[Malaria vaccines: a new tool for elimination?] / Vaccins contre le paludisme : un nouvel outil pour l'élimination ?

A malaria vaccine represents an essential complementary tool to curb the stagnation, or even increase, in malaria cases observed over the last decade due to the emergence of resistance to insecticides impregnated on mosquito nets, wars and internal conflicts, as well as global warming. In October 2021, WHO recommended the use of the RTS,S/ASO1 vaccine for children aged 5-17 months in areas of moderate to high transmission. In October 2023, a second vaccine received WHO approval for deployment in the same population, following demonstration of around 70 % efficacy in protecting young children against malaria for one year. Given their partial efficacy, however, these vaccines are not generally recommended for travelers to endemic countries.

Un vaccin contre le paludisme représente une mesure complémentaire essentielle pour juguler la stagnation, voire l'augmentation des cas de paludisme observée durant cette dernière décade en raison de l'émergence de la résistance aux insecticides imprégnés sur les moustiquaires, des guerres et conflits internes ainsi que du réchauffement climatique. En octobre 2021, l'OMS a recommandé l'emploi du vaccin RTS,S/ASO1 pour les enfants de 5 à 17 mois dans les zones de transmission modérée à forte. En octobre 2023, un second vaccin a reçu l'aval de l'OMS pour son déploiement dans la même population, suite à la démonstration d'une efficacité d'environ 70 % pour protéger les jeunes enfants contre le paludisme pendant une année. Vu leur efficacité partielle, ces vaccins ne sont cependant généralement pas recommandés pour les voyageurs se rendant dans les pays d'endémie.

Policy uptake and implementation of the RTS,S/AS01 malaria vaccine in sub-Saharan African countries: status 2 years following the WHO recommendation.

In October 2021, the WHO recommended the world's first malaria vaccine-RTS,S/AS01-to prevent malaria in children living in areas with moderate-to-high transmission in sub-Saharan Africa (SSA). A second malaria vaccine, R21/Matrix-M, was recommended for use in October 2023 and added to the WHO list of prequalified vaccines in December 2023. This study analysis assessed the country status of implementation and delivery strategies for RTS,S/AS01 by searching websites for national malaria policies, guidelines and related documents. Direct contact with individuals working in malaria programmes was made to obtain documents not publicly available. 10 countries had documents with information relating to malaria vaccine implementation, 7 referencing RTS,S/AS01 and 3 (Burkina Faso, Kenya and Nigeria) referencing RTS,S/AS01 and R21/Matrix-M. Five other countries reported plans for malaria vaccine roll-out without specifying which vaccine. Ghana, Kenya and Malawi, which piloted RTS,S/AS01, have now integrated the vaccine into routine immunisation services. Cameroon and Burkina Faso are the first countries outside the pilot countries to incorporate the vaccine into national immunisation services. Uganda plans a phased RTS,S/AS01 introduction, while Guinea plans to first pilot RTS,S/AS01 in five districts. The RTS,S/AS01 schedule varied by country, with the first dose administered at 5 or 6 months in all countries but the fourth dose at either 18, 22 or 24 months. SSA countries have shown widespread interest in rolling out the malaria vaccine, the Global Alliance for Vaccines and Immunization having approved financial support for 20 of 30 countries which applied as of March 2024. Limited availability of RTS,S/AS01 means that some approved countries will not receive the required doses. Vaccine availability and equity must be addressed even as R21/Matrix-M becomes available.

Vaccines and monoclonal antibodies: new tools for malaria control.

SUMMARYMalaria remains one of the biggest health problems in the world. While significant reductions in malaria morbidity and mortality had been achieved from 2000 to 2015, the favorable trend has stalled, rather significant increases in malaria cases are seen in multiple areas. In 2022, there were 249 million estimated cases, and 608,000 malaria-related deaths, mostly in infants and children aged under 5 years, globally. Therefore, in addition to the expansion of existing anti-malarial control measures, it is critical to develop new tools, such as vaccines and monoclonal antibodies (mAbs), to fight malaria. In the last 2 years, the first and second malaria vaccines, both targeting Plasmodium falciparum circumsporozoite proteins (PfCSP), have been recommended by the World Health Organization to prevent P. falciparum malaria in children living in moderate to high transmission areas. While the approval of the two malaria vaccines is a considerable milestone in vaccine development, they have much room for improvement in efficacy and durability. In addition to the two approved vaccines, recent clinical trials with mAbs against PfCSP, blood-stage vaccines against P. falciparum or P. vivax, and transmission-blocking vaccine or mAb against P. falciparum have shown promising results. This review summarizes the development of the anti-PfCSP vaccines and mAbs, and recent topics in the blood- and transmission-blocking-stage vaccine candidates and mAbs. We further discuss issues of the current vaccines and the directions for the development of next-generation vaccines.

Malaria vaccine acceptance among next of kin of children under 5 years of age in Gulu, northern Uganda in 2023: a community-based study.

Background: Malaria is a leading cause of death among children under 5 years of age in sub-Saharan Africa. The malaria vaccine is an important preventive measure introduced by the World Health Organization to reduce malaria and its associated mortality and morbidity. We aimed to assess the acceptance of the malaria vaccine among next of kin of children under 5 years of age in Gulu City, Northern Uganda. Methods: Between October and December 2023, we conducted a cross-sectional study in Pece-Laroo division, Gulu City, Uganda. Socio-demographic, vaccine profile and health system factors were collected. Multivariable logistic regression was performed using STATA 16 to determine factors associated with acceptance of the malaria vaccine among next of kin of children under 5 years. Results: A total of 432 participants were enrolled. Of these, the majority were female (72.5%, n = 313) with most aged 30 years and above (51.2%, n = 221). Overall, 430 (99.5%) participants had good knowledge about malaria. The majority (91.4%, n = 395) had good acceptance of the malaria vaccine. Factors independently associated with acceptance of the malaria vaccine were knowing a child who died of malaria [adjusted prevalence ratio (aPR): 1.07, 95% confidence interval (CI): 1.01-1.13, p = 0.022] and preferring the injection route for a malaria vaccine (aPR: 1.1, 95% CI: 1.06-1.22, p < 0.001). All 395 participants with good knowledge of malaria had good acceptance of the malaria vaccine (p = 0.007). Conclusion: There was a high acceptance of the malaria vaccine in Laroo-Pece division, Gulu, Uganda. However, there is a need for further health education to achieve universal acceptability of the malaria vaccine in preparation for the malaria vaccine implementation program in Uganda.

Factors associated with malaria vaccine uptake in Nsanje district, Malawi.

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.

Setting up a data system for monitoring malaria vaccine introduction readiness and uptake in 42 health districts in Cameroon.

Three months after the first shipment of RTS,S1/AS01 vaccines, Cameroon started, on 22 January 2024, to roll out malaria vaccines in 42 districts among the most at risk for malaria. Cameroon adopted and implemented the World Health Organization (WHO) malaria vaccine readiness assessment tool to monitor the implementation of preintroduction activities at the district and national levels. One week before the start of the vaccine rollout, overall readiness was estimated at 89% at a national level with two out of the five components of readiness assessment surpassing 95% of performance (vaccine, cold chain and logistics and training) and three components between 80% and 95% (planning, monitoring and supervision, and advocacy, social mobilisation and communication). 'Vaccine, cold chain and logistics' was the component with the highest number of districts recording below 80% readiness. The South-West and North-West, two regions with a high level of insecurity, were the regions with the highest number of districts that recorded a readiness performance below 80% in the five components. To monitor progress in vaccine rollout daily, Cameroon piloted a system for capturing immunisation data by vaccination session coupled with an interactive dashboard using the R Shiny platform. In addition to displaying data on vaccine uptake, this dashboard allows the generation of the monthly immunisation report for all antigens, ensuring linkage to the regular immunisation data system based on the end-of-month reporting through District Health Information Software 2. Such a hybrid system complies with the malaria vaccine rollout principle of full integration into routine immunisation coupled with strengthened management of operations.

Integration of the RTS,S/AS01 malaria vaccine into the Essential Programme on Immunisation in western Kenya: a qualitative longitudinal study from the health system perspective.

BACKGROUND: Malaria accounts for over half a million child deaths annually. WHO recommends RTS,S/AS01 to prevent malaria in children living in moderate-to-high malaria transmission regions. We conducted a qualitative longitudinal study to investigate the contextual and dynamic factors shaping vaccine delivery and uptake during a pilot introduction in western Kenya. METHODS: The study was conducted between Oct 3, 2019, and Mar 24, 2022. We conducted participant and non-participant observations and in-depth interviews with health-care providers, health managers, and national policymakers at three timepoints using an iterative approach and observations of practices and processes of malaria vaccine delivery. Transcripts were coded by content analysis using the consolidated framework for implementation research, to which emerging themes were added deductively and categorised into challenges and opportunities. FINDINGS: We conducted 112 in-depth interviews with 60 participants (25 health-care providers, 27 managers, and eight policy makers). Health-care providers highlighted limitations in RTS,S/AS01 integration into routine immunisation services due to the concurrent pilot evaluation and temporary adaptations for health reporting. Initial challenges related to the complexity of the four-dose schedule (up to 24-months); however, self-efficacy increased over time as the health-care providers gained experience in vaccine delivery. Low uptake of the fourth dose remained a challenge. Health managers cited insufficient trained immunisation staff and inadequate funding for supervision. Confidence in the vaccine increased among all participant groups owing to reductions in malaria frequency and severity. INTERPRETATION: Integration of RTS,S/AS01 into immunisation services in western Kenya presented substantial operational challenges most of which were overcome in the first 2 years, providing important lessons for other countries. Programme expansion is feasible with intensive staff training and retention, enhanced supervision, and defaulter-tracing to ensure uptake of all doses. FUNDING: PATH via World Health Organization; Gavi, the Vaccine Alliance; The Global Fund; and Unitaid.

A perspective on Oxford's R21/Matrix-M™ malaria vaccine and the future of global eradication efforts.

Malaria affects millions of lives annually, particularly in tropical and subtropical regions. Despite being largely preventable, 2021 witnessed 247 million infections and over 600,000 deaths across 85 countries. In the ongoing battle against malaria, a promising development has emerged with the endorsement by the World Health Organization (WHO) of the R21/Matrix-M™ Malaria Vaccine. Developed through a collaboration between the University of Oxford and Novavax, this vaccine has demonstrated remarkable efficacy, reaching 77% effectiveness in Phase 2 clinical trials. It is designed to be low-dose, cost-effective, and accessible, with approval for use in children under three years old. This perspective paper critically examines the R21/Matrix-M malaria vaccine, its development, potential impact on global malaria eradication efforts, and the challenges and opportunities it presents.

Second malaria vaccine gets WHO green light.

New shots could make malaria protection more plentiful, saving tens of thousands of lives.

Malaria vaccine coverage estimation using age-eligible populations and service user denominators in Kenya.

BACKGROUND: The World Health Organization approved the RTS,S/AS01 malaria vaccine for wider rollout, and Kenya participated in a phased pilot implementation from 2019 to understand its impact under routine conditions. Vaccine delivery requires coverage measures at national and sub-national levels to evaluate progress over time. This study aimed to estimate the coverage of the RTS,S/AS01 vaccine during the first 36 months of the Kenyan pilot implementation. METHODS: Monthly dose-specific immunization data for 23 sub-counties were obtained from routine health information systems at the facility level for 2019-2022. Coverage of each RTS,S/AS01 dose was determined using reported doses as a numerator and service-based (Penta 1 and Measles) or population (projected infant populations from WorldPop) as denominators. Descriptive statistics of vaccine delivery, dropout rates and coverage estimates were computed across the 36-month implementation period. RESULTS: Over 36 months, 818,648 RTSS/AS01 doses were administered. Facilities managed by the Ministry of Health and faith-based organizations accounted for over 88% of all vaccines delivered. Overall, service-based malaria vaccine coverage was 96%, 87%, 78%, and 39% for doses 1-4 respectively. Using a population-derived denominator for age-eligible children, vaccine coverage was 78%, 68%, 57%, and 24% for doses 1-4, respectively. Of the children that received measles dose 1 vaccines delivered at 9 months (coverage: 95%), 82% received RTSS/AS01 dose 3, only 66% of children who received measles dose 2 at 18 months (coverage: 59%) also received dose 4. CONCLUSION: The implementation programme successfully maintained high levels of coverage for the first three doses of RTSS/AS01 among children defined as EPI service users up to 9 months of age but had much lower coverage within the community with up to 1 in 5 children not receiving the vaccine. Consistent with vaccines delivered over the age of 1 year, coverage of the fourth malaria dose was low. Vaccine uptake, service access and dropout rates for malaria vaccines require constant monitoring and intervention to ensure maximum protection is conferred.

[Vaccination against malaria]. / Vaccination contre le paludisme.

Vaccination against malaria is an old dream that reemerged in 2015 with the European Medicines Agency's favourable opinion on a first antimalarial vaccine, RTS,S/ AS01. Six years later, the World Health Organization (WHO) is advising a wide deployment of this vaccine in sub-Saharan Africa and in regions with high and moderate transmission where Plasmodium falciparum circulates. This follows favourable results from the pilot programme in Ghana, Kenya and Malawi involving over 800,000 children since 2019. This article addresses the objectives and main vaccine candidates targeting the different stages of parasite development, highlighting the progress and limitations of these different approaches. The RTS,S saga has been a milestone in vaccine development, with a first-generation vaccine recommended by the WHO for use in children over 5 months of age in sub-Saharan Africa and other areas of moderate to high transmission of P. falciparum malaria, in combination with other prevention measures. Research efforts continue to better understand the correlates of protection. With advances in vaccine platforms, new multi-antigen, multi-stage, and even multi-species approaches might emerge and brighten the horizon for malaria control.

Implementation strategies for the introduction of the RTS,S/AS01 (RTS,S) malaria vaccine in countries with areas of highly seasonal transmission: workshop meeting report.

A workshop on implementation strategies for the introduction of the RTS,S/AS01 (RTS,S) malaria vaccine in countries with areas of highly seasonal transmission, was held as a hybrid meeting in Dakar, Senegal, and online, 23-25 January 2023. Delegates from Expanded Programmes on Immunization (EPI) and National Malaria Control Programmes (NMCPs) from 13 African countries, and representatives from key stakeholders participated. RTS,S is the first malaria vaccine to be recommended by the World Health Organization (WHO). The recommendation followed pilot implementation of the vaccine in Ghana, Kenya and Malawi, which showed that introduction of the vaccine was highly effective at scale, and was associated with a 30% reduction in hospital admissions with severe malaria in age groups eligible to have received the vaccine and no evidence of the safety signals that had been observed in the phase 3 trial. Clinical trials in Mali and Burkina Faso, showed that in children receiving Seasonal Malaria Chemoprevention (SMC), providing the vaccine just prior to high transmission seasons, matching the period of highest efficacy to the peak transmission season, resulted in substantial reduction in the incidence of clinical malaria and of severe malaria. While SMC has been successfully scaled-up despite the challenges of delivery, there is no established platform for seasonal vaccine delivery and no real-world experience. The objectives of this workshop were, therefore, to share experiences from countries that have introduced the RTS,S vaccine in routine child vaccination programmes, with SMC-implementing countries as they consider malaria vaccine introduction, and to explore implementation strategies in countries with seasonal transmission and where EPI coverage may be low especially in the second year of life. Practical implementation challenges, lessons learned for vaccine introduction, and research questions, towards facilitating the introduction of the RTS,S (and other malaria vaccines) in countries with seasonal malaria transmission were discussed.

Acceptance, availability, and feasibility of RTS, S/AS01 malaria vaccine: A review.

INTRODUCTION: In malaria-stricken regions, malaria continues to be one of the primary causes of mortality for children. The number of malaria-related fatalities has drastically decreased because of artemisinin-based pharmacological regimens. METHODS: Two independent researchers did a comprehensive literature search using PubMed/MEDLINE and Google Scholar from its inception to September 2022. RESULTS: After evaluating RTS, S/AS01 for its safety, effectiveness, and feasibility, the European Medicines Agency (EMA) issued a favorable conclusion. It was suggested that the RTS, S malaria vaccine be used extensively by the World Health Organization on October 6, 2021. The successful pilot program testing the malaria vaccine in Ghana, Kenya, and Malawi served as the basis for this proposal. CONCLUSION: Several challenges need to be addressed to ensure the success of vaccination programs. From the acceptability perspective, issues such as inadequate community engagement, concerns about side effects, and issues with the delivery and quality of healthcare services can affect the acceptance of the vaccine. From the feasibility standpoint, factors such as lack of transportation or long distances to healthcare facilities and the perception of completion of the vaccination calendar can affect the feasibility of the vaccine. Lastly, the availability of the vaccine is also a major concern as it may not be readily available to meet the demands.