The investigational vaccine, ProC6C-AlOH/Matrix-M, is designed to target multiple stages of the
Plasmodium falciparum life cycle. It incorporates epitopes from the sporozoite stage, specifically the circumsporozoite protein, as well as transmission-stage antigens Pfs230 and Pfs48/45. By combining these components with aluminium hydroxide and the Matrix-M adjuvant, the vaccine aims to induce immune responses that both prevent infection and reduce onward transmission. Earlier phase 1 studies had demonstrated acceptable safety and robust immunogenicity, prompting further evaluation in malaria-exposed populations.
The phase 2 double-blind, randomized controlled trial was conducted in Sotuba, a peri-urban area of Mali where malaria transmission is endemic. Healthy adults aged 18 to 50 years with lifelong malaria exposure were enrolled and randomly assigned in a 1:1 ratio to receive either three doses of ProC6C-AlOH/Matrix-M or a licensed rabies vaccine as a control. Vaccinations were administered intramuscularly at four-week intervals, and masking was maintained for participants and investigators, with only vaccine preparers aware of treatment allocation.
Ninety-four days after the final vaccination, participants who remained in the study underwent controlled human malaria infection through intradermal inoculation with P falciparum sporozoites. The primary outcomes included time to detectable blood-stage infection using quantitative PCR and evaluation of vaccine safety and tolerability. Vaccine efficacy was calculated using time-to-event analyses in the per-protocol population.
A total of 34 participants received at least one vaccine dose, with 17 individuals in each study group.
Key Findings:
- The ProC6C-AlOH/Matrix-M vaccine was generally well tolerated, with most adverse events being mild and no serious safety concerns reported.
- Among the 32 participants who underwent controlled malaria challenge, fewer vaccinated individuals developed Plasmodium falciparum parasitaemia compared with controls.
- In participants who became infected, the onset of detectable parasitaemia was delayed in the vaccine group.
- Time-to-event analysis demonstrated a vaccine efficacy of 76% at 12 weeks after the final dose.
- Proportional risk analysis showed vaccine efficacy exceeding 50%.
- The study provides the first evidence that a P falciparum circumsporozoite protein–based subunit vaccine can achieve this level of protection against controlled human malaria infection in adults from an endemic setting.
- The observed protection was associated with a biologically plausible immune correlate, supporting the proposed mechanism of action of the vaccine.
The investigators noted that while the study involved a relatively small number of participants, the results are highly encouraging. They emphasized the importance of further research to confirm efficacy under natural transmission conditions. Following age de-escalation studies, future phase 2 trials are planned to evaluate the vaccine’s ability to prevent clinical malaria and reduce transmission in children, who represent the population at highest risk.
"Overall, the findings suggest that ProC6C-AlOH/Matrix-M could represent a meaningful advance in malaria vaccine development, offering a multistage approach that may be particularly well suited for use in endemic settings," the authors concluded.
Reference:
Kone, M., Plieskatt, J., Thienta, M., Kamate, B., Ofori, E. A., Gmeiner, M., Haidara, B., Kanoute, M. B., Traore, B., Poudiouguo, O. A., Bayogo, H. S., Diarra, I., Bengaly, K., Zeguime, A., Sylla, D., Sacko, A., Hoffman, S. L., McCall, M. B. B., Theisen, M., . . . Richie, T. L. (2025). Efficacy of ProC6C-AlOH/Matrix-M against Plasmodium falciparum infection and mosquito transmission: A phase 2, randomised, controlled human malaria infection study. The Lancet Infectious Diseases. https://doi.org/10.1016/S1473-3099(25)00664-4
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