In August 2023 researchers in an international partnership shared the results of a Phase III study in The Lancet Infectious Diseases. The team comprised the London School of Hygiene & Tropical Medicine (LSHTM), Institut des Sciences et Techniques and Institut de Recherche en Sciences de la Santé, Burkina Faso, the Malaria Research and Training Centre, University of Sciences, Techniques, and Technologies, Mali, and PATH in the US. The results demonstrate that the combination of the RTS,S/AS01 (RTS,S) malaria vaccine and antimalarial drugs have significant benefits in settings of seasonal malaria transmission over 5 years.  

Context to the study 

The authors state that in 2021 an estimated 241 million cases of malaria and an estimated 619 000 malaria deaths occurred. Of these, 90% were in sub-Saharan Africa. In this area, the Sahel and sub-Sahelian regions continue to have “highly seasonal” malaria transmission, and it remains a “major cause of morbidity and mortality in young children”.  

To tackle this, seasonal malaria chemoprevention (SMC) was recommended for malaria control in areas with highly seasonal transmission in 2021. This involves “monthly administration of sulphadoxine-pyrimethamine plus amodiaquine” for young children four or five times during the season. In 2021 around 45 million children received SMC.  

Although SMC has “high effectiveness”, malaria continues to be the primary cause of hospital admissions and deaths in young children in many seasonal malaria transmission areas in sub-Saharan Africa. Therefore, the researchers identified a need for “additional control tools”.  

A trial in 2021 established that the additional of seasonal vaccination to the SMC programme “substantially reduced the incidence” of clinical malaria, severe malaria, and deaths from malaria in young children over 3 years. The trial was conducted in Burkina Faso and Mali. Following the results of this investigation, WHO recommended the deployment of the vaccine for the prevention of Plasmodium falciparum malaria in children who live in regions with moderate to high transmission in sub-Saharan Africa.  

The study 

The researchers hoped to assess whether the “marked reduction” in malaria incidence achieved by the combination of SMC and the vaccine that was seen in the first 3 years of the trial could be sustained until the study children reached the age of 5. At this age, SMC is no longer delivered in these countries. Furthermore, they aimed to assess the safety of administration of repeated booster doses of the RTS,S/ASO1 vaccine, with attention on incidence of meningitis and female mortality observed during the trial.  

The trial was a double-blind, individually randomised, controlled, non-inferiority and superiority Phase III trial conducted at two sites in the Bougouni district and neighbouring areas in Mali, and the Houndé district in Burkina Faso. District hospitals and community health centres provided the base for staff. Children were eligible if they had been enrolled in the initial 3-year trial and if their parents or guardians had given written informed consent.  

Exclusions included children who had suffered an allergic reaction to a study drug or vaccine and those who had developed a serious underlying illness since initial enrolment. Those who reached the age of 5 years before 1st June 2021 left the extension study at the end of the fourth year, with the remaining children followed for a fifth year.  

A substantial reduction 

Over the five-year period of the two studies the protective efficacy of the combination was similar to that seen in the first stage, the initial trial. The protective efficacy of the combination against SMC alone was 57.7% and against RTS,S alone was 59%. The authors acknowledge a substantial reduction in malaria cases and deaths through the combination of seasonal vaccination and SMC. However, what they describe as “not clear” is the “apparent synergy”. 

“One possibility is that the immune response induced by the vaccine, and by natural exposure, is more effective when faced with a low density parasitaemia induced by the drugs, than when faced by parasitaemia at high density.”  

An interesting finding was that in the fifth and final year of the study a higher incidence of clinical malaria was seen in children in the RTS,S/ASO1 group compared to those in the SMC group. This difference was “more marked” in Burkina Faso than in Mali, from which the team inferred that, as a fifth round of SMC was given at the end of malaria season, it has a significant effect. Thus, there is support for the decision of the Burkinabe National Malaria programme to deliver five rounds of SMC in parts of the country where the transmission season is longest.  

Repeat doses of the vaccine are reported as “safe”. All of the five episodes of post-vaccination febrile convulsions were recorded in the first 3 years of the study. Furthermore, no cases of meningitis were detected and there was no evidence of an excess of deaths in girls in children who received the vaccine, as had been observed in the earlier trial. This suggests that these were “chance findings”, yet the authors acknowledge the “concern” that they generate.  

Multiple tools are best 

The study reveals the combination is effective, but LSHTM’s Professor Brian Greenwood adds that “children who received the RTS,S-drug combination and also used bed nets likely had greater than 90% protection against malaria episodes during the study”.  

“This points to the importance of ensuring access to multiple malaria prevention tools for reducing the tremendous burden of malaria disease and death in these highly seasonal settings.”  

Professor Jean-Bosco Ouedraogo of the Institut des Sciences et Techniques is “tremendously” excited that the team’s research could benefit the health of “millions of children”.  

“The challenge now is to determine how best to deliver the vaccine-drug combination and to follow these highly protected children as they grow older.”  

This is exactly what will be done; children in the study will be followed for two more years to understand how long the protection lasts and whether the high level of early protection afforded by these interventions impair the acquisition of naturally acquired immunity by reducing infections in childhood. For Dr Mary Hamel, Senior Technical Officer at the WHO Product Development Research Unit and Team Lead for Malaria Vaccines, the results “come at a critical time”.  

“These data show the remarkable reduction in malaria that can be achieved by strategically delivering the vaccine with other effective interventions – and the potential for saving many young lives.”  

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