WHO’s approval of the RTS,S/AS01 (Mosquirix) malaria vaccine in 2021 was a milestone in global public health, representing not only the first vaccine approved against any parasitic human disease but a major leap towards reducing the incidence of clinical malaria and its associated mortality, write Claudia Daubenberger and Ally Olotu in an editorial in The Lancet.
Their comment is linked to a study published in the same issue of the journal showing that the introduction of the RTS,S malaria jab in routine immunisation programmes was associated with a notable reduction in mortality in children, averting about one in eight deaths.
Daubenberger and Oluto write that although vaccines with higher efficacy and longer duration of protection are highly desirable for malaria elimination, RTS,S/AS01 reduces childhood mortality significantly in moderate-to-high malaria transmission settings across Africa, and the successful development, implementation, funding and evaluation of this first-generation shot has paved the way for next-generation vaccines.o
In The Lancet study they refer to, Victor Mwapasa and colleagues described a cluster-randomised study with the primary outcome of community-level impact on child mortality of the introduction of malaria vaccine.
A total of 158 areas were randomly assigned either to immediately begin the roll-out of the RTS,S/AS01 malaria vaccine or to introduce it at a later date. The vaccine was administered according to a four-dose schedule: at six, seven, nine, and 24 months of age in Ghana and Kenya; and at five, six, seven, and 22 months in Malawi. The 79 areas where vaccine administration was delayed served as control sites.
Post-neonatal mortality was monitored by about 26 000 local reporters who notified deaths, with study staff visiting families for confirmation and verbal autopsies to rigorously assess causes of death.
During the 46-month period after the introduction of the vaccine, RTS,S/AS01 prevented 993 deaths (reduction of mortality by 13.2%; one in eight deaths averted), with no difference observed between girls and boys. Reduction of severe malaria cases in the same period was 21.6%.
Encouragingly, vaccine coverage was broadly similar in each country and no measurable differences in reduction of morbidity or mortality was seen across the three implementing countries. This strongly suggests that vaccine effectiveness can be maintained across settings with heterogeneous transmission dynamics and circulating parasite populations.
The strength of this large-scale implementation is the rigorous, close to real-world assessment of RTS,S/AS01 impact in three different countries over a 46-month period following shared protocols and reporting systems.
A major limitation is the low uptake rate of the fourth dose of vaccine across all implementation clusters. It is currently unclear how much greater reduction of overall mortality might be with higher coverage. The findings support the concept that even a partially protective malaria vaccine can reduce mortality significantly in moderate-to-high Plasmodium falciparum malaria endemic settings in young children.
In addition, vaccines like RTS,S/AS01 can reduce the emergence and spread of antimalarial drug resistance by lowering malaria incidence and, consequently, reducing antimalarial drug use. This will reduce the selection pressure favouring resistant parasites, thereby limiting their transmission and slowing the spread of resistance over time.
By reducing febrile illness, RTS,S may, in addition, reduce empirical antibiotic use in settings with limited diagnostic capacity, lowering emergence and spread of antimicrobial resistance.
RTS,S is based on a single allelic form of the circumsporozoite protein (CSP, NF54 strain), including the immunodominant central repeat region as well as the C-terminus of the protein. The vaccine forms virus-like particles that are formulated and delivered intramuscularly together with the AS01 adjuvant.
Daubenberger and Oluto write that since the initiation of the clinical development programme for RTS,S in 1987, substantial knowledge has been gathered regarding variation in vaccination outcomes across populations differentiated by location, age, sex, and levels of malaria pre-exposure.
While these findings might help to dissect the various factors driving the limited efficacy of RTS,S/AS01, they also underscore the importance of studying the diversity of the human immune system across populations as a foundation for future vaccine development programmes.
One of the striking observations in RTS,S/AS01 vaccinees is that anti-CSP antibody responses decline rapidly, with levels dropping significantly within six–12 months after the first three monthly RTS,S/AS01 vaccinations. Hence, a complicated four-dose schedule over about 24 months is needed to maintain protection, making it harder for people to complete the series, as highlighted by Mwapasa and colleagues.
Implementation research and experience from national malaria control programmes suggest that caregiver confusion about extended age eligibility, competing priorities, and weaker contact points in the second year contribute to this low completion rate, and that linking the fourth dose to other established child health contacts, such as measles boosters, or introducing bed-net distribution during a health contact, could improve uptake.6
The rapid decline of protective antibodies and lack of long-lasting immune memory development has been observed not only in children vaccinated with RTS,S/AS01, but also in populations residing in high malaria endemic settings who were given vaccines based on whole attenuated P falciparum sporozoite.
Preliminary evidence indicates that the highly repetitive nature of the immuno-dominant NANP repeats of CSP might lead to dysfunctional memory B-cell responses associated with rapidly waning humoral immunity.
Future research should be accompanied by robust immunomonitoring of vaccine-induced immunity during product development but should also track how this immunity interacts with ongoing P falciparum infections in the field over extended time periods.
According to the WHO, 24 African nations include or plan to include malaria vaccines in their childhood immunisation programmes. Five countries have fully implemented the vaccine nationwide, while 19 others currently offer it in select regions and intend to expand coverage.
Research on the RTS,S/AS01-induced cross-protection against diverse parasite genotypes shows inconsistent results as described during the pivotal phase 3 clinical study.
The question remains whether potential selection of vaccine-resistant strains can be addressed by implementing next-generation molecular surveillance tools that elegantly also allow for monitoring expression of molecular markers that confer malaria drug resistance.
Although malaria vaccines with higher efficacy and longer duration of protection are highly desirable for malaria elimination, RTS,S/AS01 reduces childhood mortality significantly in moderate-to-high malaria transmission settings across Africa.
The successful development, implementation, funding, and evaluation of the first-generation malaria vaccine has paved the way for next-generation vaccines.
Claudia Daubenberger – University of Basel; Swiss Tropical and Public Health, Switzerland
Ally Olotu – Iakara Health Institute, Tanzania
Study details
Impact of introducing RTS,S/AS01E malaria vaccine on mortality in young children in Ghana, Kenya, and Malawi: an observational evaluation of a cluster-randomised implementation programme
Victor Mwapasa, Kwaku Poku Asante, Paul Milligan et al.
Published in The Lancet on 9 May 2026
Summary
Background
Malaria vaccines have been added to immunisation schedules in 25 sub-Saharan African countries, with the expectation that deaths in young children would be prevented. The introduction of the RTS,S/AS01E malaria vaccine (RTS,S) in Ghana, Kenya, and Malawi in 2019 was evaluated over four years to show the impact on mortality in young children and to monitor severe malaria admissions, vaccine uptake, and safety. Favourable evidence on safety and impact on severe malaria admissions during the first two years contributed to WHO's recommendations on malaria vaccines. Here, we report the primary analysis of the impact on mortality at 46 months.
Methods
Clusters of administrative units (districts in Ghana, subcounties in Kenya, and groups of immunisation clinics in Malawi), each with an estimated annual birth cohort of about 4 000 children, were randomly assigned 1:1 to introduce the RTS,S malaria vaccine in 2019 (implementation areas), or to implement later (comparison areas). RTS,S was delivered in a four-dose schedule, at age 6, 7, 9, and 24 months in Ghana and Kenya, and at age 5, 6, 7, and 22 months in Malawi. Surveillance for post-neonatal mortality in children under five years was established throughout by a network of 26 000 local reporters who notified deaths in their community. The families were then visited at home by study staff to confirm details and complete a verbal autopsy. Surveillance for severe malaria and other conditions was strengthened in 18 sentinel hospitals serving part of the study area and maintained for 46 months. Uptake of RTS,S and other vaccines was monitored by the Expanded Programme on Immunisation in each country and independently through three household coverage surveys, at baseline, and at about 18 months and 30 months after introduction of RTS,S. The primary outcome of this impact evaluation was mortality due to any cause, except injury, in children eligible to receive three doses of RTS,S. Mortality rate ratios were estimated by comparing the ratio of deaths among vaccine-eligible age groups to deaths in non-eligible age groups between implementation and comparison areas.
Findings
A total of 158 clusters (66 in Ghana, 46 in Kenya, and 46 in Malawi) were selected and randomly assigned; 79 areas served as implementation areas and 79 as comparison areas. By the end of the 46-month evaluation period, 1 289 504 children had received the first dose of RTS,S, 1 158 850 had received the second dose, 1 068 039 had received a third dose, and 436 527 had received a fourth dose. Coverage assessed in 2022 was 82·8% (95% CI 80·7–84·9) for the first dose, 71·1% (68·8–73·5) for the third dose, and 39·9% (36·9–42·9) for the fourth dose. Excluding deaths due to injury, there were 5576 deaths in implementation areas versus 6152 in comparison areas in children eligible to have received the third dose of RTS,S, and 7534 versus 7044 deaths among non-eligible children. The mortality rate ratio was 0·87 (95% CI 0·77–0·97; p=0·016).
Introduction of the RTS,S malaria vaccine in routine immunisation programmes was associated with a significant reduction in mortality in young children, averting about one in eight deaths, in areas with moderate coverage of three doses of the vaccine and low uptake of the fourth dose. These results highlight the urgency to accelerate the deployment of malaria vaccines in areas of Africa where malaria continues to be a leading cause of child mortality.
The Lancet article – RTS,S/AS01 implementation reduces mortality in African children (Open access)
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