The Effect of Ecological and Host Genetics Factors on the Efficacy of the RTS,S Vaccine: Insights from Phase III trial subjects in Ghana, Gabon and Malawi

Malaria is an infectious disease that kills over half a million people globally each year. It is caused by the <em>Plasmodium </em>parasite and transmitted by the bite of an infected female <em>Anopheles </em>mosquito. Sub-Saharan Africa carries a disproportionately high percentage of the global malaria burden, but significant morbidity and mortality have also been recorded in South Asia and South America. While malaria cases have consistently increased since 2015, the largest increase in malaria incidence occurred between 2019 and 2020. In contrast, rates of malaria mortality consistently decreased between 2000 and 2019, increased in 2020 and have slightly decreased in 2021 and 2022. The WHO partially attributes these breaks in progress to pandemic-related disruptions in access to malaria treatment and prevention resources. Malaria has typically been controlled using two main vector control interventions: indoor residual spraying and insecticide treated nets both of which face threats to effectiveness due to factors including resistance of Anopheles mosquitoes to insecticides. Moreover, artemisinin combination therapies remain the most common treatment option for <em>P. falciparum </em>malaria, which is the deadliest and most prevalent malaria strain in Africa. Unfortunately, confirmed reports of partial artemisinin resistance in Africa have made it necessary to explore alternative solutions, one of which is a vaccine. Currently, there are two malaria vaccines recommended for use by the WHO. The second and most recent WHO-recommended and prequalified malaria vaccine, R21, has shown high efficacy when administered prior to the high transmission season and good efficacy when delivered according to a schedule determined by age. RTS,S is the first vaccine to be recommended and prequalified by the WHO, and results from its phase III clinical trials indicated moderate protective efficacy among children aged 5 to 17 months over 4 years of follow-up. Phase three trials results also suggested that vaccine efficacy varied widely across the eleven different study sites with environmental, behavioral, host and parasite genetics factors offered as potential contributory factors. The study upon which this paper is based explores how the above factors, individually and in combination with each other, have had an impact on vaccine efficacy in sites in Ghana, Gabon and Malawi from the RTS,S Phase III trial.<span class="Apple-converted-space">&nbsp;</span>