Combining seasonal malaria vaccination with seasonal chemoprevention, an effective approach to treat malaria

Malaria threat persists still primarily in tropical and subtropical countries. The vast majority of malaria cases and deaths are found in the WHO African Region, with nearly all cases caused by the Plasmodium falciparum parasite. In 2021, there were an estimated 241 million cases of malaria and an estimated 619 000 malaria deaths worldwide, over 90% of which occurred in sub-Saharan Africa.

A recent trial in journal The Lancet, 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/AS01E vaccine plus placebo SMC, or SMC plus RTS,S/AS01E.

The trial done previously in young children in Burkina Faso and Mali showed that the addition of seasonal vaccination with the malaria vaccine RTS,S/AS01E to SMC substantially reduced the incidence of clinical malaria, severe malaria, and deaths from malaria in young children over a 3 year period.

This led to the historic decision by WHO in October, 2021 to recommend the deployment of RTS,S/AS01E for the prevention of Plasmodium falciparum malaria in children living in regions with moderate to high transmission in sub-Saharan Africa, including an option for countries with seasonal malaria transmission to provide two seasonal booster doses. The current study aimed to establish whether the added protection provided by the combination could be sustained for a further 2 years.

The trial was a double-blind, individually randomised, controlled, non-inferiority and superiority, phase 3 trial done at two sites: the Bougouni district and neighbouring areas in Mali and Houndé district, Burkina Faso. Children who had been enrolled in the initial 3-year trial when aged 5–17 months were initially randomly assigned individually to receive SMC with sulphadoxine-pyrimethamine and amodiaquine plus control vaccines, RTS,S/AS01E plus placebo SMC, or SMC plus RTS,S/AS01E. They continued to receive the same interventions until the age of 5 years.

The primary trial endpoint was the incidence of clinical malaria over the 5-year trial period in both the modified intention-to-treat and per-protocol populations. Over the 5-year period, non-inferiority was defined as a 20% increase in clinical malaria in the RTS,S/AS01E-alone group compared with the SMC alone group. Superiority was defined as a 12% difference in the incidence of clinical malaria between the combined and single intervention groups.

The key findings of the trial are

• Out of 6861 children originally recruited, 5098 (94%) of the 5433 children who completed the initial 3-year follow-up were re-enrolled in the extension study.

• Over 5 years, the incidence of clinical malaria per 1000 person-years at risk was 313 in the SMC alone group, 320 in the RTS,S/AS01E-alone group, and 133 in the combined group.

• The combination of RTS,S/AS01E and SMC was superior to SMC (protective efficacy 57•7%), and to RTS,S/AS01E (protective efficacy 59•0%) in preventing clinical malaria. RTS,S/AS01E was non-inferior to SMC.

• The protective efficacy of the combination versus SMC over the 5-year period of the study was very similar to that seen in the first 3 years with the protective efficacy of the combination versus SMC being 57•7% and versus RTS/AS01E-alone being 59•0% .

• Hospital admissions for WHO-defined severe malaria were reduced by 66•8, for malarial anaemia by 65•9%, for blood transfusion by 68•1%, for all-cause deaths by 44•5%, for deaths excluding external causes or surgery by 41•1%, and for deaths from malaria by 66•8% in the combined group compared with the SMC alone group.

Researchers concluded that “Substantial protection against malaria was sustained over 5 years by combining seasonal malaria vaccination with seasonal chemoprevention, offering a potential new approach to malaria control in areas with seasonal malaria transmission.”

Reference: Prof Alassane Dicko, MD, Prof Jean-Bosco Ouedraogo, PhD, Issaka Zongo, PhD et al.; Seasonal vaccination with RTS,S/AS01E vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: a double-blind, randomised, controlled, phase 3 trial; DOI: https://doi.org/10.1016/S1473-3099(23)00368-7.