin, one of the key components of recommended first-line antimalarial treatments, has been reported in five countries in Southeast Asia [ 4 ]. The spread of this resistance to Africa could have serious consequences for public health. The ongoing high number of clinical cases, fatalities and resistance could justify why both national and international health authorities persist in prioritizing the implementation of malaria vaccines [ 5 , 6 ]. The perfect malaria vaccine would confer immunity against the parasite upon entry into the body, prior to liver infection, thereby reducing the onset of clinical disease and averting hepatocellular damage [ 7 ]. The brief duration of the parasite's initial entry stage in the life cycle (~ 30 minutes) means that immune responses are not swift enough to hinder infection. While focusing on the post-hepatic stage may seem more practical, it would not prevent liver infection and the resulting damage to hepatocytes. Given these constraints, a viable alternative would involve targeting the parasite during both the pre-hepatic and hepatic stages to prevent clinical disease. In early 2001, GlaxoSmithKline (GSK) and PATH joined forces to create the RTS,S vaccine as a preventive measure against clinical disease caused by P. falciparum for infants and children living in endemic areas [ 8 ]. The RTS,S/AS01E malaria vaccine targets the pre-erythrocytic stage of the parasite [ 9 ]. The vaccine is composed of a recombinant viral pseudoparticle-forming protein known as RTS,S, along with the patented AS01E adjuvant system. The RTS,S antigen is a fusion protein containing a segment of the P. falciparum circumsporozoite protein (CSP) and the hepatitis B virus surface antigen (HBsAg), which is also found in licensed hepatitis B vaccines. To stabilize the recombinant particles, the fusion protein is co-expressed with the HBsAg (S) protein in Saccharomyces cerevisiae [ 10 , 11 ]. AS01E comprises 3-O-desacyl-4'-monophosphoryl-lipid-A (MPL; produced by GSK), QS-21 (Quillaja saponaria Molina, fraction 21; licensed by GSK from Antigenics Inc., a wholly-owned subsidiary of Agenus Inc. of Delaware, USA), and liposomes. The RTS,S/AS01E vaccine is presented in two separate preservative-free vials, one containing lyophilized RTS,S powder and the other containing AS01E suspension [ 12 ]. The final vaccine is prepared by reconstituting the powder with the suspension to yield 1mL of opalescent, colorless to pale-brown liquid. A single dose of the vaccine is obtained by withdrawing 0.5mL from the vial after reconstitution. Each dose contains 25µg of RTS,S antigen, along with 25µg of each of the immunomodulatory molecules MPL and QS21 [ 13 ]. The vaccine is administered via intramuscular injection. The GSK RTS,S vaccine (Mosquirix™) is the first malaria vaccine to progress to Phase 3 trials. WHO recommended its use in children aged 5 to 17 months in a series of pilot projects using a 4-dose regimen (3 initial doses at least 4 weeks apart, preferably administered before 9 months, followed by a 4th dose administered 15 to 18 months after the 3rd dose) in areas with moderate to high malaria transmission [ 14 , 15 ]. The rationale for this decision is supported by data from phase 1 to phase 3 trials and a continuous pilot malaria vaccine implementation program (MVIP) initiated in 2019 in Ghana, Kenya, and Malawi [ 6 , 16 ]. It has been estimated that three doses of the RTS,S vaccine could prevent approximately 93,940 cases of clinical disease and 394 deaths per 100,000 children under 5 years of age [ 17 ]. Despite these results, there have been concerns about the incidence of serious adverse events (SAEs) and deaths in real-world settings [ 16 ]. These results have not been synthesized, and their association with the vaccine has not yet been proven, hence the current study. 2. Methods This systematic review and meta-analysis followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) reporting guideline [18]. The study protocol is registred under the protocol ID CRD42024321008/PROSPERO. 2.1. Search strategy We conducted a literature search on January 23, 2024, using PubMed, Cochrane Library, Wiley Online Library, and the Web of Science databases. Additional records were identified through citation searching. An example of our search strategy in PubMed and the Web of Science database is provided in Table 1. We utilized the following keywords: ("RTS,S/AS01" OR "RTSS/AS01") AND ("safety" OR "serious adverse events" OR "SAE"). 2.2. Inclusion criteria: The criteria for eligible studies included the following: (P) Population : Male and female children aged 5-17 months at the time of the first vaccination and residing in malaria-endemic areas in Sub-Saharan Africa. (I) Intervention : Male and female children aged 5-17 months who received the RTS,S/AS01E vaccine (MosquirixTM) according to the 0–1–2 months vaccination schedule. (C) Comparison : Male and female children aged 5-17 months who received the Rabies vaccine (Verorab) or Expanded Programme on Immunization (EPI) vaccines. (O) Outcomes : The proportions of overall SAEs and deaths. The proportion of frequently reported SAEs from the time of first vaccination throughout the study period. SAEs refer to significant, severe, or life-threatening medical occurrences or conditions that participants may experience after receiving the vaccine. These events go beyond the expected side effects and pose a substantial risk to the health and well-being of the individuals involved [19]. (S) Study design : Randomized controlled/clinical trials (RCTs). 2.3. Exclusion criteria: We excluded studies according to the following criteria: (I) duplicated publications; (II) letters, reviews, case reports, communication and expert opinions; (III) animal studies, basic research and non-RCTs studies; (IV) studies without sufficient data to estimate the risk ratios (RRs), odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). 2.4. Data extraction: We extracted the following items: name of the first author, published year, country, follow-up time, Phase, mean age, proportions of SAEs and number of deaths. The data extraction was independently evaluated by three investigators (Zoa, Njemguie and Longxiang), and a consensus was reached by group discussion when the disagreement occurred. 2.5. Assessment of the Risk of Bias in the included studies: The authors, Zoa and Nyangono, evaluated the quality of the literature included in this study using the "risk of bias assessment" tool from the Cochrane systematic review [20]. The assessment criteria encompass the following seven areas: generation of randomized sequences, allocation concealment, blinding of investigators and subjects, blinding of outcome evaluators, completeness of outcome information, selective reporting of study results and other sources of bias. Each item can be described as "low risk of bias", "high risk of bias", or "unclear risk". Eventually, the evaluations mentioned above were combined to create a risk of bias assessment map and quality outcomes for each piece of literature. If there is a disagreement between the two researchers, a third researcher (Nkeck) conducted an independent assessment, and the final assessment was determined through mutual agreement among all three researchers. 2.6. Data analysis: Due to the clinical variations among the children included in the studies, such as differences in outcome definition, clinical presentation, and potential misclassification of positive and negative outcomes, a random-effects meta-analysis was utilized to pool effect sizes (frequency, RR, and OR) [21]. The Mantel-Haenszel method was employed for the meta-analysis of RR and OR. RR was defined as the risk of experiencing serious adverse events (SAEs) from the malaria vaccine, while OR was defined as the odds of experiencing a specific SAE after receiving the malaria vaccine RTS,S/AS01E [22]. Heterogeneity across studies was assessed using a χ2-based test. The I2 statistic, a quantitative measure of inconsistency across studies, was also calculated [23]. In cases of significant heterogeneity (I2>50% or P<0.05), the random effects model was employed for the meta-analysis. Otherwise, a fixed effects model was adopted. All analyses were conducted using Review Manager (RevMan) version 5.4.1 (The Cochrane Collaboration, 2020) for RR and OR, and Comprehensive Meta-analysis Software V3 for pooled frequency. All statistical tests were two-sided. 2.7. Sensitivity analyses After calculating the crude overall pooled frequency of all serious adverse events (SAEs) and deaths in children with RTS,S/AS01E, we conducted sensitivity analyses that included only studies reporting proportions of main SAEs to assess the robustness of our findings. An odds ratio (OR) greater than 1 indicates an increased likelihood of a specific SAE in the RTS,S/AS01E group compared to the control group. The significance of the pooled risk ratio (RR) and OR was determined using the Z test, with a P value <0.05 considered statistically significant. 3. Results 3.1. Study selection and characteristics A flow diagram showing our literature search and screening strategy is presented in Figure 1. We initially obtained 161 articles, among which 157 from databases records and 4 from citations searching. After removing 39 duplicates, we screened 122 records by reading the abstracts. We removed 43 letters, reviews, case reports and communications, 18 animal studies/basic research, and 16 non-RCTs studies. We evaluated 45 full-text articles for eligibility, and finally, we included 10 articles with 30,573 children (19,769 RTS,S/AS01E recipients and 10,804 control recipients) in the meta-analysis [16,24–32]. The included studies were published between 2008 and 2020. 9,396 of 30,573 (17.56%) patients were from Kenya, 4968 (16.25%) from Ghana, 4832 (15.81%) from Tanzania, 3938 (12.88%) from Gabon, 3823 (12.5%) from Mozambique, 3823 (12.5%) from Burkina-Faso and 3823 (12.5%) from Malawi. Nine studies used Rabies vaccine (Verorab) as control [16,24,25,27–32], and one study used EPI vaccines as control [26]. The participants were children from 5-17 months in all the studies. Seven of ten studies provided information on the number of children who died during the study [16,24,25,27,29,30,32]. six of ten provided the frequency of the main SAEs [25–27,29–31]. Further detailed descriptions of these eligible articles are listed in the table 2. 3.2. Meta-analysis Ten studies provided sufficient data to estimate the combined incidence of all SAEs and their relative risks (RRs) [16,24–32], while seven studies had enough data to estimate the combined incidence for all deaths and their corresponding RRs [16,24,25,27,29,30,32]. 3.2.1. Combined incidence of all SAEs and death in RTS,S/AS01E and control groups The pooled frequency of all SAEs among children who received RTS,S/AS01E was 17.6% (10 studies, 19,769 children, 95% CI: [15.3, 20.2], P <0.0001), and 22.0% (10 studies, 10,804 children, 95% CI: [20.4, 23.7], P <0.0001) in the control group. The pooled frequency of all deaths in children receiving RTS,S/AS01E was 1% (7 studies, 18,929 children, 95% CI: [0.8, 1.2]), while the pooled frequency of all deaths in controls was 0.7% (7 studies, 9,962 children 95% CI: [0.3, 1.7]). The table 3 summarizes parameters relative to the pooled frequency of overall SAEs and death in malaria vaccine and control groups. 3.2.2. Comparison of the incidence of SAEs and death in children receiving RTS,S/AS01E and controls We employed a random effect model to calculate the RR and 95% CI for both SAEs and death due to statistical heterogeneity (I 2 =71% and P =0.77 respectively). The findings revealed that the children in RTS,S/AS01E group had a significant reduced risk of SAEs (10 studies, 30,573 children, RR = 0.80, 95% CI: [0.72, 0.90], P =0.0002, fig. 2), but a non-significant increased risk of death (7 studies, 18929 children, RR = 1.04, 95% CI: [0.77, 1.41], P =0.79, fig. 3) compared to control. 3.2.3. Incidence of the mains SAEs Due to significant heterogeneity, we performed subgroup analyses (by main SAEs). Four studies had enough data to estimate the pooled frequency and corresponding ORs for severe malaria, pneumonia, gastroenteritis and anemia [27,29–31]. Three studies had enough data to estimate the pooled frequency and corresponding ORs for febrile convulsions [27,30,31]. The pooled frequencies of the main SAEs were as follow: severe malaria (25.9% and 44.6%), pneumonia (31.5% and 27.5%), gastroenteritis (14.8% and 15.1%), anemia (16.7% and 19.4%), and febrile convulsions (26.5% and 23.3%) in RTS,S/AS01E and control groups respectively. Table 3 summarize information relative to the pooled frequency of the main SAEs in malaria vaccine and control groups. 3.2.4. Comparison of the frequencies of the main SAEs in children receiving RTS,S/AS01E and controls We used a random effect model to calculate the ORs and 95% CIs for the main SAEs due to statistical heterogeneity (I 2 >50 or P >0.05). The results indicated that children in the RTS,S/AS01E group exhibited significantly reduced odds of severe malaria (4 studies, 1238 children, OR = 0.47, 95% CI: [0.29, 0.76], P=0.002), and febrile convulsions (3 studies, 1199 children, OR = 1.26, 95% CI: [1.00, 1.59], P=0.005) compared to the control group. However, there was a non-significant increase in the Odds of pneumonia (4 studies, 1238 children, OR = 1.19, 95% CI: [0.98, 1.45], P=0.07), gastroenteritis (4 studies, 1238 children, OR = 0.99, 95% CI: [0.65, 152]), anemia (4 studies, 1238 children, OR = 0.70, 95% CI: [0.33-1.47], P=0.34), and death (7 studies, 18929 children, RR = 1.04, 95% CI: [0.77, 1.41], P=0.79, fig. 4) compared to the control group. 3.3. Assessment of publication bias The included studies underwent a thorough quality assessment. One study exhibited a high risk of bias in terms of blinding of participants and personnel [25]. Another study showed a high risk of selective reporting [28]. Additionally, four studies did not provide data on the proportions of various serious adverse events (SAEs), resulting in an unclear risk of bias [16,24,28,29]. However, overall, all of the selected studies demonstrated low risks of selection, performance, detection, and reporting biases due to the proper execution of these randomized controlled trials (RCTs) [16,24–32], which encompassed the randomization process, deviations from the intended interventions, measurement of the outcome data, gaps in the outcome analysis, and reported result selection. In conclusion, the included studies exhibited high methodological quality and a low likelihood of bias (Figure 5). 4. Discussion For an extended period, the exclusive methods for malaria prevention in Africa and globally encompassed antimalarial drugs (including seasonal chemoprophylaxis and intermittent preventive treatment during pregnancy) and vector control [ 5 , 33 ]. They led to a modest decrease in the malaria-related mortality rate; however, malaria continues to be the fourth leading cause of death among children under 5 years of age in sub-Saharan Africa [ 3 ]. Faced with this scenario, the World Health Organization (WHO), in collaboration with national and international health authorities, embarked on the development of a vaccine. The RTS,S/AS01E was the initial vaccine to enter phase 3 trial conducted in two age-groups (6–12 weeks and 5–17 months), and was approved for use in children in 2021 [ 1 ]. The Malaria Vaccine Implementation Program (MVIP) was thus developed, planned, and launched to facilitate the distribution of RTS,S/AS01E through regular immunization programs, and to gather evidence on its safety, effectiveness, and operational feasibility in routine use in Ghana, Malawi, and Kenya [ 6 ]. This prompted the WHO to expand the vaccination program to additional countries in sub-Saharan Africa, facilitated by the donation of 18 million doses [ 34 ]. Today, over 2 million children in Africa have received this vaccine. The doubts regarding the effectiveness and safety of this vaccination within the African population prompted the current study, which aimed to summarize and analyze the frequency of serious adverse events (SAEs) and mortality in children aged 5–17 months. A meta-analysis of 30,573 children from 10 studies was conducted [ 16 , 24 – 32 ]. The findings indicated that children who received the RTS,S/AS01E vaccine had a combine incidence of 17.6% with reduced risk (RR = 0.8) of experiencing SAEs compared to those who did not. This outcome aligns with the conclusions of multiple authors [ 26 , 27 , 30 ] who observed a higher incidence of SAEs in children who were not administered RTS,S/AS01E. There might be multiple explanations for this phenomenon: at this stage of development, the immune system may not be fully competent, and the malaria vaccine works to enhance it by generating anti-CSP antibodies. Another factor could be adherence to vector control measures (such as long-lasting insecticidal mosquito nets, etc.) following vaccination. We also sought to examine the occurrence of mortality in each of these studies. Initially, we observed that few studies provided data on the number of children who had died [ 16 , 24 , 25 , 27 , 29 , 30 , 32 ]. However, among the included studies, we determined that there was no significant difference in the incidence of death between those who received malaria vaccine and those who did not (Fig. 2). This aligns with the conclusions of several authors who suggested that mortality and serious adverse events (SAEs) were not necessarily linked to vaccine administration [ 28 , 35 , 36 ]. We conducted a subgroup analysis based on the type of serious adverse events (SAEs) and discovered that Plasmodium falciparum infection was more prevalent in children with malaria vaccine than in those without. This supports the overall findings regarding the incidence of SAEs. This observation could be explained by the fact that vaccinated children are protected and experience fewer malaria cases, thus demonstrating the efficacy of the vaccine in these children [ 31 ]. Recent studies have indicated that the vaccine effectiveness (VE) of RTS,S/AS01E is over 45% two years after the final dose [ 6 , 37 ]. Additionally, other effects such as pneumonia, gastroenteritis, febrile convulsions, anemia, and upper respiratory infections were present, but did not reach statistical significance. 5. Conclusion Despite the effectiveness and safety of the RTS,S/AS01E malaria vaccine, it would have been necessary to conduct clinical studies on a larger population before its widespread use, due to the potential risk of death, which although not significant, remains present. We regret the insufficiency of data on deaths, which could have enhanced the depth and discussion of this work. Additionally, we advocate for studies to be conducted across various regions in Africa (western, central, southern, northern, etc.) and among different continents to facilitate a comprehensive analysis of genetic diversity and environmental factors. Malaria continues to be a disease associated with unsanitary conditions, and it is essential to always integrate the use of vaccines with environmental sanitation measures, which have been instrumental in eradicating the disease in developed countries such as the USA, China, Germany, South Africa, etc… Abbreviations SAEs serious adverse events PRISMA preferred reporting items for systematic review and meta-analysis MVIP malaria vaccine implementation program RR risk ratio OR odds ratio CI confidence interval CSP circumsporozoite protein MPLA monophosphoryl-lipid-A GSK glaxosmithkline. Declarations Acknowledgements None Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interest "The authors declare that they have no competing interests" Funding This work was supported by grants from the National Natural Science Foundation of China (No. 82360573) and the Innovation Project of Gannan Medical University (No. TD201703). Authors' contributions: (I) Conception and design: Z.B.A., N.L.R., Y.L.X.; (II) Administrative support: N.N.M., L.X.P., T.Y.T; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: Z.B.A., N.L.R., N.J.R, Z.J.; (V) Data analysis and interpretation: Z.B.A., N.L.R., L.X.P., N.J.R., T.Y.T.; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors References WHO. World malaria report 2023 [Internet]. World Health Organization. 2023. 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Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5–17 months in Kenya and Tanzania: a randomised controlled trial. Lancet Infect Dis. 2011;11(2):102–9. Agnandji ST, Lell B, Soulanoudjingar SS, Fernandes JF, Abossolo BP, Conzelmann C, et al. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med. 2011;365(20):1863–75. Minsoko PA, Bertrand L, Fernandes JF, Abossolo BP, Kabwende AL. Efficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites. PLoS Med. 2014;11(7):e1001685. Olotu A, Fegan G, Wambua J, Nyangweso G, Leach A, Lievens M, et al. Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children. N Engl J Med. 2016;374(26):2519–29. Otieno L, Guerra Mendoza Y, Adjei S, Agbenyega T, Agnandji ST, Aide P, et al. Safety and immunogenicity of the RTS,S/AS01 malaria vaccine in infants and children identified as HIV-infected during a randomized trial in sub-Saharan Africa. Vaccine. 2020;38(4):897–906. Chandramohan D, Zongo I, Sagara I, Cairns M, Yerbanga R-S, Diarra M, et al. Seasonal Malaria Vaccination with or without Seasonal Malaria Chemoprevention. N Engl J Med. 2021;385(11):1005–17. WHO. 18 million doses of first-ever malaria vaccine allocated to 12 African countries for 2023–2025: Gavi, WHO and UNICEF [Internet]. World Health Organization. 2023. Available from: https://www.who.int/news/item/05-07-2023-18-million-doses-of-first-ever-malaria-vaccine-allocated-to-12-african-countries-for-2023-2025--gavi--who-and-unicef . Asante KP, Abdulla S, Agnandji S, Lyimo J, Vekemans J, Soulanoudjingar S, et al. Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial. Lancet Infect Dis. 2011;11(10):741–9. Witte D, Cunliffe NA, Turner AM, Ngulube E, Ofori-Anyinam O, Vekemans J, et al. Safety and Immunogenicity of Seven Dosing Regimens of the Candidate RTS,S/AS01E Malaria Vaccine Integrated Within an Expanded Program on Immunization Regimen: A Phase II, Single-Center, Open, Controlled Trial in Infants in Malawi. Pediatr Infect Dis J. 2018;37(5):483–91. Vandoolaeghe P, Schuerman L. [The RTS,S/AS01 malaria vaccine in children aged 5–17 months at first vaccination]. Pan Afr Med J. 2018;30:142. Tables Table 1: Literature search strategy for Pubmed and Web of Science databases SEARCH TERMS RESULTS Pubmed Web of Science #1 "RTS,S/AS01" OR "RTSS/AS01" 273 268 #2 "safety" OR "serious adverse events" OR "SAE" 928,132 958,748 #1AND#2 61 96 Search update: 1/23/2024 Table 2: Characteristics of RCTs for 0,1,2-month groups First Author, Year Location Trial Period Follow-Up (Months) Phases Mean age±SD (Months) Sample Size Overall SAEs (%) Overall Deaths SAEs (RTS:Ctrl) RTS Ctrl RTS Ctrl RTS Ctrl Bejon, 2008 Kenya Tanzania 2007/3 - 2007/8 7.9 IIB 11.3 447 447 10.5 18.3 1 0 N/R Owusu-Agyei, 2009 Ghana 2006/8 - 2008/5 10 II 11 ± 3.5 90 45 14.4 13.33 0 1 Severe malaria (0:1) Lusingu, 2010 Kenya Tanzania 2007/3 - 2007/8 14 IIB 11.4 ± 3.5 447 447 22.9 21 1 1 Pneumonia (16:26) Febrile convulsion (14:20) severe malaria (9:31) Gastroenteritis (10:22) Anemia (5:2) Agnandji, 2010* Ghana Tanzania Gabon 2009/5 - 2011/2 8 II N/R 170 171 11.4 19.6 N/R N/R Anemia (6/14) Gastroenteritis (19/14) Pneumonia (11/10) Severe malaria (5/16) Olotu, 2011 Ghana Tanzania 2007/3 - 2008/10 18 IIB N/R 447 447 11.4 22.7 N/R N/R Pneumonia (N/R) Febrile Convulsion (N/R) Gastroenteritis (N/R) Severe malaria (N/R) RTS,S Clinical Trials Partnership, 2011 Burkina Faso Gabon Ghana Kenya Malawi Mozambique Tanzanie 2009/3 - 2011/1 18 III N/R 5949 2974 17.6 21.6 56 28 Seizure (7/1) Meningitis (11/1) RTS,S Clinical Trials Partnership, 2014 Burkina Faso Gabon Ghana Kenya Malawi Mozambique Tanzanie 2009/3 - 2011/1 20 III N/R 5949 2974 18.6 22.7 1 2 Anemia (190/155) Enteritis (21/12) Meningitis (9/1) Pneumonia (353/189) Severe malaria (400/313) Febrile Convulsion (224/112) RTS,S Clinical Trials Partnership, 2015 Burkina Faso Gabon Ghana Kenya Malawi Mozambique Tanzanie 2009/3 - 2011/1 18 III 10.6 5948 2974 22 23.1 59 26 N/R Olotu, 2016 Kenya 2007/3 - 2014/11 24 II 11 ± 3.6 223 224 17.9 25.4 N/R N/R Anemia (5/12) Gastroenteritis (7/12) Severe malaria (14/30) Pneumonia (9/10) Febrile convulsion (15/20) Otieno, 2016 Kenya 2010/7 - 2013/05 14 III 9.5 99 101 41.4 36.6 5 4 Pneumonia (N/R) Febrile convulsions (N/R) RTS: RTS,S/AS01E, Ctrl: Rabies or EPI vaccine, SAEs: serious adverse events, EPI: Expanded Programme on Immunization, N/R: not reported. * WHO Stage 1,2 HIV disease Table 3 : Sample size, proportion and corresponding 95% CIs of the overall SAEs and death in RTS,S/AS01E and Control groups Overall Parameters Groups RTS,S/AS01E Control SAEs Sample size 19769 10804 Proportion (%) 17.6 22.0 95% CI 15.3-20.2 20.4-23.7 P-value <0.0001 <0.0001 I 2 Inconsistency 93.28% 62.24% Egger's test P = 0.5030 P = 0.8083 Death Sample size 18929 9962 Proportion (%) 1 0.7 95% CI 0.8-1.2 0.3-1.7 P-value <0.0001 <0.0001 I 2 Inconsistency 95.07% 88.2% Egger's test P = 0.8715 P = 0.6921 CI: confidence interval Table 4 : Sample size, proportion and corresponding 95% CIs of the main SAEs in RTS,S/AS01E and Control groups Groups Parameters Main SAES Severe anemia Pneumonia Gastroenteritis Anemia Febrile convulsions RTS,S/AS01E Sample size 1238 1238 1238 1238 1199 Proportion (%) 25.9 31.5 14.8 16.7 26.5 95% CI 14.9-38.7 28.1-34.1 2.5-54.1 14.7-18.9 17.4-38.0 P-value 0.0004 <0.0001 0.073 <0.0001 <0.0001 I 2 Inconsistency 83.66% 95.62% 96.73% 0.00% 72.98% Egger's test P = 0.1912 P = 0.2662 P = 0.0518 P = 0.1982 P = 0.1938 Control Sample size 857 857 857 857 821 Proportion (%) 44.6 27.5 15.1 19.4 23.3 95% CI 38.5-50.9 24.6-30.7 3.7-47.4 10.5-33.2 14.4-35.3 P-value 0.1613 <0.001 0.028 <0.0001 <0.0001 I 2 Inconsistency 41.72% 8.06% 96.98% 94.11% 82.34% Egger's test P = 0.7723 P = 0.5885 P = 0.0199 P = 0.7668 P = 0.2073 SAEs: serious adverse events, CI: confidence interval Additional Declarations No competing interests reported. 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Ebolowa","correspondingAuthor":false,"prefix":"","firstName":"Rachi-metou","middleName":"Njemguie","lastName":"Linjouom","suffix":""},{"id":275515852,"identity":"c3bd0409-baa1-42ed-b971-c2abe24efdfe","order_by":2,"name":"Martin Nyangono Ndongo","email":"","orcid":"","institution":"University of Yaoundé I","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"Nyangono","lastName":"Ndongo","suffix":""},{"id":275515853,"identity":"7207089b-aae6-4cf2-9807-1a9bf80d4625","order_by":3,"name":"Jan Rene Nkeck","email":"","orcid":"","institution":"University of Yaoundé I","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"Rene","lastName":"Nkeck","suffix":""},{"id":275515854,"identity":"93fc18ad-b5ea-4a52-b20d-785fc45ca5a0","order_by":4,"name":"Longxiang Yan","email":"","orcid":"","institution":"Gannan Medical 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Tian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtElEQVRIiWNgGAWjYLCCBAYGOTb25gNEa2BsAGox5uM5lkCCFiCROE8iR4E49fyze48/eFBzJ72NIYeB4UfFNsJaJO6cS2xIOPYst43h7AHGnjO3ibDmRo5hQwLb4dw2xr4EZsY2IrTIg7X8O5zOxsxjQJwWA5CWxLbDCWxsxGoxBGqZkdh32LCNhy3hIFF+kbuRY/Dxx7fD8vLzHx988KOCGO8jgwMkqh8Fo2AUjIJRgAsAACOxPnPEbB0CAAAAAElFTkSuQmCC","orcid":"","institution":"Gannan Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yuantong","middleName":"","lastName":"Tian","suffix":""}],"badges":[],"createdAt":"2024-02-21 13:04:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3975532/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3975532/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51973560,"identity":"0d1ff762-3767-4fd4-aaf0-baeee526cb04","added_by":"auto","created_at":"2024-03-04 19:01:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":53795,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow diagram\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-3975532/v1/3ff01f23a9932a1267c7b40d.png"},{"id":51974376,"identity":"229dfddd-bd9d-435a-b8a7-dd6374206c3d","added_by":"auto","created_at":"2024-03-04 19:09:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":194632,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of comparison: overall serious adverse events and death [RTS,S/AS01E vs Control] in 5-17 months children, outcome: Risk Ratio (RR).\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-3975532/v1/74db26efd14ed987a7dcd7f5.png"},{"id":51973558,"identity":"2ad77a77-c893-4eaf-9eef-63d3b309d3f3","added_by":"auto","created_at":"2024-03-04 19:01:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":160247,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of comparison: overall death [RTS,S/AS01E vs Control] in 5-17 months children, outcome: Risk Ratio (RR).\u003c/p\u003e","description":"","filename":"Slide3.png","url":"https://assets-eu.researchsquare.com/files/rs-3975532/v1/1419d2c30c1cfd839df0a2fa.png"},{"id":51976583,"identity":"be52c034-d844-48b9-beba-3863e0b8af57","added_by":"auto","created_at":"2024-03-04 19:17:51","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":162356,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of comparison: incidence of the main serious adverse events [RTS,S/AS01E vs Control] in 5-17 months children, outcome: Odds Ratio (OR).\u003c/p\u003e","description":"","filename":"Slide4.png","url":"https://assets-eu.researchsquare.com/files/rs-3975532/v1/67fa9b2b8b5d710f32d313f1.png"},{"id":51974374,"identity":"28c21c98-7155-4aa2-816c-fe309a488fd4","added_by":"auto","created_at":"2024-03-04 19:09:51","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":144840,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.\u003c/p\u003e","description":"","filename":"Slide5.png","url":"https://assets-eu.researchsquare.com/files/rs-3975532/v1/a5c4d9cae2451961562cd695.png"},{"id":54905621,"identity":"32a63608-8d84-4f34-9e95-000fa6fe3784","added_by":"auto","created_at":"2024-04-18 11:30:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1402369,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3975532/v1/baced875-d4d6-4107-b8f0-ff92afccca79.pdf"},{"id":51973563,"identity":"6b886be6-0133-4ede-b022-fefc4df733a1","added_by":"auto","created_at":"2024-03-04 19:01:51","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":252732,"visible":true,"origin":"","legend":"","description":"","filename":"prisma2020checklist.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3975532/v1/0a673eb2a3f677e555ba4fea.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Frequency of serious adverse events and death in 5-17 months children receiving RTS,S/AS01E vaccine - a systematic review and meta-analysis of RCTs.","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eMalaria represents a substantial global burden of infectious disease. The World Health Organization (WHO) documented over 249\u0026nbsp;million cases of malaria and 608,000 malaria-related fatalities in 2022 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], with 76.8% of these deaths happening in children under 5 years of age. Among the four primary malaria-causing agents in humans, \u003cem\u003ePlasmodium falciparum\u003c/em\u003e is the deadliest and accounts for the most prevalent infection in Africa [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Current malaria control measures, largely based on chemoprevention and vector control, have led to a modest reduction in the malaria death rate [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These measures are facing \u003cem\u003eP. falciparum\u003c/em\u003e and \u003cem\u003eAnopheles\u003c/em\u003e resistance. Resistance to artemisinin, one of the key components of recommended first-line antimalarial treatments, has been reported in five countries in Southeast Asia [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The spread of this resistance to Africa could have serious consequences for public health. The ongoing high number of clinical cases, fatalities and resistance could justify why both national and international health authorities persist in prioritizing the implementation of malaria vaccines [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The perfect malaria vaccine would confer immunity against the parasite upon entry into the body, prior to liver infection, thereby reducing the onset of clinical disease and averting hepatocellular damage [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The brief duration of the parasite's initial entry stage in the life cycle (~\u0026thinsp;30 minutes) means that immune responses are not swift enough to hinder infection. While focusing on the post-hepatic stage may seem more practical, it would not prevent liver infection and the resulting damage to hepatocytes. Given these constraints, a viable alternative would involve targeting the parasite during both the pre-hepatic and hepatic stages to prevent clinical disease.\u003c/p\u003e \u003cp\u003eIn early 2001, GlaxoSmithKline (GSK) and PATH joined forces to create the RTS,S vaccine as a preventive measure against clinical disease caused by \u003cem\u003eP. falciparum\u003c/em\u003e for infants and children living in endemic areas [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The RTS,S/AS01E malaria vaccine targets the pre-erythrocytic stage of the parasite [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The vaccine is composed of a recombinant viral pseudoparticle-forming protein known as RTS,S, along with the patented AS01E adjuvant system. The RTS,S antigen is a fusion protein containing a segment of the \u003cem\u003eP. falciparum\u003c/em\u003e circumsporozoite protein (CSP) and the hepatitis B virus surface antigen (HBsAg), which is also found in licensed hepatitis B vaccines. To stabilize the recombinant particles, the fusion protein is co-expressed with the HBsAg (S) protein in \u003cem\u003eSaccharomyces cerevisiae\u003c/em\u003e [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. AS01E comprises 3-O-desacyl-4'-monophosphoryl-lipid-A (MPL; produced by GSK), QS-21 (Quillaja saponaria Molina, fraction 21; licensed by GSK from Antigenics Inc., a wholly-owned subsidiary of Agenus Inc. of Delaware, USA), and liposomes. The RTS,S/AS01E vaccine is presented in two separate preservative-free vials, one containing lyophilized RTS,S powder and the other containing AS01E suspension [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The final vaccine is prepared by reconstituting the powder with the suspension to yield 1mL of opalescent, colorless to pale-brown liquid. A single dose of the vaccine is obtained by withdrawing 0.5mL from the vial after reconstitution. Each dose contains 25\u0026micro;g of RTS,S antigen, along with 25\u0026micro;g of each of the immunomodulatory molecules MPL and QS21 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The vaccine is administered via intramuscular injection.\u003c/p\u003e \u003cp\u003eThe GSK RTS,S vaccine (Mosquirix\u0026trade;) is the first malaria vaccine to progress to Phase 3 trials. WHO recommended its use in children aged 5 to 17 months in a series of pilot projects using a 4-dose regimen (3 initial doses at least 4 weeks apart, preferably administered before 9 months, followed by a 4th dose administered 15 to 18 months after the 3rd dose) in areas with moderate to high malaria transmission [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The rationale for this decision is supported by data from phase 1 to phase 3 trials and a continuous pilot malaria vaccine implementation program (MVIP) initiated in 2019 in Ghana, Kenya, and Malawi [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. It has been estimated that three doses of the RTS,S vaccine could prevent approximately 93,940 cases of clinical disease and 394 deaths per 100,000 children under 5 years of age [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Despite these results, there have been concerns about the incidence of serious adverse events (SAEs) and deaths in real-world settings [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These results have not been synthesized, and their association with the vaccine has not yet been proven, hence the current study.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eThis systematic review and meta-analysis followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) reporting guideline [18]. The study protocol is registred under the protocol ID CRD42024321008/PROSPERO.\u003c/p\u003e\n\u003ch3\u003e2.1. Search strategy\u003c/h3\u003e\n\u003cp\u003eWe conducted a literature search on January 23, 2024, using PubMed, Cochrane Library, Wiley Online Library, and the Web of Science databases. Additional records were identified through citation searching. An example of our search strategy in PubMed and the Web of Science database is provided in Table 1. We utilized the following keywords: (\u0026quot;RTS,S/AS01\u0026quot; OR \u0026quot;RTSS/AS01\u0026quot;) AND (\u0026quot;safety\u0026quot; OR \u0026quot;serious adverse events\u0026quot; OR \u0026quot;SAE\u0026quot;).\u003c/p\u003e\n\u003ch3\u003e2.2. Inclusion criteria:\u003c/h3\u003e\n\u003cp\u003eThe criteria for eligible studies included the following:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(P) Population\u003c/strong\u003e: Male and female children aged 5-17 months at the time of the first vaccination and residing in malaria-endemic areas in Sub-Saharan Africa.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(I) Intervention\u003c/strong\u003e: Male and female children aged 5-17 months who received the RTS,S/AS01E vaccine (MosquirixTM) according to the 0\u0026ndash;1\u0026ndash;2 months vaccination schedule.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(C) Comparison\u003c/strong\u003e: Male and female children aged 5-17 months who received the Rabies vaccine (Verorab) or Expanded Programme on Immunization (EPI) vaccines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(O) Outcomes\u003c/strong\u003e: The proportions of overall SAEs and deaths. The proportion of frequently reported SAEs from the time of first vaccination throughout the study period. SAEs refer to significant, severe, or life-threatening medical occurrences or conditions that participants may experience after receiving the vaccine. These events go beyond the expected side effects and pose a substantial risk to the health and well-being of the individuals involved [19].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(S) Study design\u003c/strong\u003e: Randomized controlled/clinical trials (RCTs).\u003c/p\u003e\n\u003ch3\u003e2.3. Exclusion criteria:\u003c/h3\u003e\n\u003cp\u003eWe excluded studies according to the following criteria: (I) duplicated publications; (II) letters, reviews, case reports, communication and expert opinions; (III) animal studies, basic research and non-RCTs studies; (IV) studies without sufficient data to estimate the risk ratios (RRs), odds ratios (ORs) and their corresponding 95% confidence intervals (CIs).\u003c/p\u003e\n\u003ch3\u003e2.4. Data extraction:\u003c/h3\u003e\n\u003cp\u003eWe extracted the following items: name of the first author, published year, country, follow-up time, Phase, mean age, proportions of SAEs and number of deaths. The data extraction was independently evaluated by three investigators (Zoa, Njemguie and Longxiang), and a consensus was reached by group discussion when the disagreement occurred.\u003c/p\u003e\n\u003ch3\u003e2.5. Assessment of the Risk of Bias in the included studies:\u003c/h3\u003e\n\u003cp\u003eThe authors, Zoa and Nyangono, evaluated the quality of the literature included in this study using the \u0026quot;risk of bias assessment\u0026quot; tool from the Cochrane systematic review [20]. The assessment criteria encompass the following seven areas: generation of randomized sequences, allocation concealment, blinding of investigators and subjects, blinding of outcome evaluators, completeness of outcome information, selective reporting of study results and other sources of bias. Each item can be described as \u0026quot;low risk of bias\u0026quot;, \u0026quot;high risk of bias\u0026quot;, or \u0026quot;unclear risk\u0026quot;. Eventually, the evaluations mentioned above were combined to create a risk of bias assessment map and quality outcomes for each piece of literature. If there is a disagreement between the two researchers, a third researcher (Nkeck) conducted an independent assessment, and the final assessment was determined through mutual agreement among all three researchers.\u003c/p\u003e\n\u003ch3\u003e2.6. Data analysis:\u003c/h3\u003e\n\u003cp\u003eDue to the clinical variations among the children included in the studies, such as differences in outcome definition, clinical presentation, and potential misclassification of positive and negative outcomes, a random-effects meta-analysis was utilized to pool effect sizes (frequency, RR, and OR) [21]. The Mantel-Haenszel method was employed for the meta-analysis of RR and OR. RR was defined as the risk of experiencing serious adverse events (SAEs) from the malaria vaccine, while OR was defined as the odds of experiencing a specific SAE after receiving the malaria vaccine RTS,S/AS01E [22]. Heterogeneity across studies was assessed using a \u0026chi;2-based test. The I2 statistic, a quantitative measure of inconsistency across studies, was also calculated [23]. In cases of significant heterogeneity (I2\u0026gt;50% or P\u0026lt;0.05), the random effects model was employed for the meta-analysis. Otherwise, a fixed effects model was adopted. All analyses were conducted using Review Manager (RevMan) version 5.4.1 (The Cochrane Collaboration, 2020) for RR and OR, and Comprehensive Meta-analysis Software V3 for pooled frequency. All statistical tests were two-sided.\u003c/p\u003e\n\u003ch3\u003e2.7. Sensitivity analyses\u003c/h3\u003e\n\u003cp\u003eAfter calculating the crude overall pooled frequency of all serious adverse events (SAEs) and deaths in children with RTS,S/AS01E, we conducted sensitivity analyses that included only studies reporting proportions of main SAEs to assess the robustness of our findings. An odds ratio (OR) greater than 1 indicates an increased likelihood of a specific SAE in the RTS,S/AS01E group compared to the control group. The significance of the pooled risk ratio (RR) and OR was determined using the Z test, with a P value \u0026lt;0.05 considered statistically significant.\u003c/p\u003e"},{"header":"3. Results","content":"\u003ch3\u003e3.1. Study selection and characteristics\u003c/h3\u003e\n\u003cp\u003eA flow diagram showing our literature search and screening strategy is presented in Figure 1. We initially obtained 161 articles, among which 157 from databases records and 4 from citations searching. After removing 39 duplicates, we screened 122 records by reading the abstracts. We removed 43 letters, reviews, case reports and communications, 18 animal studies/basic research, and 16 non-RCTs studies. We evaluated 45 full-text articles for eligibility, and finally, we included 10 articles with 30,573 children (19,769 RTS,S/AS01E recipients and 10,804 control recipients) in the meta-analysis [16,24\u0026ndash;32].\u003c/p\u003e\n\u003cp\u003eThe included studies were published between 2008 and 2020. 9,396 of 30,573 (17.56%) patients were from Kenya, 4968 (16.25%) from Ghana, 4832 (15.81%) from Tanzania, 3938 (12.88%) from Gabon, 3823 (12.5%) from Mozambique, 3823 (12.5%) from Burkina-Faso and 3823 (12.5%) from Malawi. Nine studies used Rabies vaccine (Verorab) as control [16,24,25,27\u0026ndash;32], and one study used EPI vaccines as control [26]. The participants were children from 5-17 months in all the studies. Seven of ten studies provided information on the number of children who died during the study [16,24,25,27,29,30,32]. six of ten provided the frequency of the main SAEs [25\u0026ndash;27,29\u0026ndash;31]. Further detailed descriptions of these eligible articles are listed in the table 2.\u003c/p\u003e\n\u003ch3\u003e3.2. Meta-analysis\u003c/h3\u003e\n\u003cp\u003eTen studies provided sufficient data to estimate the combined incidence of all SAEs and their relative risks (RRs) [16,24\u0026ndash;32], while seven studies had enough data to estimate the combined incidence for all deaths and their corresponding RRs [16,24,25,27,29,30,32].\u003c/p\u003e\n\u003ch4\u003e3.2.1. Combined incidence of all SAEs and death in RTS,S/AS01E and control groups\u003c/h4\u003e\n\u003cp\u003eThe pooled frequency of all SAEs among children who received RTS,S/AS01E was 17.6% (10 studies, 19,769 children, 95% CI: [15.3, 20.2], \u003cem\u003eP\u003c/em\u003e\u0026lt;0.0001), and 22.0% (10 studies, 10,804 children, 95% CI: [20.4, 23.7], \u003cem\u003eP\u003c/em\u003e\u0026lt;0.0001) in the control group. The pooled frequency of all deaths in children receiving RTS,S/AS01E was 1% (7 studies, 18,929 children, 95% CI: [0.8, 1.2]), while the pooled frequency of all deaths in controls was 0.7% (7 studies, 9,962 children 95% CI: [0.3, 1.7]). The table 3 summarizes parameters relative to the pooled frequency of overall SAEs and death in malaria vaccine and control groups.\u003c/p\u003e\n\u003ch4\u003e3.2.2. Comparison of the incidence of SAEs and death in children receiving RTS,S/AS01E and controls\u003c/h4\u003e\n\u003cp\u003eWe employed a random effect model to calculate the RR and 95% CI for both SAEs and death due to statistical heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=71% and \u003cem\u003eP\u003c/em\u003e=0.77 respectively). The findings revealed that the children in RTS,S/AS01E group had a significant reduced risk of SAEs (10 studies, 30,573 children, RR = 0.80, 95% CI: [0.72, 0.90], \u003cem\u003eP\u003c/em\u003e=0.0002, fig. 2), but a non-significant increased risk of death (7 studies, 18929 children, RR = 1.04, 95% CI: [0.77, 1.41], \u003cem\u003eP\u003c/em\u003e=0.79, fig. 3) compared to control.\u003c/p\u003e\n\u003ch4\u003e3.2.3. Incidence of the mains SAEs\u003c/h4\u003e\n\u003cp\u003eDue to significant heterogeneity, we performed subgroup analyses (by main SAEs). Four studies had enough data to estimate the pooled frequency and corresponding ORs for severe malaria, pneumonia, gastroenteritis and anemia [27,29\u0026ndash;31]. Three studies had enough data to estimate the pooled frequency and corresponding ORs for febrile convulsions [27,30,31]. The pooled frequencies of the main SAEs were as follow: severe malaria (25.9% and 44.6%), pneumonia (31.5% and 27.5%), gastroenteritis (14.8% and 15.1%), anemia (16.7% and 19.4%), and febrile convulsions (26.5% and 23.3%) in RTS,S/AS01E and control groups respectively. Table 3 summarize information relative to the pooled frequency of the main SAEs in malaria vaccine and control groups.\u003c/p\u003e\n\u003ch4\u003e3.2.4. Comparison of the frequencies of the main SAEs in children receiving RTS,S/AS01E and controls\u003c/h4\u003e\n\u003cp\u003eWe used a random effect model to calculate the ORs and 95% CIs for the main SAEs due to statistical heterogeneity (I\u003csup\u003e2\u003c/sup\u003e\u0026gt;50 or \u003cem\u003eP\u003c/em\u003e\u0026gt;0.05). The results indicated that children in the RTS,S/AS01E group exhibited significantly reduced odds of severe malaria (4 studies, 1238 children, OR = 0.47, 95% CI: [0.29, 0.76], P=0.002), and febrile convulsions (3 studies, 1199 children, OR = 1.26, 95% CI: [1.00, 1.59], P=0.005) compared to the control group. However, there was a non-significant increase in the Odds of pneumonia (4 studies, 1238 children, OR = 1.19, 95% CI: [0.98, 1.45], P=0.07), gastroenteritis (4 studies, 1238 children, OR = 0.99, 95% CI: [0.65, 152]), anemia (4 studies, 1238 children, OR = 0.70, 95% CI: [0.33-1.47], P=0.34), and death (7 studies, 18929 children, RR = 1.04, 95% CI: [0.77, 1.41], P=0.79, fig. 4) compared to the control group.\u003c/p\u003e\n\u003ch3\u003e3.3. Assessment of publication bias\u003c/h3\u003e\n\u003cp\u003eThe included studies underwent a thorough quality assessment. One study exhibited a high risk of bias in terms of blinding of participants and personnel [25]. Another study showed a high risk of selective reporting [28]. Additionally, four studies did not provide data on the proportions of various serious adverse events (SAEs), resulting in an unclear risk of bias [16,24,28,29]. However, overall, all of the selected studies demonstrated low risks of selection, performance, detection, and reporting biases due to the proper execution of these randomized controlled trials (RCTs) [16,24\u0026ndash;32], which encompassed the randomization process, deviations from the intended interventions, measurement of the outcome data, gaps in the outcome analysis, and reported result selection. In conclusion, the included studies exhibited high methodological quality and a low likelihood of bias (Figure 5).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eFor an extended period, the exclusive methods for malaria prevention in Africa and globally encompassed antimalarial drugs (including seasonal chemoprophylaxis and intermittent preventive treatment during pregnancy) and vector control [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. They led to a modest decrease in the malaria-related mortality rate; however, malaria continues to be the fourth leading cause of death among children under 5 years of age in sub-Saharan Africa [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Faced with this scenario, the World Health Organization (WHO), in collaboration with national and international health authorities, embarked on the development of a vaccine. The RTS,S/AS01E was the initial vaccine to enter phase 3 trial conducted in two age-groups (6\u0026ndash;12 weeks and 5\u0026ndash;17 months), and was approved for use in children in 2021 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The Malaria Vaccine Implementation Program (MVIP) was thus developed, planned, and launched to facilitate the distribution of RTS,S/AS01E through regular immunization programs, and to gather evidence on its safety, effectiveness, and operational feasibility in routine use in Ghana, Malawi, and Kenya [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This prompted the WHO to expand the vaccination program to additional countries in sub-Saharan Africa, facilitated by the donation of 18\u0026nbsp;million doses [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Today, over 2\u0026nbsp;million children in Africa have received this vaccine.\u003c/p\u003e \u003cp\u003eThe doubts regarding the effectiveness and safety of this vaccination within the African population prompted the current study, which aimed to summarize and analyze the frequency of serious adverse events (SAEs) and mortality in children aged 5\u0026ndash;17 months. A meta-analysis of 30,573 children from 10 studies was conducted [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25 CR26 CR27 CR28 CR29 CR30 CR31\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The findings indicated that children who received the RTS,S/AS01E vaccine had a combine incidence of 17.6% with reduced risk (RR\u0026thinsp;=\u0026thinsp;0.8) of experiencing SAEs compared to those who did not. This outcome aligns with the conclusions of multiple authors [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] who observed a higher incidence of SAEs in children who were not administered RTS,S/AS01E. There might be multiple explanations for this phenomenon: at this stage of development, the immune system may not be fully competent, and the malaria vaccine works to enhance it by generating anti-CSP antibodies. Another factor could be adherence to vector control measures (such as long-lasting insecticidal mosquito nets, etc.) following vaccination. We also sought to examine the occurrence of mortality in each of these studies. Initially, we observed that few studies provided data on the number of children who had died [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, among the included studies, we determined that there was no significant difference in the incidence of death between those who received malaria vaccine and those who did not (Fig.\u0026nbsp;2). This aligns with the conclusions of several authors who suggested that mortality and serious adverse events (SAEs) were not necessarily linked to vaccine administration [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe conducted a subgroup analysis based on the type of serious adverse events (SAEs) and discovered that \u003cem\u003ePlasmodium falciparum\u003c/em\u003e infection was more prevalent in children with malaria vaccine than in those without. This supports the overall findings regarding the incidence of SAEs. This observation could be explained by the fact that vaccinated children are protected and experience fewer malaria cases, thus demonstrating the efficacy of the vaccine in these children [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Recent studies have indicated that the vaccine effectiveness (VE) of RTS,S/AS01E is over 45% two years after the final dose [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Additionally, other effects such as pneumonia, gastroenteritis, febrile convulsions, anemia, and upper respiratory infections were present, but did not reach statistical significance.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eDespite the effectiveness and safety of the RTS,S/AS01E malaria vaccine, it would have been necessary to conduct clinical studies on a larger population before its widespread use, due to the potential risk of death, which although not significant, remains present. We regret the insufficiency of data on deaths, which could have enhanced the depth and discussion of this work. Additionally, we advocate for studies to be conducted across various regions in Africa (western, central, southern, northern, etc.) and among different continents to facilitate a comprehensive analysis of genetic diversity and environmental factors. Malaria continues to be a disease associated with unsanitary conditions, and it is essential to always integrate the use of vaccines with environmental sanitation measures, which have been instrumental in eradicating the disease in developed countries such as the USA, China, Germany, South Africa, etc\u0026hellip;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAEs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eserious adverse events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePRISMA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epreferred reporting items for systematic review and meta-analysis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMVIP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emalaria vaccine implementation program\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erisk ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eodds ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCSP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecircumsporozoite protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMPLA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emonophosphoryl-lipid-A\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGSK\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eglaxosmithkline.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eNone\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026quot;The authors declare that they have no competing interests\u0026quot;\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by grants from the National Natural Science Foundation of China (No. 82360573) and the Innovation Project of Gannan Medical University (No. TD201703).\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(I) Conception and design: Z.B.A., N.L.R., Y.L.X.; (II) Administrative support: N.N.M., L.X.P., T.Y.T; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: Z.B.A., N.L.R., N.J.R, Z.J.; (V) Data analysis and interpretation: Z.B.A., N.L.R., L.X.P., N.J.R., T.Y.T.; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWHO. 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PLoS ONE. 2009;4(10):e7302.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgnandji ST, Asante KP, Lyimo J, Vekemans J, Soulanoudjingar SS, Owusu R, et al. Evaluation of the safety and immunogenicity of the RTS,S/AS01E malaria candidate vaccine when integrated in the expanded program of immunization. J Infect Dis. 2010;202(7):1076\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLusingu J, Olotu A, Leach A, Lievens M, Vekemans J, Olivier A, et al. Safety of the malaria vaccine candidate, RTS,S/AS01E in 5 to 17 month old Kenyan and Tanzanian Children. PLoS ONE. 2010;5(11):e14090.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOlotu A, Lusingu J, Leach A, Lievens M, Vekemans J, Msham S, et al. Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5\u0026ndash;17 months in Kenya and Tanzania: a randomised controlled trial. 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Pan Afr Med J. 2018;30:142.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable\u0026nbsp;1:\u0026nbsp;Literature search strategy for Pubmed and Web of Science databases\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.535353535353536%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSEARCH TERMS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"46.464646464646464%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eRESULTS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"52.17391304347826%\" style=\"width: 24.252%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePubmed\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"47.82608695652174%\" style=\"width: 25.623%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeb of Science\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.535353535353536%\" valign=\"top\"\u003e\n \u003cp\u003e#1 \u0026quot;RTS,S/AS01\u0026quot; OR \u0026quot;RTSS/AS01\u0026quot;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\" style=\"width: 24.252%;\"\u003e\n \u003cp\u003e273\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" valign=\"top\" style=\"width: 25.623%;\"\u003e\n \u003cp\u003e268\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.535353535353536%\" valign=\"top\"\u003e\n \u003cp\u003e#2 \u0026quot;safety\u0026quot; OR \u0026quot;serious adverse events\u0026quot; OR \u0026quot;SAE\u0026quot;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\" style=\"width: 24.252%;\"\u003e\n \u003cp\u003e928,132\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" valign=\"top\" style=\"width: 25.623%;\"\u003e\n \u003cp\u003e958,748\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"53.535353535353536%\" valign=\"top\"\u003e\n \u003cp\u003e#1AND#2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.242424242424242%\" valign=\"top\" style=\"width: 24.252%;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" valign=\"top\" style=\"width: 25.623%;\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eSearch update: 1/23/2024\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;2: Characteristics of RCTs for 0,1,2-month groups\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.458333333333334%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eFirst Author, Year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eTrial Period\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-Up\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(Months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.291666666666667%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean age\u0026plusmn;SD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(Months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample Size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall SAEs\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall Deaths\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.541666666666666%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSAEs\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(RTS:Ctrl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCtrl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCtrl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCtrl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eBejon, 2008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eKenya\u003c/p\u003e\n \u003cp\u003eTanzania\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e2007/3 -\u003c/p\u003e\n \u003cp\u003e2007/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e7.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.368421052631579%\"\u003e\n \u003cp\u003eIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e10.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e18.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.2105263157894735%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.68421052631579%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eOwusu-Agyei, 2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eGhana\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e2006/8 - 2008/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.368421052631579%\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e11 \u0026plusmn; 3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e14.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e13.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.2105263157894735%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.68421052631579%\"\u003e\n \u003cp\u003eSevere malaria (0:1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eLusingu, 2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eKenya\u003c/p\u003e\n \u003cp\u003eTanzania\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2007/3 -\u003c/p\u003e\n \u003cp\u003e2007/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.368421052631579%\"\u003e\n \u003cp\u003eIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e11.4 \u0026plusmn; 3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e22.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.2105263157894735%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.68421052631579%\"\u003e\n \u003cp\u003ePneumonia (16:26)\u003c/p\u003e\n \u003cp\u003eFebrile convulsion (14:20)\u003c/p\u003e\n \u003cp\u003esevere malaria (9:31)\u003c/p\u003e\n \u003cp\u003eGastroenteritis (10:22)\u003c/p\u003e\n \u003cp\u003eAnemia (5:2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eAgnandji, 2010*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eGhana\u003c/p\u003e\n \u003cp\u003eTanzania\u003c/p\u003e\n \u003cp\u003eGabon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e2009/5 - 2011/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.368421052631579%\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e170\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e19.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.2105263157894735%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.68421052631579%\"\u003e\n \u003cp\u003eAnemia (6/14)\u003c/p\u003e\n \u003cp\u003eGastroenteritis (19/14)\u003c/p\u003e\n \u003cp\u003ePneumonia (11/10)\u003c/p\u003e\n \u003cp\u003eSevere malaria (5/16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eOlotu, 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eGhana\u003c/p\u003e\n \u003cp\u003eTanzania\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e2007/3 -\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2008/10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.368421052631579%\"\u003e\n \u003cp\u003eIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e447\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e22.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.2105263157894735%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.68421052631579%\"\u003e\n \u003cp\u003ePneumonia (N/R)\u003c/p\u003e\n \u003cp\u003eFebrile Convulsion (N/R)\u003c/p\u003e\n \u003cp\u003eGastroenteritis (N/R)\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eSevere\u0026nbsp;\u003c/em\u003emalaria (N/R)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eRTS,S Clinical Trials Partnership, 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eBurkina Faso\u003c/p\u003e\n \u003cp\u003eGabon\u003c/p\u003e\n \u003cp\u003eGhana\u003c/p\u003e\n \u003cp\u003eKenya\u003c/p\u003e\n \u003cp\u003eMalawi\u003c/p\u003e\n \u003cp\u003eMozambique\u003c/p\u003e\n \u003cp\u003eTanzanie\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e2009/3 - 2011/1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.368421052631579%\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e5949\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e2974\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e17.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e21.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.2105263157894735%\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.68421052631579%\"\u003e\n \u003cp\u003eSeizure (7/1)\u003c/p\u003e\n \u003cp\u003eMeningitis (11/1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eRTS,S Clinical Trials Partnership, 2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eBurkina Faso\u003c/p\u003e\n \u003cp\u003eGabon\u003c/p\u003e\n \u003cp\u003eGhana\u003c/p\u003e\n \u003cp\u003eKenya\u003c/p\u003e\n \u003cp\u003eMalawi\u003c/p\u003e\n \u003cp\u003eMozambique\u003c/p\u003e\n \u003cp\u003eTanzanie\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e2009/3 - 2011/1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.368421052631579%\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e5949\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e2974\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e18.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e22.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.2105263157894735%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.68421052631579%\"\u003e\n \u003cp\u003eAnemia (190/155)\u003c/p\u003e\n \u003cp\u003eEnteritis (21/12)\u003c/p\u003e\n \u003cp\u003eMeningitis (9/1)\u003c/p\u003e\n \u003cp\u003ePneumonia (353/189)\u003c/p\u003e\n \u003cp\u003eSevere malaria (400/313)\u003c/p\u003e\n \u003cp\u003eFebrile Convulsion (224/112)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eRTS,S Clinical Trials Partnership, 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eBurkina Faso\u003c/p\u003e\n \u003cp\u003eGabon\u003c/p\u003e\n \u003cp\u003eGhana\u003c/p\u003e\n \u003cp\u003eKenya\u003c/p\u003e\n \u003cp\u003eMalawi\u003c/p\u003e\n \u003cp\u003eMozambique\u003c/p\u003e\n \u003cp\u003eTanzanie\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e2009/3 - 2011/1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.368421052631579%\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e10.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e5948\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e2974\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e23.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.2105263157894735%\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.68421052631579%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eOlotu, 2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eKenya\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e2007/3 - 2014/11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.368421052631579%\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e11 \u0026plusmn; 3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e223\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e224\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e17.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e25.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.2105263157894735%\"\u003e\n \u003cp\u003eN/R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.68421052631579%\"\u003e\n \u003cp\u003eAnemia (5/12)\u003c/p\u003e\n \u003cp\u003eGastroenteritis (7/12)\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eSevere\u0026nbsp;\u003c/em\u003emalaria (14/30)\u003c/p\u003e\n \u003cp\u003ePneumonia (9/10)\u003c/p\u003e\n \u003cp\u003eFebrile convulsion (15/20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eOtieno, 2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eKenya\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e2010/7 - 2013/05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.368421052631579%\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e9.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e41.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e36.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.2631578947368425%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.2105263157894735%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.68421052631579%\"\u003e\n \u003cp\u003ePneumonia (N/R)\u003c/p\u003e\n \u003cp\u003eFebrile convulsions (N/R)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eRTS: RTS,S/AS01E, Ctrl: Rabies or EPI vaccine, SAEs: serious adverse events, EPI: Expanded Programme on Immunization, N/R: not reported. * WHO Stage 1,2 HIV disease\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003cstrong\u003e: Sample size, proportion and corresponding 95% CIs of the overall SAEs and death in RTS,S/AS01E and Control groups\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.161616161616163%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.35353535353536%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"48.484848484848484%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"55.319148936170215%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS,S/AS01E\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"44.680851063829785%\" style=\"width: 25.752%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.161616161616163%\" rowspan=\"6\"\u003e\n \u003cp\u003e\u003cstrong\u003eSAEs\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.35353535353536%\"\u003e\n \u003cp\u003eSample size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.262626262626263%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003e19769\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003e10804\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.16867469879518%\"\u003e\n \u003cp\u003e\u003cstrong\u003eProportion (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.325301204819276%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e17.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.50602409638554%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e22.0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.16867469879518%\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.325301204819276%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003e15.3-20.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.50602409638554%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003e20.4-23.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.16867469879518%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.325301204819276%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.50602409638554%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.16867469879518%\"\u003e\n \u003cp\u003eI\u003csup\u003e2\u003c/sup\u003e Inconsistency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.325301204819276%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003e93.28%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.50602409638554%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003e62.24%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.16867469879518%\"\u003e\n \u003cp\u003eEgger\u0026apos;s test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.325301204819276%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003eP = 0.5030\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.50602409638554%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003eP = 0.8083\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.161616161616163%\" rowspan=\"6\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeath\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.35353535353536%\"\u003e\n \u003cp\u003eSample size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.262626262626263%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003e18929\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003e9962\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.16867469879518%\"\u003e\n \u003cp\u003e\u003cstrong\u003eProportion (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.325301204819276%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.50602409638554%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.16867469879518%\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.325301204819276%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003e0.8-1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.50602409638554%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003e0.3-1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.16867469879518%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.325301204819276%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.50602409638554%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.16867469879518%\"\u003e\n \u003cp\u003eI\u003csup\u003e2\u003c/sup\u003e Inconsistency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.325301204819276%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003e95.07%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.50602409638554%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003e88.2%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"42.16867469879518%\"\u003e\n \u003cp\u003eEgger\u0026apos;s test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.325301204819276%\" style=\"width: 19.373%;\"\u003e\n \u003cp\u003eP = 0.8715\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.50602409638554%\" colspan=\"2\" style=\"width: 26.502%;\"\u003e\n \u003cp\u003eP = 0.6921\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCI: confidence interval\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003cstrong\u003e: Sample size, proportion and corresponding 95% CIs of the main SAEs in RTS,S/AS01E and Control groups\u003c/strong\u003e\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.346938775510203%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"68.36734693877551%\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eMain SAES\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.181818181818183%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSevere anemia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePneumonia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.757575757575758%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGastroenteritis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnemia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.696969696969695%\"\u003e\n \u003cp\u003e\u003cstrong\u003eFebrile convulsions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.52577319587629%\" rowspan=\"6\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTS,S/AS01E\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eSample size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\"\u003e\n \u003cp\u003e1238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e1238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e1238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e1238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e1199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5%\"\u003e\n \u003cp\u003e\u003cstrong\u003eProportion\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15%\"\u003e\n \u003cp\u003e\u003cstrong\u003e25.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003e31.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003e14.8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.75%\"\u003e\n \u003cp\u003e\u003cstrong\u003e16.7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003e26.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5%\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15%\"\u003e\n \u003cp\u003e14.9-38.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e28.1-34.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25%\"\u003e\n \u003cp\u003e2.5-54.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.75%\"\u003e\n \u003cp\u003e14.7-18.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e17.4-38.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15%\"\u003e\n \u003cp\u003e0.0004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25%\"\u003e\n \u003cp\u003e0.073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.75%\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5%\"\u003e\n \u003cp\u003eI\u003csup\u003e2\u003c/sup\u003e Inconsistency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15%\"\u003e\n \u003cp\u003e83.66%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e95.62%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25%\"\u003e\n \u003cp\u003e96.73%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.75%\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e72.98%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5%\"\u003e\n \u003cp\u003eEgger\u0026apos;s test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15%\"\u003e\n \u003cp\u003eP =\u003c/p\u003e\n \u003cp\u003e0.1912\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003eP =\u003c/p\u003e\n \u003cp\u003e0.2662\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25%\"\u003e\n \u003cp\u003eP =\u003c/p\u003e\n \u003cp\u003e0.0518\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.75%\"\u003e\n \u003cp\u003eP =\u003c/p\u003e\n \u003cp\u003e0.1982\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003eP =\u003c/p\u003e\n \u003cp\u003e0.1938\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.52577319587629%\" rowspan=\"6\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\"\u003e\n \u003cp\u003eSample size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.371134020618557%\"\u003e\n \u003cp\u003e857\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e857\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.52577319587629%\"\u003e\n \u003cp\u003e857\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\"\u003e\n \u003cp\u003e857\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.402061855670103%\"\u003e\n \u003cp\u003e821\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5%\"\u003e\n \u003cp\u003e\u003cstrong\u003eProportion\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15%\"\u003e\n \u003cp\u003e\u003cstrong\u003e44.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003e27.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003e15.1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.75%\"\u003e\n \u003cp\u003e\u003cstrong\u003e19.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e\u003cstrong\u003e23.3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5%\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15%\"\u003e\n \u003cp\u003e38.5-50.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e24.6-30.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25%\"\u003e\n \u003cp\u003e3.7-47.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.75%\"\u003e\n \u003cp\u003e10.5-33.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e14.4-35.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5%\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15%\"\u003e\n \u003cp\u003e0.1613\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25%\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.75%\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5%\"\u003e\n \u003cp\u003eI\u003csup\u003e2\u003c/sup\u003e Inconsistency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15%\"\u003e\n \u003cp\u003e41.72%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e8.06%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25%\"\u003e\n \u003cp\u003e96.98%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.75%\"\u003e\n \u003cp\u003e94.11%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003e82.34%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.5%\"\u003e\n \u003cp\u003eEgger\u0026apos;s test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15%\"\u003e\n \u003cp\u003eP =\u003c/p\u003e\n \u003cp\u003e0.7723\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003eP =\u003c/p\u003e\n \u003cp\u003e0.5885\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25%\"\u003e\n \u003cp\u003eP =\u003c/p\u003e\n \u003cp\u003e0.0199\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.75%\"\u003e\n \u003cp\u003eP =\u003c/p\u003e\n \u003cp\u003e0.7668\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.25%\"\u003e\n \u003cp\u003eP =\u003c/p\u003e\n \u003cp\u003e0.2073\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eSAEs: serious adverse events, CI: confidence interval\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"RTS, S/AS01E, serious adverse events, clinical trials, Africa, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-3975532/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3975532/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe RTS,S/AS01E vaccine has been authorized for use in children in sub-Saharan Africa from the age of 5 months. Nevertheless, there is a limited number of clinical studies documenting serious adverse events (SAEs) and their correlation with the vaccine. This systematic review and meta-analysis aimed to analyze and summarize the data published to date on the primary serious adverse events (SAEs) associated with the RTS,S/AS01E malaria vaccine in children aged 5–17 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe systematic review adhered to the PRISMA 2020 guidelines. An extensive search was conducted across multiple databases, including PubMed, Cochrane Library, Wiley Online Library, and Web of Science, without any restrictions on publication year and language. The final search of databases and registries was completed on January 23, 2024. Randomized clinical trials (RCTs) related to SAEs of RTS,S/AS01E in children aged 5–17 months, for 0, 1, 2-schedule, were included in the study. The primary outcomes focused on the proportions of SAEs and deaths in RTS,S/AS01E vaccine recipients. Pooled effect size estimates and their 95% confidence intervals were obtained through random-effect models meta-analysis. Publication bias among included studies was evaluated using the \"risk of bias assessment\" tool from the Cochrane systematic review. Outcomes were tested for significance using Z tests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis meta-analysis comprised 10 studies and 30,573 children (19,769 recipients of RTS,S/AS01E and 10,804 control recipients). The combined frequency of all SAEs was 17.6% (95% CI: [15.3, 20.2]) among RTS,S/AS01E recipients, which was significantly lower than the combined frequency of 22% (95% CI: [0.204, 0.237]) observed in the control group, with a combined risk ratio (RR) of 0.80 (95% CI: [0.72, 0.90], \u003cem\u003eP\u003c/em\u003e = 0.0002). The combined frequency of all deaths was 1% (95% CI: [08, 1.2], \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001) among RTS,S/AS01E recipients, which was not significantly higher than the combined frequency of 0.7% (95% CI: [0.3, 1.7]) observed in the control group, with a combined RR of 1.04 (95% CI: [0.77, 1.41], \u003cem\u003eP\u003c/em\u003e = 0.79. Throughout the follow-up period, the frequently reported SAEs were as follows: severe malaria (25.9% and 44.6%), pneumonia (31.5% and 27.5%), gastroenteritis (14.8% and 15.1%), anemia (16.7% and 19.4%), and febrile convulsions (26.5% and 23.3%) in the RTS,S/AS01E and control groups, respectively. The corresponding odds ratios (ORs) were as follows: severe malaria 0.47 (95% CI: [0.29, 0.76], \u003cem\u003eP\u003c/em\u003e = 0.002), pneumonia 1.19 (95% CI: [0.98, 1.45], \u003cem\u003eP\u003c/em\u003e = 0.07), gastroenteritis 0.99 (95% CI: [0.65, 152], \u003cem\u003eP\u003c/em\u003e = 0.97), anemia 0.70 (95% CI: [0.33–1.47], \u003cem\u003eP\u003c/em\u003e = 0.34), and febrile convulsions 1.26 (95% CI: [1.00, 1.59], \u003cem\u003eP\u003c/em\u003e = 0.005).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe occurrence of major serious adverse events (SAEs) with the RTS vaccine is rare, and their frequency does not seem to differ from that in unvaccinated children. As a result, there were no significant major side effects associated with the vaccine. However, additional long-term data is required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCRD42024321008 / PROSPERO.\u003c/p\u003e","manuscriptTitle":"Frequency of serious adverse events and death in 5-17 months children receiving RTS,S/AS01E vaccine - a systematic review and meta-analysis of RCTs.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-04 19:01:46","doi":"10.21203/rs.3.rs-3975532/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b4aedf4c-ac1e-478f-934d-6d720b71715f","owner":[],"postedDate":"March 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-18T11:22:11+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-04 19:01:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3975532","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3975532","identity":"rs-3975532","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}