Perennial malaria chemoprevention in the malaria vaccine ERA (PMC-VAC) - malaria due to plasmodium falciparum (PF) remains a highly lethal disease, resulting in 610,000 deaths annually

The National Institute of Allergy and Infectious Diseases, part of the Department of Health and Human Services, awarded The Leland Stanford Junior University $1,818,562 on May 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to evaluate optimal antimalarial chemoprevention regimens combined with the R21 malaria vaccine in perennial, high-transmission settings.

The research will test whether combining the R21 vaccine with either monthly dihydroartemisinin-piperaquine (PMC-DP) or sulfadoxine-pyrimethamine-amodiaquine (PMC-SPAQ) chemoprevention delivers superior malaria protection compared with vaccination alone, whether PMC-DP proves more efficacious and better tolerated than PMC-SPAQ, and whether both chemoprevention arms enhance R21 immunogenicity and durability without significantly promoting parasite drug resistance. The work addresses a gap in current knowledge: while R21 is now deployed in Uganda and other African countries for infants beginning at five to six months of age, the burden of malaria in high-transmission settings remains substantial prior to when vaccine-elicited protection is expected to begin, and vaccine efficacy and durability are anticipated to be suboptimal. The study will take place in Busia District and operate through April 30, 2033. Place of performance is Palo Alto, California.

In the US, there are ~2000 malaria cases and 5-10 deaths each year, nearly all contracted in africa, and malaria poses a significant and growing risk to US international travelers and military personnel in endemic deployments. Notably, competent anopheles mosquito vectors persist across the united states, raising the specter of domestic malaria RE-emergence. Optimizing malaria prevention is therefore a pressing US public health priority. An affordable malaria vaccine, R21, is now being deployed in uganda and other african countries for infants beginning at 5-6 months of age. However, in perennial, high transmission settings, the burden of malaria can be high prior to the age at which R21-elicited protection is expected to begin, and vaccine efficacy and durability are expected to be sub-optimal. In these settings, additional interventions will be needed to best prevent malaria. A promising approach to enhance protection is to administer vaccine along with antimalarial chemoprevention, although optimal regimens and dosing schedules for perennial malaria transmission settings (PMC) are undefined. Two regimens are promising: PMC with spaq (currently used for seasonal malaria chemoprevention), or DP (which we have found to be safe and highly effective when used as monthly chemoprevention in infants). However, their efficacy when given at expanded programme on immunization (EPI) visits remains unevaluated. We will test the hypothesis that R21 combined with either PMC-DP or PMC-spaq will offer better protection against malaria compared with R21 alone, that PMC-DP will be more efficacious and better tolerated than PMC-spaq, and that both PMC arms will enhance R21 immunogenicity and durability without significantly impacting parasite drug resistance. We will test these hypotheses in busia district, uganda, an area with high, perennial malaria transmission. As PF malaria is not endemic in the united states, IT is not possible to conduct this trial domestically, and since the overwhelming burden of PF cases are in sub-saharan africa, conducting this trial there allows US to accrue sufficient endpoints far more rapidly than would ever be feasible domestically. Busia district, uganda-where our team has established regulatory approvals, community trust, and health infrastructure over 15+ years-is uniquely positioned as R21 is now deployed as uganda's standard of care for infants. We will randomize 1290 infants to receive 8 doses of PMC-DP, PMC-spaq, or placebo between 10 weeks and 18 months of age, given at the time of EPI visits. All subjects will receive R21 at 6, 7, 8, and 18 months of age, the standard of care in uganda. Children will be followed to 5 years of age to determine the long-term effects of these interventions. This first-of-its-kind trial will thus have direct policy implications. Knowledge gained will inform travel guidelines and chemoprevention strategies, as well as our understanding of malarial immunity and drug resistance. Control of malaria in africa also advances US economic interests, international stability, and national security.