Phase Ia trial of RH5.1 protein with Matrix-M adjuvant in malaria-naive UK adults showed safety and similar immunogenicity across two booster regimens.

An efficacious blood-stage malaria vaccine would serve as a highly useful public health tool alongside licensed vaccines targeting the pre-erythrocytic life cycle stage of the Plasmodium falciparum parasite. RH5 is the leading blood-stage malaria vaccine candidate antigen due to its highly-conserved sequence and non-redundant role in merozoite invasion of red blood cells. Following encouraging immunogenicity data in UK and Tanzanian Phase Ia/b vaccine trials, RH5-based vaccines have progressed to Phase IIb evaluation in Burkina Faso in recent years. Here, we report a Phase Ia clinical trial in malaria-naive UK adults to assess the safety and immunogenicity of the malaria vaccine candidate RH5.1 soluble protein with Matrix-M adjuvant using two different booster dosing regimens: 10-10-10 micrograms versus 50-50-10 micrograms RH5.1, both delivered in a 0-1-6-month schedule with 50 micrograms Matrix-M adjuvant per dose (ClinicalTrials.gov NCT06141057). A total of n=24 participants were recruited to this study, with n=23 completing all follow-up visits through to 1 year following final vaccination. The RH5.1/Matrix-M formulation was well-tolerated in this population, with injection site pain, myalgia and fatigue being the most commonly reported symptoms up to 7 days post-vaccination. There were no serious adverse events, adverse events of special interest, or suspected unexpected serious adverse reactions reported over the course of the trial. Both vaccination regimens were similarly immunogenic; no differences were observed in peak anti-RH5.1 serum IgG concentrations, in vitro functional anti-parasitic activity, avidity, or durability. Our findings build on other observations from clinical trials of adjuvanted RH5.1 indicating that humoral immunogenicity can be enhanced by delaying the final booster vaccination, but that there is limited impact of fractionation of the final dose. These insights can help to guide the next steps of multi-antigen, multi-stage malaria vaccine development in malaria-endemic settings.