The final results of a landmark study published in the Lancet Infectious Diseases confirm that the benefits of combining the malaria vaccine with antimalarial drugs in settings of highly seasonal malaria transmission continue over five years.
The vaccine-drug combination reduced clinical malaria episodes, including cases of severe malaria, and deaths from malaria in young children by nearly two-thirds compared with either RTS,S vaccination or seasonal malaria chemoprevention (SMC) alone.
The Phase 3 study was coordinated by the London School of Hygiene and Tropical Medicine, with partners Institut des Sciences et Techniques and Institut de Recherche en Sciences de la Santé, Burkina Faso; the Malaria Research and Training Center, University of Sciences, Techniques and Technologies of Bamako, Mali; and PATH, Seattle, Washington, USA.
Following more than 5,000 children over a total of five years, the study also confirmed that the efficacy of the Vaccine (RTS,S/AS01E) in preventing malaria in highly seasonal settings was similar, or ‘non-inferior,’ to that of SMC.
The findings from five years of follow-up are consistent with those from the first three years, which were published in 2021 Those findings contributed to the World Health Organization’s decision that year to recommend the RTS,S vaccine for use in settings of moderate-to-high malaria transmission, including its use in areas with highly seasonal malaria or in areas of perennial malaria transmission with seasonal peaks.
These new findings confirm the potential of seasonal vaccination to provide a high level of protection in young children over the first five years of life, a period when this protection is needed.
Professor Brian Greenwood, MD, a member of the research team, said, “In addition to the study’s findings, we can say that children who received the RTS,S-drug combination and also used bednets likely had greater than 90 percent protection against malaria episodes during the study.”
This apparently 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, PhD, of Institut des Sciences et Techniques, said, “It is tremendously exciting to know that our research could benefit the health of millions of children at high risk of malaria in countries like Burkina Faso and Mali.”
The challenge however is to determine how best to deliver the vaccine-drug combination and to follow these highly protected children as they grow older.
In light of what is already known about the potential for malaria “rebound” following the withdrawal of malaria prevention, children in the study who received SMC and the vaccine are being followed for a further two years.
This additional follow-up will help to determine how long protection lasts and whether the high level of protection against malaria provided by the combination of SMC and seasonal RTS,S vaccination impaired the acquisition of naturally acquired immunity among the children in the study by reducing the number of infections they received in early life.
Currently, SMC is not given to children above the age of 5 years in most countries where it is deployed.
The newly published results come from a two-year extension of the Phase 3 study begun in Burkina Faso and Mali in 2017.
The extension began in April 2020, when 5,048 (94 percent) of the 5,433 children who completed the initial three-year follow-up were re-enrolled.
Over the full five years, protective efficacy of the RTS,S-SMC combination was very similar to that seen in the first three years.
Protective efficacy of the combination versus SMC alone being 57.7 percent and versus RTS,S alone, 59 Percent.
The comparable figures for the first three years of the study were 62.8 Percent and 59.6 percent respectively.
The protective efficacy of each intervention alone could not be assessed because all children participating in the study received one or both interventions; there was not a group of children who received neither intervention.
Compared with SMC alone, the RTS,S-SMC combination, reduced by two-thirds hospital admissions for WHO-defined severe malaria (66.8%), malarial anemia (65.9%), blood transfusions (68.1%), and malaria deaths (66.8%).
Professor Alassane Dicko, MD, of the Malaria Research and Training Center and a member of the research team, said, “Our study showed that administering the RTS,S vaccine seasonally every year reduces the burden of malaria drastically in children under the age of 5, who are the most affected by this disease. Rapid implementation of this new additional tool is needed to reduce the huge burden of malaria on children in our countries.”
SMC, which involves giving antimalarial drugs Sulfadoxine-Pyrimethamine and Amodiaquine to young children four or five times during the rainy season when malaria transmission peaks, is highly effective in preventing malaria and was recommended by WHO in 2012 for use in areas with highly seasonal transmission.
The study took advantage of the fact that RTS,S efficacy is highest in the months immediately after vaccination, at about 70 percent.
There were no safety issues following multiple annual booster doses of RTS,S, with some children receiving four seasonal booster doses after the initial three-dose primary series.
Mark Palmer, DPhil, Director of International Relations at the Medical Research Council, which funded the study, said, “It is exciting to see the potential for a significant reduction in malaria cases and deaths in children under 5 demonstrated by this landmark study. This crucial evidence expands the range of tools available to combat this disease in the future.”
“Around 45 million children were reached with SMC in 2021,” said Professor Greenwood. “Yet malaria is still killing tens of thousands of children each year in areas where SMC is used, and many more are hospitalized.”
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