A NOVEL multistage malaria vaccine has demonstrated encouraging efficacy and safety in African adults with lifelong exposure to malaria, according to results from a randomised controlled trial conducted in Mali. The investigational vaccine, ProC6C-AlOH/MM, is designed to target multiple stages of the Plasmodium falciparum life cycle, including both infection and transmission phases.
ProC6C combines epitopes from the circumsporozoite protein (PfCSP), expressed during the sporozoite stage, with transmission-stage antigens Pfs230 and Pfs48/45. The vaccine is adsorbed to aluminium hydroxide and adjuvanted with Matrix-M to enhance immune responses. Previous Phase 1 studies demonstrated favourable safety and immunogenicity, prompting evaluation in a malaria-endemic setting.
Testing a Multistage Malaria Vaccine Using Human Challenge
The double-blind study was conducted in Sotuba, a peri-urban area of Mali, and enrolled healthy adults aged 18–50 years with prior malaria exposure. Participants were randomly assigned to receive three doses of ProC6C-AlOH/MM or a rabies vaccine control, administered 4 weeks apart.
Ninety-four days after the final vaccination, participants underwent controlled human malaria infection (CHMI) using intradermal inoculation of P. falciparum sporozoites. This approach allowed researchers to directly assess vaccine efficacy by measuring time to blood-stage infection using sensitive PCR methods.
Of the 32 participants who underwent CHMI, significantly fewer individuals in the ProC6C vaccine group developed parasitaemia compared with controls. Among those who did become infected, the median time to detectable infection was delayed by 2 days in vaccinated participants, indicating partial protection.
Promising Efficacy and Safety
In the per-protocol analysis, the multistage malaria vaccine achieved a vaccine efficacy of 76%, with proportional analysis showing efficacy exceeding 50%. These results mark the first time an anti-PfCSP subunit vaccine has surpassed this efficacy threshold at 12 weeks post-vaccination in a CHMI setting.
The vaccine was generally well tolerated. While adverse events were more common in the vaccine group than in controls, most were mild and self-limiting, supporting an acceptable safety profile in malaria-exposed adults.
Implications for Future Malaria Prevention Strategies
These findings provide strong proof of concept for a multistage approach to malaria vaccination, addressing both infection risk and onward transmission. Importantly, the study also identified a mechanistically plausible immune correlate of protection, strengthening confidence in the biological basis of the observed efficacy.
Following age de-escalation, researchers plan to advance ProC6C into Phase 2 trials to evaluate its effectiveness against naturally acquired malaria in children, the population most affected by severe disease. If successful, this multistage malaria vaccine could represent a significant advance in global malaria control and elimination efforts.
Reference
Kone M et al. Efficacy of ProC6C-AlOH/Matrix-M against Plasmodium falciparum infection and mosquito transmission: a phase 2, randomised, controlled human malaria infection study. Lancet Infect Dis. 2025; DOI:10.1016/S1473-3099(25)00664-4.
