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The recommendations of the Immunization and Vaccines-related Implementation Research Advisory Committee (IVIR-AC) are based on discussions during a virtual meeting of IVIR-AC on 26 February-1 March 2024. (1) Four sessions [...]

Malaria remains a significant global health challenge, with millions of cases and high mortality rates annually, especially in low-income countries. Africa bears a substantial burden, with direct costs of malaria among children under five reaching millions of dollars in countries like Ghana, Tanzania, and Kenya. In 2021, over 610,000 malaria-related deaths were reported, 96% of which occurred in sub-Saharan Africa. Despite existing interventions, such as long-lasting insecticidal nets, indoor residual spraying, and intermittent preventive treatment, the re-emergence of malaria underscores the need for innovative preventive strategies. This study explores the potential of utilizing mobile phone caller tunes to raise awareness and promote the uptake of the RTS,S malaria vaccine. The technology acceptance model (TAM) provides a framework for understanding how users perceive and adopt new technologies. Caller tunes, a mobile phone feature that plays audio for callers waiting to be connected, have been effective in health communication campaigns in Asia and Africa. This approach could be leveraged to enhance malaria vaccine awareness, particularly in low-income countries where vaccine hesitancy is prevalent and malaria endemic. Overall, mobile technologies have significantly improved healthcare delivery in Africa, facilitating communication, monitoring, and treatment adherence in remote areas. Integrating caller tunes with health messages about the malaria vaccine could address vaccine hesitancy and improve uptake. This would require collaboration with telecommunication companies, healthcare providers, and policymakers to design culturally and linguistically appropriate messages. However, the cost of caller tune services, the need for internet access, and cultural differences are the expected challenge that may occur in this approach. Therefore, strategic partnerships and intersectoral approaches can mitigate these issues, making caller tunes a viable tool for public health communication. Raising awareness through this innovative method could enhance the adoption of the RTS,S vaccine and support ongoing malaria control efforts in Africa. [ABSTRACT FROM AUTHOR]

Aim: Malaria vaccine is one of the critical areas in tropical health research, considering the success recorded in other vaccine‐preventable diseases. This study is aimed at reviewing recent trends in global malaria vaccine research from 2005 to 2022. Method: A validated search strategy was undertaken to identify scientific literature on the malaria vaccine in the Scopus database. Bibliometric indicators identified include a pattern of publication growth and citations over the study period; top authors, countries, funding organizations, and journals; keywords, including different malarial parasite species, and the overall research themes. Result: A total of 6457 documents were found from 2005 to 2022, published in 160 journals/sources in 189 countries/territories. Malaria Journal published the highest number of research outputs (478, 7.4%) within the study period, and the highest number of documents (468, 7.3%) were published in 2021. There were 214,323 total citations, with 33.2 average citations per document and 167 documents' h‐index. The United States, United Kingdom, and Australia combined produced more than 60% of the publication output, with most collaboration with African countries such as Kenya. Plasmodium falciparum is the most occurring parasite species keyword (754, 11.7%), with a growing interest in Plasmodium knowlesi (30, 0.5%). Merozoite surface protein, characterization, trials, infant/children, traveler, and research/review were the six themes that emerged from the studies. Conclusion: The last one and half decades have seen a significant increase in malaria vaccine research and citations, mainly targeting vaccine development, safety, and efficacy in Africa. This necessitates more international efforts to improve the vaccines' effectiveness considering different Plasmodium species. [ABSTRACT FROM AUTHOR]

Background: The RTS,S malaria vaccine has been prequalified for use in endemic settings prioritizing areas with moderate to high disease transmission. The impact of a vaccine at the population level may differ from observations during clinical trial due to programmatic, and individual-related factors, among others. The objective of this study was to assess the impact of the RTS,S malaria vaccine on uncomplicated malaria among children aged 12–59 months in the Phase IV study districts, Upper East Region, Ghana. Methods: A retrospective study was conducted using routine malaria surveillance data for the period 2020–2022. The burden of uncomplicated malaria was compared between the implementing (Kasena Nankana East and West districts) and comparator areas (Builsa North and South districts). The impact of RTS,S malaria vaccine was assessed by estimating the percentage reduction in uncomplicated malaria and incidence averted in the implementing area, accounting for the effect of confounders. Results: Over 50,000 episodes of uncomplicated malaria among children aged 12–59 months were included in the study. Uncomplicated malaria was reduced by 33% (95%CI 29–36) over the entire study period, but the malaria incidence averted declined from 324/1,000 (95% CI 298–339; p < 0.0001) in 2020 to 287/1000 (95% CI 274–299; p < 0.0001) in 2022. Conclusion: The RTS,S malaria vaccine significantly reduced the burden of uncomplicated malaria among children aged 12–59 months in the implementing area. The sequential marginal declines in malaria incidence averted over the study period might be due to waning of protective immunity and acquisition of natural immunity as children age. Strengthening uptake of the currently recommended vaccines and other malaria control interventions is required to improve public health impact. [ABSTRACT FROM AUTHOR]

Aim: The review summarizes the recent empirical evidence on the efficacy, safety, and community perception of malaria vaccines in Africa. Methods: Academic Search Complete, African Journals Online, CINAHL, Medline, PsychInfo, and two gray literature sources were searched in January 2023, and updated in June 2023. Relevant studies published from 2012 were included. Studies were screened, appraised, and synthesized in line with the review aim. Statistical results are presented as 95% Confidence Intervals and proportions/percentages. Results: Sixty-six (N = 66) studies met the inclusion criteria. Of the vaccines identified, overall efficacy at 12 months was highest for the R21 vaccine (N = 3) at 77.0%, compared to the RTS,S vaccine (N = 15) at 55%. The efficacy of other vaccines was BK-SE36 (11.0–50.0%, N = 1), ChAd63/MVA ME-TRAP (− 4.7–19.4%, N = 2), FMP2.1/AS02A (7.6–9.9%, N = 1), GMZ2 (0.6–60.0%, N = 5), PfPZ (20.0–100.0%, N = 5), and PfSPZ-CVac (24.8–33.6%, N = 1). Injection site pain and fever were the most common adverse events (N = 26), while febrile convulsion (N = 8) was the most reported, vaccine-related Serious Adverse Event. Mixed perceptions of malaria vaccines were found in African communities (N = 17); awareness was generally low, ranging from 11% in Tanzania to 60% in Nigeria (N = 9), compared to willingness to accept the vaccines, which varied from 32.3% in Ethiopia to 96% in Sierra Leone (N = 15). Other issues include availability, logistics, and misconceptions. Conclusion: Malaria vaccines protect against malaria infection in varying degrees, with severe side effects rarely occurring. Further research is required to improve vaccine efficacy and community involvement is needed to ensure successful widespread use in African communities. [ABSTRACT FROM AUTHOR]

Maintaining high-affinity antibodies after vaccination may be important for long-lasting immunity to malaria, but data on induction and kinetics of affinity is lacking. In a phase 1 malaria vaccine trial, antibody affinity increased following a second vaccination but declined substantially over 12 months, suggesting poor maintenance of high-affinity antibodies. Clinical Trials Registration Australian New Zealand Clinical Trials Registry ACTRN12607000552482. [ABSTRACT FROM AUTHOR]

Abstract Malaria remains a significant global health challenge, with millions of cases and high mortality rates annually, especially in low-income countries. Africa bears a substantial burden, with direct costs of malaria among children under five reaching millions of dollars in countries like Ghana, Tanzania, and Kenya. In 2021, over 610,000 malaria-related deaths were reported, 96% of which occurred in sub-Saharan Africa. Despite existing interventions, such as long-lasting insecticidal nets, indoor residual spraying, and intermittent preventive treatment, the re-emergence of malaria underscores the need for innovative preventive strategies. This study explores the potential of utilizing mobile phone caller tunes to raise awareness and promote the uptake of the RTS,S malaria vaccine. The technology acceptance model (TAM) provides a framework for understanding how users perceive and adopt new technologies. Caller tunes, a mobile phone feature that plays audio for callers waiting to be connected, have been effective in health communication campaigns in Asia and Africa. This approach could be leveraged to enhance malaria vaccine awareness, particularly in low-income countries where vaccine hesitancy is prevalent and malaria endemic. Overall, mobile technologies have significantly improved healthcare delivery in Africa, facilitating communication, monitoring, and treatment adherence in remote areas. Integrating caller tunes with health messages about the malaria vaccine could address vaccine hesitancy and improve uptake. This would require collaboration with telecommunication companies, healthcare providers, and policymakers to design culturally and linguistically appropriate messages. However, the cost of caller tune services, the need for internet access, and cultural differences are the expected challenge that may occur in this approach. Therefore, strategic partnerships and intersectoral approaches can mitigate these issues, making caller tunes a viable tool for public health communication. Raising awareness through this innovative method could enhance the adoption of the RTS,S vaccine and support ongoing malaria control efforts in Africa.

Abstract Background The RTS,S malaria vaccine has been prequalified for use in endemic settings prioritizing areas with moderate to high disease transmission. The impact of a vaccine at the population level may differ from observations during clinical trial due to programmatic, and individual-related factors, among others. The objective of this study was to assess the impact of the RTS,S malaria vaccine on uncomplicated malaria among children aged 12–59 months in the Phase IV study districts, Upper East Region, Ghana. Methods A retrospective study was conducted using routine malaria surveillance data for the period 2020–2022. The burden of uncomplicated malaria was compared between the implementing (Kasena Nankana East and West districts) and comparator areas (Builsa North and South districts). The impact of RTS,S malaria vaccine was assessed by estimating the percentage reduction in uncomplicated malaria and incidence averted in the implementing area, accounting for the effect of confounders. Results Over 50,000 episodes of uncomplicated malaria among children aged 12–59 months were included in the study. Uncomplicated malaria was reduced by 33% (95%CI 29–36) over the entire study period, but the malaria incidence averted declined from 324/1,000 (95% CI 298–339; p

Abstract Apical membrane antigen 1 (AMA1) of malaria parasites plays an important role in host cell invasion. Antibodies to AMA1 can inhibit malaria merozoite invasion of erythrocytes while vaccine-induced specific cytotoxic T cell responses to this protein are associated with clinical protection. Polymorphisms in AMA1 of Plasmodium falciparum (PfAMA1) and P. vivax (PvAMA1) are of concern for vaccine development. To date, little is known about sequence diversity in ama1 of P. inui (Piama1), an emerging zoonotic malaria parasite. In this study, 80 complete Piama1 coding sequences were obtained from 57 macaques in Thailand that defined 60 haplotypes clustering in two phylogenetic lineages. In total, 74 nucleotide substitutions were identified and distributed unevenly across the gene. Blockwise analysis of the rates of synonymous (d S) and nonsynonymous (d N) nucleotide substitutions did not show a significant deviation from neutrality among Thai isolates. However, significantly negative Tajima’s D values were detected in domain I and the loop region of domain II, implying purifying selection. Codon-based analysis of d N/d S has identified 12 and 14 codons under positive and negative selections, respectively. Meanwhile, 85 amino acid substitutions were identified among 80 Thai and 11 non-Thai PiAMA1 sequences. Of these, 48 substituted residues had a significant alteration in physicochemical properties, suggesting positive selection. More than half of these positively selected amino acids (32 of 48) corresponded to the predicted B-cell or T-cell epitopes, suggesting that selective pressure could be mediated by host immunity. Importantly, 14 amino acid substitutions were singletons and predicted to be deleterious that could be subject to ongoing purifying selection or elimination. Besides genetic drift and natural selection, intragenic recombination identified in domain II could generate sequence variation in Piama1. It is likely that malarial ama1 exhibits interspecies differences in evolutionary histories. Knowledge of the sequence diversity of the Piama1 locus further provides an evolutionary perspective of this important malaria vaccine candidate.

Introduction In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of [...]

Abstract Background Globally, malaria continues to pose a major health challenge, with approximately 247 million cases of the illness and 627,000 deaths reported in 2021. However, the threat is particularly pronounced in sub-Saharan African countries, where pregnant women and children under the age of five face heightened vulnerability to the disease. As a result, the imperative to develop malaria vaccines especially for these vulnerable populations, remains crucial in the pursuit of malaria eradication. However, despite decades of research, effective vaccine development faces technical challenges, including the rapid spread of drug-resistant parasite strains, the complex parasite lifecycle, the development of liver hypnozoites with potential for relapse, and evasion of the host immune system. This review aims to discuss the different malaria vaccine candidates in the pipeline, highlighting different approaches used for adjuvating these candidates, their benefits, and outcomes, and summarizing the progress of these vaccine candidates under development. Method A comprehensive web-based search for peer-reviewed journal articles published in SCOPUS, MEDLINE (via PubMed), Science Direct, WHO, and Advanced Google Scholar databases was conducted from 1990 to May 2022. Context-specific keywords such as “Malaria”, “Malaria Vaccine”, “Malaria Vaccine Candidates”, “Vaccine Development”, “Vaccine Safety”, “Clinical Trials”, “mRNA Vaccines”, “Viral Vector Vaccines”, “Protein-based Vaccines”, “Subunit Vaccines”, “Vaccine Adjuvants”, “Vaccine-induced Immune Responses”, and “Immunogenicity” were emphatically considered. Articles not directly related to malaria vaccine candidates in preclinical and clinical stages of development were excluded. Results Various approaches have been studied for malaria vaccine development, targeting different parasite lifecycle stages, including the pre-erythrocytic, erythrocytic, and sexual stages. The RTS, S/AS01 vaccine, the first human parasite vaccine reaching WHO-listed authority maturity level 4, has demonstrated efficacy in preventing clinical malaria in African children. However, progress was slow in introducing other safe, and feasible malaria vaccines through clinical trials . Recent studies highlight the potential effectiveness of combining pre-erythrocytic and blood-stage vaccines, along with the advantages of mRNA vaccines for prophylaxis and treatment, and nonstructural vaccines for large-scale production. Conclusion Malaria vaccine candidates targeting different lifecycle stages of the parasite range from chemoprophylaxis vaccination to cross-species immune protection. The use of a multi-antigen, multi-stage combinational vaccine is therefore essential in the context of global health. This demands careful understanding and critical consideration of the long-term multi-faceted interplay of immune interference, co-dominance, complementary immune response, molecular targets, and adjuvants affecting the overall vaccine-induced immune response. Despite challenges, advancements in clinical trials and vaccination technology offer promising possibilities for novel approaches in malaria vaccine development.

Background The RTS,S/AS01E (RTS,S) malaria vaccine is recommended for children in malaria endemic areas. This phase 2b trial evaluates RTS,S fractional- and full-dose regimens in Ghana and Kenya. Methods In total, 1500 children aged 5–17 months were randomized (1:1:1:1:1) to receive RTS,S or rabies control vaccine. RTS,S groups received 2 full RTS,S doses at months 0 and 1 and either full (groups R012-20, R012-14-26) or fractional doses (one-fifth; groups Fx012-14-26, Fx017-20-32). Results At month 32 post-dose 1, vaccine efficacy against clinical malaria (all episodes) ranged from 38% (R012-20; 95% confidence interval [CI]: 24%–49%) to 53% (R012-14-26; 95% CI: 42%–62%). Vaccine impact (cumulative number of cases averted/1000 children vaccinated) was 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), and 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional vs full dose; post hoc analysis), we estimated cases averted/1000 RTS,S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), and 880 (Fx017-20-32). Conclusions Vaccine efficacy was similar across RTS,S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If maintained through trial end, these observations underscore the means to reduce cost per regimen thus maximizing impact and optimizing supply. Clinical Trials Registration NCT03276962 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]

Background: The development, approval and adoption of the malaria vaccine has provided effective supplemental protection against malaria for children in Ghana. However, heightened awareness of the new vaccine will play a critical role in its mass deployment and acceptance among potential recipients. This study therefore determined the sociodemographic characteristics associated with malaria vaccine awareness and ascertained the influence of traditional media exposure on awareness in Ghana. Methods: The study used the Demographic and Health Survey 2019 Malaria Indicator Survey Data. After necessary recoding, chi-square and complex survey bivariate/multivariate logistic regression analyses were performed using STATA 18.0. Results: Among the participants, 35.65% (95% CI: 33.83%–37.51%) had heard about the malaria vaccine. Positive predictors of awareness included higher education attainment (AOR = 1.92, 95% CI: 1.28–2.88), rural residency (AOR = 1.28, 95% CI: 1.05–1.56) and being in the northern part of the country (AOR 1.54, 95% CI: 1.14–2.07). Other positive predictors of awareness were Guan ethnicity (AOR = 1.75, 95% CI: 1.09–2.81), malaria health education (AOR = 1.73, 95% CI: 1.45–2.07) and radio set ownership (AOR = 1.39, 95% CI: 1.19–1.62). Television ownership (AOR = 0.84, 95% CI: 0.69–1.01) showed no significant relationship with awareness. Conclusion: The general nationwide awareness has not yet reached a desirable level. This study suggests that, the awareness drive, preferably through radio campaigns, must target individuals with less than tertiary education and urban communities. Awareness campaigns on televisions should be evaluated and possibly redesigned for effectiveness. [ABSTRACT FROM AUTHOR]

Background: Globally, malaria continues to pose a major health challenge, with approximately 247 million cases of the illness and 627,000 deaths reported in 2021. However, the threat is particularly pronounced in sub-Saharan African countries, where pregnant women and children under the age of five face heightened vulnerability to the disease. As a result, the imperative to develop malaria vaccines especially for these vulnerable populations, remains crucial in the pursuit of malaria eradication. However, despite decades of research, effective vaccine development faces technical challenges, including the rapid spread of drug-resistant parasite strains, the complex parasite lifecycle, the development of liver hypnozoites with potential for relapse, and evasion of the host immune system. This review aims to discuss the different malaria vaccine candidates in the pipeline, highlighting different approaches used for adjuvating these candidates, their benefits, and outcomes, and summarizing the progress of these vaccine candidates under development. Method: A comprehensive web-based search for peer-reviewed journal articles published in SCOPUS, MEDLINE (via PubMed), Science Direct, WHO, and Advanced Google Scholar databases was conducted from 1990 to May 2022. Context-specific keywords such as "Malaria", "Malaria Vaccine", "Malaria Vaccine Candidates", "Vaccine Development", "Vaccine Safety", "Clinical Trials", "mRNA Vaccines", "Viral Vector Vaccines", "Protein-based Vaccines", "Subunit Vaccines", "Vaccine Adjuvants", "Vaccine-induced Immune Responses", and "Immunogenicity" were emphatically considered. Articles not directly related to malaria vaccine candidates in preclinical and clinical stages of development were excluded. Results: Various approaches have been studied for malaria vaccine development, targeting different parasite lifecycle stages, including the pre-erythrocytic, erythrocytic, and sexual stages. The RTS, S/AS01 vaccine, the first human parasite vaccine reaching WHO-listed authority maturity level 4, has demonstrated efficacy in preventing clinical malaria in African children. However, progress was slow in introducing other safe, and feasible malaria vaccines through clinical trials. Recent studies highlight the potential effectiveness of combining pre-erythrocytic and blood-stage vaccines, along with the advantages of mRNA vaccines for prophylaxis and treatment, and nonstructural vaccines for large-scale production. Conclusion: Malaria vaccine candidates targeting different lifecycle stages of the parasite range from chemoprophylaxis vaccination to cross-species immune protection. The use of a multi-antigen, multi-stage combinational vaccine is therefore essential in the context of global health. This demands careful understanding and critical consideration of the long-term multi-faceted interplay of immune interference, co-dominance, complementary immune response, molecular targets, and adjuvants affecting the overall vaccine-induced immune response. Despite challenges, advancements in clinical trials and vaccination technology offer promising possibilities for novel approaches in malaria vaccine development. [ABSTRACT FROM AUTHOR]

Background Malaria is preventable yet causes >600 000 deaths annually. RTS,S, the first marketed malaria vaccine, has modest efficacy, but improvements are needed for eradication. Methods We conducted an open-label, dose escalation phase 1 study of a full-length recombinant circumsporozoite protein vaccine (rCSP) administered with adjuvant glucopyranosyl lipid A–liposome Quillaja saponaria 21 formulation (GLA-LSQ) on days 1, 29, and 85 or 1 and 490 to healthy, malaria-naive adults. The primary end points were safety and reactogenicity. The secondary end points were antibody responses and Plasmodium falciparum parasitemia after homologous controlled human malaria infection. Results Participants were enrolled into 4 groups receiving rCSP/GLA-LSQ: 10 µg × 3 (n = 20), 30 µg × 3 (n = 10), 60 µg × 3 (n = 10), or 60 µg × 2 (n = 9); 10 participants received 30 µg rCSP alone × 3, and there were 6 infectivity controls. Participants experienced no serious adverse events. Rates of solicited and unsolicited adverse events were similar among groups. All 26 participants who underwent controlled human malaria infection 28 days after final vaccinations developed malaria. Increasing vaccine doses induced higher immunoglobulin G titers but did not achieve previously established RTS,S benchmarks. Conclusions rCSP/GLA-LSQ had favorable safety results. However, tested regimens did not induce protective immunity. Further investigation could assess whether adjuvant or schedule adjustments improve efficacy. Clinical Trials Registration NCT03589794 [ABSTRACT FROM AUTHOR]

Background and Objective: Despite the significant burden of Plasmodium falciparum (Pf) malaria and the licensure of two vaccines for use in infants and young children that are partially effective in preventing clinical malaria caused by Pf, a highly effective vaccine against Pf infection is still lacking. Live attenuated vaccines using Pf sporozoites as the immunogen (PfSPZ Vaccines) hold promise for addressing this gap. Here we review the safety and efficacy of two of the most promising PfSPZ approaches: PfSPZ Vaccine (radiation attenuated PfSPZ) and PfSPZ-CVac (chemo-attenuated PfSPZ). Methods: We conducted a systematic review and meta-analysis by searching PubMed, EMBASE, SCOPUS, CENTRAL, and WOS until 22nd December 2021. We included randomized controlled trials (RCTs) of these two vaccine approaches that measured protection against parasitaemia following controlled human malaria infection (CHMI) in malaria-naive and malaria-exposed adults or following exposure to naturally transmitted Pf malaria in African adults and children (primary outcome) and that also measured the incidence of solicited and unsolicited adverse events as indicators of safety and tolerability after vaccination (secondary outcome). We included randomized controlled trials (RCTs) that measured the detected parasitaemia after vaccination (primary outcome) and the incidence of various solicited and unsolicited adverse events (secondary outcome). The quality of the included RCTs using the Cochrane ROB 1 tool and the quality of evidence using the GRADE system were evaluated. We pooled dichotomous data using the risk ratio (RR) for development of parasitemia in vaccinees relative to controls as a measure of vaccine efficacy (VE), including the corresponding confidence interval (CI). This study was registered with PROSPERO (CRD42022308057). Results: We included 19 RCTs. Pooled RR favoured PfSPZ Vaccine (RR: 0.65 with 95% CI [0.53, 0.79], P = 0.0001) and PfSPZ-table (RR: 0.42 with 95% CI [0.27, 0.67], P = 0.0002) for preventing parasitaemia, relative to normal saline placebo. Pooled RR showed no difference between PfSPZ Vaccine and the control in the occurrence of any solicited adverse event (RR: 1.00 with 95% CI [0.82, 1.23], P = 0.98), any local solicited adverse events (RR: 0.73 with 95% CI [0.49, 1.08], P = 0.11), any systemic solicited adverse events (RR: 0.94 with 95% CI [0.75, 1.17], P = 0.58), and any unsolicited adverse event (RR: 0.93 with 95% CI [0.78, 1.10], P = 0.37). Conclusion: PfSPZ and PfSPZ-CVacs showed comparable efficacy. Therefore, they can introduce a promising strategy for malaria prophylaxis, but more large-scale field trials are required to sustain efficacy and yield clinically applicable findings. [ABSTRACT FROM AUTHOR]

Introduction: The uptake trend of a new vaccine is unpredictable and may reflect the quality of introduction process and community acceptance. The objective of this study was to conduct a trend analysis of RTS,S malaria vaccine uptake in the seven pilot regions of Ghana from 2019 to 2022. The findings are envisaged to strengthen malaria vaccine introductions in the future. Methods: A retrospective analysis was conducted on routine childhood immunisation data for 2019–2022. Coverages for the first (RTS,S1), second (RTS,S2), third (RTS,S3) and fourth (RTS,S4) doses of malaria vaccine; third dose of diphtheria, tetanus, pertussis-containing vaccine (DTP3/Penta3); first dose measles-rubella (MR1) and second dose measles-rubella (MR2) vaccines were calculated. Dropout rates and uptake gaps were estimated to assess variations in the uptake of consecutive RTS,S schedules; and the differences in the uptake of RTS,S and the comparator vaccines, respectively. Results: Nationally, the coverages of the first three doses of the RTS,S malaria vaccine rose sharply from 2019 (RTS,S1 = 54.9 %; RTS,S2 = 54.6 %; RTS,S3 = 38.6 %) through 2020 (RTS,S1 = 70.7 %; RTS,S2 = 67.4 %; RTS,S3 = 66.3 %) to peaks in 2021 (RTS,S1 = 76.0 %; RTS,S2 = 73.1 %; RTS,S3 = 74.2 %), and declined marginally in 2022 (RTS,S1 = 74.0 %; RTS,S2 = 69.9 %; RTS,S3 = 71.3 %). For the fourth dose, the low uptake in 2020 (7.5 %) was followed by a steep rise in 2021 (46.9 %) that continued, but at a reduced rate to 50.6% in 2022. The dropout rates and uptake gaps were initially high but declined consistently over the study period. Generally, the trends in vaccination coverages, and dropout rates and uptake gaps at the national level were reflected in the respective regions. Conclusion: The coverage of RTS,S malaria vaccine improved consistently over the study period despite the low uptake in the early phase of the pilot. While the decreasing dropout rates and uptake gaps may indicate improved community acceptance, strengthening immunisation service delivery is crucial in sustaining the observed trajectory.

Abstract Background In 2021 and 2023, the World Health Organization approved RTS,S/AS01 and R21/Matrix M malaria vaccines, respectively, for routine immunization of children in African countries with moderate to high transmission. These vaccines are made of Plasmodium falciparum circumsporozoite protein (PfCSP), but polymorphisms in the gene raise concerns regarding strain-specific responses and the long-term efficacy of these vaccines. This study assessed the Pfcsp genetic diversity, population structure and signatures of selection among parasites from areas of different malaria transmission intensities in Mainland Tanzania, to generate baseline data before the introduction of the malaria vaccines in the country. Methods The analysis involved 589 whole genome sequences generated by and as part of the MalariaGEN Community Project. The samples were collected between 2013 and January 2015 from five regions of Mainland Tanzania: Morogoro and Tanga (Muheza) (moderate transmission areas), and Kagera (Muleba), Lindi (Nachingwea), and Kigoma (Ujiji) (high transmission areas). Wright’s inbreeding coefficient (Fws), Wright’s fixation index (FST), principal component analysis, nucleotide diversity, and Tajima’s D were used to assess within-host parasite diversity, population structure and natural selection. Results Based on Fws (

Abstract Background There are giant steps taken in the introduction of the novel malaria vaccine poised towards reducing mortality and morbidity associated with malaria. Objectives This study aimed to determine the knowledge of malaria vaccine and factors militating against willingness to accept the vaccine among mothers presenting in nine hospitals in Enugu metropolis. Methods This was a cross-sectional study carried out among 491 mothers who presented with their children in nine hospitals in Enugu metropolis, South-East Nigeria. A pre-tested and interviewer-administered questionnaire was used in this study. Results A majority of the respondents, 72.1% were aware of malaria vaccine. A majority of the respondents, 83.1% were willing to receive malaria vaccine. Similarly, a majority of the mothers, 92.9%, were willing to vaccinate baby with the malaria vaccine, while 81.1% were willing to vaccinate self and baby with the malaria vaccine. The subjects who belong to the low socio-economic class were five times less likely to vaccinate self and baby with malaria vaccine when compared with those who were in the high socio-economic class (AOR = 0.2, 95% CI 0.1–0.5). Mothers who had good knowledge of malaria vaccination were 3.3 times more likely to vaccinate self and baby with malaria vaccine when compared with those who had poor knowledge of malaria vaccination (AOR = 3.3, 95% CI 1–6–6.8). Conclusion Although the study documented a high vaccine acceptance among the mothers, there exists a poor knowledge of the malaria vaccine among them.

Abstract Background Malaria remains a significant global health burden affecting millions of people, children under 5 years and pregnant women being most vulnerable. In 2019, the World Health Organization (WHO) endorsed the introduction of RTS,S/AS01 malaria vaccine as Phase IV implementation evaluation in three countries: Malawi, Kenya and Ghana. Acceptability and factors influencing vaccination coverage in implementing areas is relatively unknown. In Malawi, only 60% of children were fully immunized with malaria vaccine in Nsanje district in 2021, which is below 80% WHO target. This study aimed at exploring factors influencing uptake of malaria vaccine and identify approaches to increase vaccination. Methods In a cross-sectional study conducted in April–May, 2023, 410 mothers/caregivers with children aged 24–36 months were selected by stratified random sampling and interviewed using a structured questionnaire. Vaccination data was collected from health passports, for those without health passports, data was collected using recall history. Regression analyses were used to test association between independent variables and full uptake of malaria vaccine. Results Uptake of malaria vaccine was 90.5% for dose 1, but reduced to 87.6%, 69.5% and 41.2% for dose 2, 3, and 4 respectively. Children of caregivers with secondary or upper education and those who attended antenatal clinic four times or more had increased odds of full uptake of malaria vaccine [OR: 2.43, 95%CI 1.08–6.51 and OR: 1.89, 95%CI 1.18–3.02], respectively. Children who ever suffered side-effects following immunization and those who travelled long distances to reach the vaccination centre had reduced odds of full uptake of malaria vaccine [OR: 0.35, 95%CI 0.06–0.25 and OR: 0.30, 95%CI 0.03–0.39] respectively. Only 17% (n = 65) of mothers/caregivers knew the correct schedule for vaccination and 38.5% (n = 158) knew the correct number of doses a child was to receive. Conclusion Only RTS,S dose 1 and 2 uptake met WHO coverage targets. Mothers/caregivers had low level of information regarding malaria vaccine, especially on numbers of doses to be received and dosing schedule. The primary modifiable factor influencing vaccine uptake was mother/caregiver knowledge about the vaccine. Thus, to increase the uptake Nsanje District Health Directorate should strengthen communities’ education about malaria vaccine. Programmes to strengthen mother/caregiver knowledge should be included in scale-up of the vaccine in Malawi and across sub-Saharan Africa.

Background: In 2021 and 2023, the World Health Organization approved RTS,S/AS01 and R21/Matrix M malaria vaccines, respectively, for routine immunization of children in African countries with moderate to high transmission. These vaccines are made of Plasmodium falciparum circumsporozoite protein (PfCSP), but polymorphisms in the gene raise concerns regarding strain-specific responses and the long-term efficacy of these vaccines. This study assessed the Pfcsp genetic diversity, population structure and signatures of selection among parasites from areas of different malaria transmission intensities in Mainland Tanzania, to generate baseline data before the introduction of the malaria vaccines in the country. Methods: The analysis involved 589 whole genome sequences generated by and as part of the MalariaGEN Community Project. The samples were collected between 2013 and January 2015 from five regions of Mainland Tanzania: Morogoro and Tanga (Muheza) (moderate transmission areas), and Kagera (Muleba), Lindi (Nachingwea), and Kigoma (Ujiji) (high transmission areas). Wright's inbreeding coefficient (Fws), Wright's fixation index (FST), principal component analysis, nucleotide diversity, and Tajima's D were used to assess within-host parasite diversity, population structure and natural selection. Results: Based on Fws (< 0.95), there was high polyclonality (ranging from 69.23% in Nachingwea to 56.9% in Muheza). No population structure was detected in the Pfcsp gene in the five regions (mean FST = 0.0068). The average nucleotide diversity (π), nucleotide differentiation (K) and haplotype diversity (Hd) in the five regions were 4.19, 0.973 and 0.0035, respectively. The C-terminal region of Pfcsp showed high nucleotide diversity at Th2R and Th3R regions. Positive values for the Tajima's D were observed in the Th2R and Th3R regions consistent with balancing selection. The Pfcsp C-terminal sequences revealed 50 different haplotypes (H_1 to H_50), with only 2% of sequences matching the 3D7 strain haplotype (H_50). Conversely, with the NF54 strain, the Pfcsp C-terminal sequences revealed 49 different haplotypes (H_1 to H_49), with only 0.4% of the sequences matching the NF54 strain (Hap_49). Conclusions: The findings demonstrate high diversity of the Pfcsp gene with limited population differentiation. The Pfcsp gene showed positive Tajima's D values, consistent with balancing selection for variants within Th2R and Th3R regions. The study observed differences between the intended haplotypes incorporated into the design of RTS,S and R21 vaccines and those present in natural parasite populations. Therefore, additional research is warranted, incorporating other regions and more recent data to comprehensively assess trends in genetic diversity within this important gene. Such insights will inform the choice of alleles to be included in the future vaccines. [ABSTRACT FROM AUTHOR]

Background: There are giant steps taken in the introduction of the novel malaria vaccine poised towards reducing mortality and morbidity associated with malaria. Objectives: This study aimed to determine the knowledge of malaria vaccine and factors militating against willingness to accept the vaccine among mothers presenting in nine hospitals in Enugu metropolis. Methods: This was a cross-sectional study carried out among 491 mothers who presented with their children in nine hospitals in Enugu metropolis, South-East Nigeria. A pre-tested and interviewer-administered questionnaire was used in this study. Results: A majority of the respondents, 72.1% were aware of malaria vaccine. A majority of the respondents, 83.1% were willing to receive malaria vaccine. Similarly, a majority of the mothers, 92.9%, were willing to vaccinate baby with the malaria vaccine, while 81.1% were willing to vaccinate self and baby with the malaria vaccine. The subjects who belong to the low socio-economic class were five times less likely to vaccinate self and baby with malaria vaccine when compared with those who were in the high socio-economic class (AOR = 0.2, 95% CI 0.1–0.5). Mothers who had good knowledge of malaria vaccination were 3.3 times more likely to vaccinate self and baby with malaria vaccine when compared with those who had poor knowledge of malaria vaccination (AOR = 3.3, 95% CI 1–6–6.8). Conclusion: Although the study documented a high vaccine acceptance among the mothers, there exists a poor knowledge of the malaria vaccine among them. [ABSTRACT FROM AUTHOR]

Background: Malaria remains a significant global health burden affecting millions of people, children under 5 years and pregnant women being most vulnerable. In 2019, the World Health Organization (WHO) endorsed the introduction of RTS,S/AS01 malaria vaccine as Phase IV implementation evaluation in three countries: Malawi, Kenya and Ghana. Acceptability and factors influencing vaccination coverage in implementing areas is relatively unknown. In Malawi, only 60% of children were fully immunized with malaria vaccine in Nsanje district in 2021, which is below 80% WHO target. This study aimed at exploring factors influencing uptake of malaria vaccine and identify approaches to increase vaccination. Methods: In a cross-sectional study conducted in April–May, 2023, 410 mothers/caregivers with children aged 24–36 months were selected by stratified random sampling and interviewed using a structured questionnaire. Vaccination data was collected from health passports, for those without health passports, data was collected using recall history. Regression analyses were used to test association between independent variables and full uptake of malaria vaccine. Results: Uptake of malaria vaccine was 90.5% for dose 1, but reduced to 87.6%, 69.5% and 41.2% for dose 2, 3, and 4 respectively. Children of caregivers with secondary or upper education and those who attended antenatal clinic four times or more had increased odds of full uptake of malaria vaccine [OR: 2.43, 95%CI 1.08–6.51 and OR: 1.89, 95%CI 1.18–3.02], respectively. Children who ever suffered side-effects following immunization and those who travelled long distances to reach the vaccination centre had reduced odds of full uptake of malaria vaccine [OR: 0.35, 95%CI 0.06–0.25 and OR: 0.30, 95%CI 0.03–0.39] respectively. Only 17% (n = 65) of mothers/caregivers knew the correct schedule for vaccination and 38.5% (n = 158) knew the correct number of doses a child was to receive. Conclusion: Only RTS,S dose 1 and 2 uptake met WHO coverage targets. Mothers/caregivers had low level of information regarding malaria vaccine, especially on numbers of doses to be received and dosing schedule. The primary modifiable factor influencing vaccine uptake was mother/caregiver knowledge about the vaccine. Thus, to increase the uptake Nsanje District Health Directorate should strengthen communities' education about malaria vaccine. Programmes to strengthen mother/caregiver knowledge should be included in scale-up of the vaccine in Malawi and across sub-Saharan Africa. [ABSTRACT FROM AUTHOR]

Efficacy data on two malaria vaccines, RTS,S and R21, targeting Plasmodium falciparum circumsporozoite protein (PfCSP), are encouraging. Efficacy may be improved by induction of additional antibodies to neutralizing epitopes outside of the central immunodominant repeat domain of PfCSP. We designed four rPfCSP-based vaccines in an effort to improve the diversity of the antibody response. We also evaluated P. falciparum merozoite surface protein 8 (PfMSP8) as a malaria-specific carrier protein as an alternative to hepatitis B surface antigen. We measured the magnitude, specificity, subclass, avidity, durability, and efficacy of vaccine-induced antibodies in outbred CD1 mice. In comparison to N-terminal- or C-terminal-focused constructs, immunization with near full-length vaccines, rPfCSP (#1) or the chimeric rPfCSP/8 (#2), markedly increased the breadth of B cell epitopes recognized covering the N-terminal domain, junctional region, and central repeat. Both rPfCSP (#1) and rPfCSP/8 (#2) also elicited a high proportion of antibodies to conformation-dependent epitopes in the C-terminus of PfCSP. Fusion of PfCSP to PfMSP8 shifted the specificity of the T cell response away from PfCSP toward PfMSP8 epitopes. Challenge studies with transgenic Plasmodium yoelii sporozoites expressing PfCSP demonstrated high and consistent sterile protection following rPfCSP/8 (#2) immunization. Of note, antibodies to conformational C-terminal epitopes were not required for protection. These results indicate that inclusion of the N-terminal domain of PfCSP can drive responses to protective, repeat, and non-repeat B cell epitopes and that PfMSP8 is an effective carrier for induction of high-titer, durable anti-PfCSP antibodies. [ABSTRACT FROM AUTHOR]

Cameroon introduced the malaria vaccine in its routine immunization program on 22 January 2024 in the 42 districts out of 200 that are among the most at risk of malaria. A cross-sectional analysis of the data on key vaccine events in the introduction roadmap and the vaccine uptake during the first 30 days was conducted. In addition to available gray literature related to the introduction of the malaria vaccine, data on the malaria vaccine uptake by vaccination session, collected through a digital platform, were analyzed. A total of 1893 reports were received from 22 January 2024 to 21 February 2024 from 766 health facilities (84% of overall completeness). Two regions out of ten recorded less than 80% completeness. As of 21 February 2024, 13,811 children had received the first dose of the malaria vaccine, including 7124 girls (51.6%) and 6687 boys (48.4%). In total, 36% of the children were vaccinated through outreach sessions, while 61.5% were vaccinated through sessions in fixed posts. The overall monthly immunization coverage with the first dose was 37%. Early results have shown positive attitudes towards and acceptance of malaria vaccines. Suboptimal completeness of data reporting and a low coverage highlight persistent gaps and challenges in the vaccine rollout. [ABSTRACT FROM AUTHOR]

Malaria, caused by different species of protists of the genus Plasmodium, remains among the most common causes of death due to parasitic diseases worldwide, mainly for children aged under 5. One of the main obstacles to malaria eradication is the speed with which the pathogen evolves resistance to the drug schemes developed against it. For this reason, it remains urgent to find innovative therapeutic strategies offering sufficient specificity against the parasite to minimize resistance evolution and drug side effects. In this context, nanotechnology‐based approaches are now being explored for their use as antimalarial drug delivery platforms due to the wide range of advantages and tuneable properties that they offer. However, major challenges remain to be addressed to provide a cost‐efficient and targeted therapeutic strategy contributing to malaria eradication. The present work contains a systematic review of nanotechnology‐based antimalarial drug delivery systems generated during the last 10 years. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease [ABSTRACT FROM AUTHOR]

Abstract Background Malaria is a major global health challenge, and for the elimination and eradication of this disease, transmission-blocking vaccines (TBVs) are a priority. Plasmodium falciparum Generative Cell Specific 1 (PfGCS1), a promising TBV candidate, is essential for gamete fertilization. The HAP2-GCS1 domain of this antigen as well as its cd loop could induce antibodies that partially inhibit transmission of P. falciparum. Methods In the current study, a new synthetic fusion antigen containing cd loop and HAP2-GCS1 domain (cd-HAP) of PfGCS1 was evaluated as a transmission blocking vaccine candidate. Initially, the profile of naturally acquired IgG antibodies to the cd-HAP antigen was analysed in Iranian individuals infected with P. falciparum, to confirm that this new fusion protein has the appropriate structure containing common epitopes with the native form of PfGCS1. Then, the immunogenicity of cd-HAP was evaluated in BALB/c mice, using different adjuvant systems such as CpG, MPL, QS-21, and a combination of them (CMQ). Furthermore, the blocking efficacy of polyclonal antibodies induced against these formulations was also assessed by oocyst intensity and infection prevalence in the Standard Membrane Feeding Assay (SMFA). Results The naturally acquired antibodies (dominantly IgG1 and IgG3 subclasses) induced in P. falciparum-infected individuals could recognize the cd-HAP antigen which implies that the new fusion protein has a proper conformation that mimics the native structure of PfGCS1. Concerning the immunogenicity of cd-HAP antigen, the highest IgG levels and titers, by a Th1-type immune profile, and elevated antibody avidity were induced in mice immunized with the cd-HAP antigen formulated with a combination of adjuvants (P

Information on the dynamics and decline/persistence of antibody titres is important in vaccine development. A recent vaccine trial in malaria-exposed, healthy African adults and children living in a malaria hyperendemic and seasonal area (Ouagadougou, Burkina Faso) was the first study in which BK-SE36/CpG was administered to different age groups. In 5- to 10-year-old children, the risk of malaria infection was markedly lower in the BK-SE36/CpG arm compared to the control arm. We report here data on antibody titres measured in this age-group after the high malaria transmission season of 2021 (three years after the first vaccine dose was administered). At Year 3, 83% of children had detectable anti-SE36 total IgG antibodies. Geometric mean antibody titres and the proportion of children with detectable anti-SE36 antibodies were markedly higher in the BK-SE36/CpG arm than the control (rabies) arm. The information obtained in this study will guide investigators on future vaccine/booster schedules for this promising blood-stage malaria vaccine candidate. [ABSTRACT FROM AUTHOR]

In 2019, national immunization programs in Ghana, Kenya, and Malawi commenced the implementation of RTS,S/AS01 vaccination in large-scale pilot schemes. Understanding the implementation context of this malaria vaccination in the pilot countries can provide useful insights for enhancing implementation outcomes in new countries. There has not yet been a proper synthesis of the implementation determinants of malaria vaccination programs. A rapid review was conducted to identify the implementation determinants of the pilot malaria vaccination programs in Ghana, Kenya, and Malawi, and describe the mechanism by which these determinants interact with each other. A literature search was conducted in November 2023 in PubMed and Google Scholar to identify those studies that described the factors affecting malaria vaccine implementation in Ghana, Kenya, and Malawi. Thirteen studies conducted between 2021 and 2023 were included. A total of 62 implementation determinants of malaria vaccination across all five domains of the consolidated framework for implementation research (CFIR) were identified. A causal loop diagram showed that these factors are interconnected and interrelated, identifying nine reinforcing loops and two balancing loops. As additional countries in Africa prepare for a malaria vaccine roll-out, it is pertinent to ensure that they have access to adequate information about the implementation context of countries that are already implementing malaria vaccination programs so that they understand the potential barriers and facilitators. This information can be used to inform context-specific systems enhancement to maximize implementation success. Going forward, primary implementation studies that incorporate the causal loop diagram should be integrated into the malaria vaccine implementation program to enable immunization program managers and other key stakeholders to identify and respond to emerging implementation barriers in a timely and systematic manner, to improve overall implementation performance. [ABSTRACT FROM AUTHOR]

Background: Malaria is a major global health challenge, and for the elimination and eradication of this disease, transmission-blocking vaccines (TBVs) are a priority. Plasmodium falciparum Generative Cell Specific 1 (PfGCS1), a promising TBV candidate, is essential for gamete fertilization. The HAP2-GCS1 domain of this antigen as well as its cd loop could induce antibodies that partially inhibit transmission of P. falciparum. Methods: In the current study, a new synthetic fusion antigen containing cd loop and HAP2-GCS1 domain (cd-HAP) of PfGCS1 was evaluated as a transmission blocking vaccine candidate. Initially, the profile of naturally acquired IgG antibodies to the cd-HAP antigen was analysed in Iranian individuals infected with P. falciparum, to confirm that this new fusion protein has the appropriate structure containing common epitopes with the native form of PfGCS1. Then, the immunogenicity of cd-HAP was evaluated in BALB/c mice, using different adjuvant systems such as CpG, MPL, QS-21, and a combination of them (CMQ). Furthermore, the blocking efficacy of polyclonal antibodies induced against these formulations was also assessed by oocyst intensity and infection prevalence in the Standard Membrane Feeding Assay (SMFA). Results: The naturally acquired antibodies (dominantly IgG1 and IgG3 subclasses) induced in P. falciparum-infected individuals could recognize the cd-HAP antigen which implies that the new fusion protein has a proper conformation that mimics the native structure of PfGCS1. Concerning the immunogenicity of cd-HAP antigen, the highest IgG levels and titers, by a Th1-type immune profile, and elevated antibody avidity were induced in mice immunized with the cd-HAP antigen formulated with a combination of adjuvants (P < 0.0001). Additionally, cytokine profiling of the immunized mice displayed that a high level of IFN-γ response, a Th1-type immune response, was produced by splenocytes from immunized mice that received cd-HAP antigen in combination with CMQ adjuvants (P < 0.0001). This formulation of cd-HAP antigen with CMQ adjuvants could reduce oocyst intensity and infection prevalence by 82%, evidenced by the SMFA and hold significant implications for future malaria vaccine development. Conclusion: Altogether, the results showed that cd-HAP antigen formulated with a combination of the adjuvants (CMQ), could be a promising formulation to develop a PfGCS1-based transmission-blocking vaccine. [ABSTRACT FROM AUTHOR]

We previously reported a protective antibody response in mice immunized with synthetic microparticle vaccines made using layer-by-layer fabrication (LbL-MP) and containing the conserved T1BT* epitopes from the P. falciparum circumsporozoite protein. To further optimize the vaccine candidate, a benchtop tangential flow filtration method (LbL-by-TFF) was developed and utilized to produce vaccine candidates that differed in the status of base layer crosslinking, inclusion of a TLR2 ligand in the antigenic peptide, and substitution of serine or alanine for an unpaired cysteine residue in the T* epitope. Studies in mice revealed consistent superiority of the Pam3Cys-modified candidates and a modest benefit of base layer crosslinking, as evidenced by higher and more persistent antibody titers (up to 18 months post-immunization), a qualitative improvement of T-cell responses toward a Th1 phenotype, and greater protection from live parasite challenges compared to the unmodified prototype candidate. Immunogenicity was also tested in a non-human primate model, the rhesus macaque. Base layer-crosslinked LbL-MP loaded with T1BT* peptide with or without covalently linked Pam3Cys elicited T1B-specific antibody responses and T1BT*-specific T-cell responses dominated by IFNγ secretion with lower levels of IL-5 secretion. The Pam3Cys-modified construct was more potent, generating antibody responses that neutralized wild-type P. falciparum in an in vitro hepatocyte invasion assay. IgG purified from individual macaques immunized with Pam3Cys.T1BT* LbL-MP protected naïve mice from challenges with transgenic P. berghei sporozoites that expressed the full-length PfCS protein, with 50–88% of passively immunized mice parasite-free for ≥15 days. Substitution of serine for an unpaired cysteine in the T* region of the T1BT* subunit did not adversely impact immune potency in the mouse while simplifying the manufacture of the antigenic peptide. In a Good Laboratory Practices compliant rabbit toxicology study, the base layer-crosslinked, Pam3Cys-modified, serine-substituted candidate was shown to be safe and immunogenic, eliciting parasite-neutralizing antibody responses and establishing the dose/route/regimen for a clinical evaluation of this novel synthetic microparticle pre-erythrocytic malaria vaccine candidate. [ABSTRACT FROM AUTHOR]

Abstract Background Malaria is a significant public health threat in sub-Saharan Africa, particularly among children. The RTS,S/AS01 malaria vaccine reduces the risk and severity of malaria in children. RTS,S/AS01 was piloted in three African countries, Ghana, Kenya and Malawi, to assess safety, feasibility and cost-effectiveness in real-world settings. A qualitative longitudinal study was conducted as part of the feasibility assessment. This analysis explores RTS,S/AS01 vaccination barriers and identifies potential motivators among caregivers in three sub-counties in western Kenya. Methods A cohort of 63 caregivers with a malaria vaccine eligible child was interviewed at three time points over 24 months. A sub-set of 11 caregivers whose eligible children were either partially or non-vaccinated were selected for this sub-analysis. The 5A Taxonomy for root causes of under-vaccination was used to organise the inductively-coded data into categories (awareness, acceptance, access, affordability, and activation) and identify the factors influencing uptake across caregivers. A trajectory analysis was conducted to understand changes in factors over time within each caregiver experience. Caregiver narratives are used to illustrate how the factors influencing uptake were interrelated and changed over time. Results Lack of awareness, previous negative experiences with routine childhood immunisations and the burden of getting to the health facility contributed to caregivers initially delaying uptake of the vaccine. Over time concerns about vaccine side effects diminished and anticipated vaccination benefits strongly motivated caregivers to vaccinate their children. Persistent health system barriers (e.g., healthcare provider strikes, vaccine stockouts, negative provider attitudes) meant some children missed the first-dose eligibility window by aging-out. Conclusions Caregivers in this study believed the RTS,S/AS01 to be effective and were motivated to have their children vaccinated. Despite these positive perceptions of the malaria vaccine, uptake was substantially hindered by persistent health system constraints. Negative provider attitudes emerged as a powerful deterrent to attending immunisation services and hampered uptake of the vaccine. Strategies that focus on improving interpersonal communication skills among healthcare providers are needed.