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Background In October 2021, the World Health Organization (WHO) recommended the RTS,S/AS01 E (RTS,S) malaria vaccine for the prevention of Plasmodium falciparum malaria in children living in endemic areas informed by evidence from the subnational pilot introduction and evaluation in Ghana, Kenya, and Malawi as part of the WHO-coordinated Malaria Vaccine Implementation Programme (MVIP). With the global vaccine supply boosted by the pre-qualification of a second malaria vaccine, R21/Matrix-M (R21), in October 2023, many endemic countries (20 as of April 2025) have introduced malaria vaccines into their national childhood immunization and malaria control programmes. More endemic countries are expected to introduce or scale up malaria vaccines in 2025 and beyond. This paper summarizes key operational lessons from the pilot countries to facilitate the introduction and scale-up of malaria vaccination in other countries. Methods Pilot areas were identified, in part, based on local malaria epidemiology. RTS,S was initially introduced in randomly selected areas, while other areas served as comparators until the four-dose schedule vaccine was scaled up following the WHO recommendation in 2021. In Ghana and Kenya, the vaccine was administered at ages 6, 7, 9, and 24 months (Ghana switched to administer the fourth dose at age 18 months in 2023), and Malawi chose a schedule of 5, 6, 7, and 22 months. Results Vaccination coverage improved over time, reaching about 80% for the first dose and around 75% for the third dose by 2023 in the initial pilot areas. Implementation challenges included an inadequate understanding of age eligibility among healthcare workers during the early phase of introduction, low fourth dose coverage (with a median coverage of 46% in 2023 across the three countries), and disruptions to service delivery caused by disease outbreaks and other natural disasters. Health stakeholders and caregivers attested to the positive impact of introducing the malaria vaccine, including a reduction in malaria hospitalizations and the strengthening of the National Immunization Programme (NIP) through routine immunization refresher training and supportive supervision. Conclusions The pilot highlighted lessons for malaria vaccine introduction: (1) clearly outlined roles and responsibilities of key stakeholders including NIP and National Malaria Programme (NMP); (2) appropriate approach to vaccine introduction launch, communication, and demand generation to enhance vaccine uptake; (3) flexibility with dose scheduling to optimize coverage; and (4) updated data collection tools for accurate documentation, and data quality.

Recent advances in mosquito eradication and antimalarial treatments have reduced the malaria burden only modestly. An effective malaria vaccine remains a high priority, but its development has several challenges. Among many potential candidates, the RTS,S/AS01 vaccine (Mosquirix ) remains the leading candidate. This review aims to understand the advances in the RTS,S/AS01 vaccine, and future comments regarding the vaccine's effectiveness in malaria eradication. Literature review for the past five decades was performed searching PubMed, EMBASE Ovid, and Cochrane Library, with using the following search items: (\"malaria\" OR \"WHO's malaria\" OR \"Plasmodium falciparum\" OR \"RTS,S\" OR \"RTS,S/AS01\" OR \"RTS,S/AS02\" OR \"pre-erythrocytic malaria\" OR \"circumsporozoite\" OR \"Mosquirix\") AND (\"vaccine\" OR \"vaccination\"). RTS,S/AS01, a recombinant pre-erythrocytic vaccine containing surface-protein (circumsporozoite) antigen, is safe, well-tolerated, and immunogenic in children. Three doses, along with a booster, have a modest efficacy of about 36% in children (age 5-17 months) and about 26% in infants (age 6-12 weeks) against clinical malaria during a 48-month follow-up. However, the efficacy varies among population subgroups and with the parasite strain, it reduces without a booster and offers protection for a limited duration. Because of its potential cost-effectiveness and positive public health effect, the vaccine is being investigated in a pilot program for mortality benefits and broader deployment. The RTS,S/AS01 vaccine prevents malaria; however, it should be considered another addition to the malaria-control program and not as an eradication tool because of its relatively low to modest efficacy.

Background. Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologie responses. Methods. In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (FxO17M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. Results. A total of 26 of 30 subjects in the FxO17M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P<.0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P=.0009) were protected against infection, and protection differed between schedules (P=.040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. Discussions. A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. Clinical Trials Registration. NCT01857869.

This article presents the World Health Organization’s (WHO) recommendations on the use of malaria vaccine excerpted from the WHO position paper on malaria vaccine published in the Weekly epidemiological Record in January 2016 [1]. The current document is the first WHO position paper on malaria vaccination and focuses primarily on the available evidence concerning the only malaria vaccine having received a positive regulation assessment from the European Medicines Agency (EMA) [2]. The position paper gives consideration to the epidemiological features of the disease and assesses the potential use of the vaccine for public health benefits. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence to recommendation table. 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 vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO’s current position on the use of vaccines in the global context. This paper reflects the joint recommendation of the WHO’s Strategic Advisory Group of Experts (SAGE) on immunization and the Malaria Policy Advisory Committee (MPAC). These recommendations were discussed by SAGE and MPAC at the October 2015 SAGE meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html.

Background Following a 30-year development process, RTS,S/AS01 E (GSK, Belgium) is the first malaria vaccine to reach Phase IV assessments. The World Health Organization-commissioned Malaria Vaccine Implementation Programme (MVIP) is coordinating the delivery of RTS,S/AS01 E through routine national immunization programmes in areas of 3 countries in sub-Saharan Africa. The first doses were given in the participating MVIP areas in Malawi on 23 April, Ghana on 30 April, and Kenya on 13 September 2019. The countries participating in the MVIP have little or no baseline incidence data on rare diseases, some of which may be associated with immunization, a deficit that could compromise the interpretation of possible adverse events reported following the introduction of a new vaccine in the paediatric population. Further, effects of vaccination on malaria transmission, existing malaria control strategies, and possible vaccine-mediated selective pressure on Plasmodium falciparum variants, could also impact long-term malaria control. To address this data gap and as part of its post-approval commitments, GSK has developed a post-approval plan comprising of 4 complementary Phase IV studies that will evaluate safety, effectiveness and impact of RTS,S/AS01 E through active participant follow-up in the context of its real-life implementation. Methods EPI-MAL-002 (NCT02374450) is a pre-implementation safety surveillance study that is establishing the background incidence rates of protocol-defined adverse events of special interest. EPI-MAL-003 (NCT03855995) is an identically designed post-implementation safety and vaccine impact study. EPI-MAL-005 (NCT02251704) is a cross-sectional pre- and post-implementation study to measure malaria transmission intensity and monitor the use of other malaria control interventions in the study areas, and EPI-MAL-010 (EUPAS42948) will evaluate the P. falciparum genetic diversity in the periods before and after vaccine implementation. Conclusion GSK’s post-approval plan has been designed to address important knowledge gaps in RTS,S/AS01 E vaccine safety, effectiveness and impact. The studies are currently being conducted in the MVIP areas. Their implementation has provided opportunities and posed challenges linked to conducting large studies in regions where healthcare infrastructure is limited. The results from these studies will support ongoing evaluation of RTS,S/AS01 E ’s benefit-risk and inform decision-making for its potential wider implementation across sub-Saharan Africa. Graphic abstract

We previously demonstrated that RTS,S/AS01B and RTS,S/AS01E vaccination regimens including at least one delayed fractional dose can protect against Plasmodium falciparum malaria in a controlled human malaria infection (CHMI) model, and showed inferiority of a two-dose versus three-dose regimen. In this follow-on trial, we evaluated whether fractional booster vaccination extended or induced protection in previously protected (P-Fx) or non-protected (NP-Fx) participants. 49 participants (P-Fx: 25; NP-Fx: 24) received a fractional (1/5th dose-volume) RTS,S/AS01E booster 12 months post-primary regimen. They underwent P. falciparum CHMI three weeks later and were then followed for six months for safety and immunogenicity. Overall vaccine efficacy against re-challenge was 53% (95% CI: 37–65%), and similar for P-Fx (52% [95% CI: 28–68%]) and NP-Fx (54% [95% CI: 29–70%]). Efficacy appeared unaffected by primary regimen or previous protection status. Anti-CS (repeat region) antibody geometric mean concentrations (GMCs) increased post-booster vaccination. GMCs were maintained over time in primary three-dose groups but declined in the two-dose group. Protection after re-challenge was associated with higher anti-CS antibody responses. The booster was well-tolerated. A fractional RTS,S/AS01E booster given one year after completion of a primary two- or three-dose RTS,S/AS01 delayed fractional dose regimen can extend or induce protection against CHMI. Clinical Trial Registration: NCT03824236. A video linked to this article can be found on the Research Data as well as Figshare https://figshare.com/s/ee025150f9d1ac739361

Background While Ghana has a good track record in the Expanded Programme on Immunization, there are substantial challenges with regards to subsequent vaccinations, particularly after the first year of life of the child. Given that the last dose of the RTS, S/AS01 E vaccine against malaria is administered at 24 months, there is a high likelihood of default. Hence, it is imperative to understand the dynamics and reasons for the defaults to enable the development of effective implementation strategies. This study explored why caregivers default on the RTS, S/AS01 E vaccine from the perspective of health service providers and caregivers. Methods This study employed an exploratory, descriptive approach. Using a purposive sampling technique, caregivers who defaulted and health service providers directly involved in the planning and delivery of the RTS, S/AS01 E vaccine at the district level were recruited. A total of five health service providers and 30 mothers (six per FGD) participated in this study. Data analysis was done using NVivo-12 following Collaizi’s thematic framework for qualitative analysis. The study relies on the Standards for Reporting Qualitative Research. Results Reasons for defaulting included the overlap of timing of the last dose and the child starting school, disrespectful attitudes of some health service providers, concerns about adverse side effects and discomforts, travel out of the implementing district, the perception that the vaccines are too many, and lack of support from partners. Conclusion To reduce the occurrence of defaulting on the RTS, S/AS01 E  vaccine programme, stakeholders must reconsider the timing of the last dose of the vaccine. The schedule of the RTS, S/AS01 E vaccine should be aligned with the established EPI schedule of Ghana. This will significantly limit the potential of defaults, particularly for the last dose. Also, the findings from this study underscore a need to encourage male partner involvement in the RTS, S/AS01 E vaccine programme. Health promotion programmes could be implemented to raise caregivers’ awareness of potential adverse reactions and discomforts—this is necessary to prepare the caregiver for the vaccine process psychologically.

Background The World Health Organization (WHO) recommends the use of malaria vaccines for the prevention of Plasmodium falciparum malaria in moderate to high transmission areas, administered in a 4-dose schedule in children from 5 months of age. The vaccine is a ground-breaking new tool to add to the existing package of recommended malaria interventions to reduce malaria morbidity and mortality. Ghana, Kenya, and Malawi were the first countries to introduce the RTS,S/AS01 E (RTS,S) malaria vaccine into their childhood immunization programmes in 2019 as part of a pilot programme called the Malaria Vaccine Implementation Programme (MVIP). Methods The WHO’s post-introduction evaluation (PIE) methodology was adapted to evaluate malaria vaccine implementation in each of the three pilot countries at least a year after the vaccine’s introduction. Semi-structured questionnaires were used to interview immunization staff at national, sub-national, and health facility levels, supplemented with systematic observations of vaccination sessions and vaccine storage sites. At the health facility, a sample of caregivers of eligible children was also interviewed. Sites were purposively selected to include a range of past immunization coverage and varied demographics among the populations served. Results All three countries successfully introduced the malaria vaccine during the MVIP. Reported malaria vaccine median coverage at least 2 years after the start of the pilot ranged from 69–91% for dose 1, 62–82% for dose 2, to 58–81% for dose 3 by 24–30 months from the start of the pilot. Coverage for dose 4 was lower as fewer children were eligible during the PIE reporting timeframe. Best practices identified during the PIEs included: early involvement of subnational stakeholders; advance updating and distribution of recording and reporting tools to include malaria vaccine; pre-assessment of cold chain capacity and scale-up; investment of time and resources in health worker trainings and refreshers; involvement of community health workers; robust defaulter tracing mechanisms; ensuring community “dialogue” with continuity of advocacy, communication, and social mobilization activities after initial introduction; regular onsite supervisory visits before, during and after introduction; and use of social media for messaging. Conclusions Malaria vaccine is an important intervention as part of a comprehensive malaria control strategy. Conducting a PIE is useful to identify best practices and lessons learned. New vaccination contacts take time to establish and achieve high coverage as communities become aware of and understand when, why, and how to access the malaria vaccine. The malaria vaccine was successfully introduced as part of the routine childhood immunization programme with strong intersectoral collaboration and planning, involving both immunization and malaria stakeholders, comprehensive training, and social mobilization efforts pre- and post-introduction.

Background A recent trial of 5920 children in Burkina Faso and Mali showed that the combination of seasonal vaccination with the RTS,S/AS01 E malaria vaccine (primary series and two seasonal boosters) and seasonal malaria chemoprevention (four monthly cycles per year) was markedly more effective than either intervention given alone in preventing clinical malaria, severe malaria, and deaths from malaria. Methods In order to help optimise the timing of these two interventions, trial data were reanalysed to estimate the duration of protection against clinical malaria provided by RTS,S/AS01 E when deployed seasonally, by comparing the group who received the combination of SMC and RTS,S/AS01 E with the group who received SMC alone. The duration of protection from SMC was also estimated comparing the combined intervention group with the group who received RTS,S/AS01 E alone. Three methods were used: Piecewise Cox regression, Flexible parametric survival models and Smoothed Schoenfeld residuals from Cox models, stratifying on the study area and using robust standard errors to control for within-child clustering of multiple episodes. Results The overall protective efficacy from RTS,S/AS01 E over 6 months was at least 60% following the primary series and the two seasonal booster doses and remained at a high level over the full malaria transmission season. Beyond 6 months, protective efficacy appeared to wane more rapidly, but the uncertainty around the estimates increases due to the lower number of cases during this period (coinciding with the onset of the dry season). Protection from SMC exceeded 90% in the first 2–3 weeks post-administration after several cycles, but was not 100%, even immediately post-administration. Efficacy begins to decline from approximately day 21 and then declines more sharply after day 28, indicating the importance of preserving the delivery interval for SMC cycles at a maximum of four weeks. Conclusions The efficacy of both interventions was highest immediately post-administration. Understanding differences between these interventions in their peak efficacy and how rapidly efficacy declines over time will help to optimise the scheduling of SMC, malaria vaccination and the combination in areas of seasonal transmission with differing epidemiology, and using different vaccine delivery systems. Trial registration The RTS,S-SMC trial in which these data were collected was registered at clinicaltrials.gov: NCT03143218

Ensuring that malaria vaccines deliver maximum public health impact is non-trivial. Drawing on current research, this article examines hurdles that malaria immunization may face to reach high-risk children and explores the policy implications. The analysis finds health system related risks with the potential to reduce the ability of malaria vaccines to provide equitable protection. Deployment of effective frameworks to tackle these risks so as to strengthen within-country equity and progress tracking should be entangled with the deployment of the vaccines. To capture more comprehensively disease- and system-related risks to child health and survival, vaccine allocation criteria should expand their data and indicator breadth. Factoring molecular, clinical, and epidemiological features of antimalarial drug resistance into vaccine allocation frameworks is critical to effectively reflect current and future risks to malaria control interventions. It is proposed that approximately 6–15 children would need to be vaccinated to prevent a malaria adverse outcome. Vaccine purchasing and delivery costs may overwhelm endemic countries’ health systems given the sizeable number needed to vaccinate, the population of at-risk children, and limited government financing of the health sector. Innovations in health financing are pivotal to ensuring the cost-effectiveness and sustainability of immunization programs aiming to attain and maintain universal and equitable protection.