Trial of malaria vaccine plus drugs confirms two-thirds reduction in infections, deaths

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The final results of a phase 3 trial on the combination of a seasonal malaria vaccine and antimalarial drugs in children confirms a two-thirds decrease in the mosquito-borne illness, including severe cases and deaths, over 5 years in Burkina Faso and Mali.

Yesterday in The Lancet Infectious Diseases, a team led by researchers from the University of Science, Technology and Techniques of Bamako (USTTB) in Mali describe the comparison of seasonal malaria chemoprevention (SMC) with sulphadoxine-pyrimethamine and amodiaquine plus control vaccines, the RTS,S/AS01_E vaccine plus placebo SMC, or SMC plus RTS,S/AS01_E.

The World Health Organization (WHO) recommends monthly SMC during the rainy season, when malaria transmission peaks. GlaxoSmithKline's circumsporozoite protein-based RTS,S/AS01_E vaccine is licensed for malarial control in Africa. Circumsporozoite protein is the antigenic target of the vaccine.

Superior to preventive drugs, vaccine alone

Children enrolled in the initial 3-year trial at ages 5 to 17 months in 2017 were randomly assigned to receive one of the three interventions until they were 5 years old. In the phase 3 trial, children randomly assigned to receive the RTS,S/AS01_E vaccine were vaccinated at months 0, 1, and 2, followed by a booster dose at month 20.

Non-inferiority was defined as a 20% increase in clinical malaria in the RTS,S/AS01_E-alone group compared with the SMC-alone group, and superiority was defined as a 12% difference in the incidence of clinical malaria between the combined and single-intervention groups.

In April 2020, 5,098 (94%) of the 5,433 children who completed the initial 3-year follow-up were re-enrolled in the 2-year extension study. The incidence of clinical malaria per 1,000 person-years at risk over 5 years was 313 in the SMC-alone group, 320 in the RTS,S/AS01_E-alone group, and 133 in the combination group.

The combination of RTS,S/AS01_E and SMC was superior to SMC (protective efficacy, 57.7%) and to RTS,S/AS01_E (protective efficacy, 59.0%) in preventing malaria. RTS,S/AS01_E was non-inferior to SMC (hazard ratio, 1.03). The protective efficacy of the combination compared with SMC over 5 years was comparable to that observed in the first 3 years (protective efficacy of the combination vs SMC, 57.7% and vs RTS/AS01_E-alone, 59.0%).

We can say that children who received the RTS,S-drug combination and also used bednets likely had greater than 90% protection against malaria episodes during the study.

Brian Greenwood, MD

In comparison, the respective protective efficacy during the first 3 years of the study was 62.8% and 59.6%. Hospitalizations fell for severe malaria (by 66.8%), malarial anemia (65.9%), blood transfusion (68.1%), all-cause death (44.5%), deaths excluding others causes or surgery (41.1%), and deaths from malaria (66.8%) in the combined group versus the SMC-alone group. No safety signals were identified.

Importance of multiple prevention tools

"We can say that children who received the RTS,S-drug combination and also used bednets likely had greater than 90% protection against malaria episodes during the study," senior author Brian Greenwood, MD, of the London School of Hygiene & Tropical Medicine, said in a PATH news release. "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."

Children in the study who received SMC and/or the vaccine are now being followed up for another 2 years. "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," coauthor Jean-Bosco Ouedraogo, PhD, of Institut des Sciences et Techniques, said in the release.

In a related commentary, Sheetij Dutta, PhD, of Walter Reed Army Institute of Research, and Mahamadou Thera, MD, PhD, MPH, of USTTB, wrote, "Given the scarce resources available for malaria control, cost-effectiveness of this complex intervention tool, will need to be balanced against improved bednets, alternative SMC regimens, and future circumsporozoite protein-based interventions under investigation."

"Malaria burden has shifted to older children in areas where SMC has been effective since 2013," they added. "WHO has recommended to extend the age of SMC to older school-aged children. It remains to be established how the inclusion of RTS,S/AS01_E will affect SMC effects at the population level."