Efficacy of ProC6C-AlOH/Matrix-M against #Plasmodium falciparum #infection and #mosquito #transmission: a phase 2, randomised, controlled human malaria infection study

 

Summary

Background

An investigational multistage malaria vaccine, ProC6C, based on distinct Plasmodium falciparum epitopes from the sporozoite stage (P falciparum circumsporozoite protein [PfCSP]) and the transmission stages (Pfs230 and Pfs48/45), adsorbed to aluminium hydroxide (AlOH) and adjuvanted with Matrix-M adjuvant (ProC6C-AlOH/MM), has previously shown safety and immunogenicity in phase 1 studies. We aimed to study vaccine efficacy, safety, and immunogenicity in African adults with lifelong malaria exposure.

Methods

This randomised controlled double-blind vaccination and controlled human malaria infection (CHMI) study was conducted in Sotuba, a peri-urban setting in Mali. Healthy adults (aged 18–50 years), who were malaria experienced and met eligibility criteria, were randomly assigned (1:1) to receive three intramuscular injections of ProC6C-AlOH/MM (100 μg ProC6C and 50 μg Matrix-M adjuvant) or Verorab rabies vaccine (control) 4 weeks apart. Randomisation was done in randomly permuted blocks (random varying block size of two and four) using R Statistical Software (randomizr and blockrand). The content of syringes was masked to ensure blinding and only those responsible for vaccine preparation were unblinded. 94 days after the last vaccination, all participants still in the study underwent CHMI by intradermal inoculation of 22 500 P falciparum sporozoites (Sanaria PfSPZ Challenge [NF54]). Primary outcomes were time to blood-stage infection (quantitative PCR detection of P falciparum, with vaccine efficacy defined as 1 – Cox hazard ratio in the per-protocol population) and vaccine safety and tolerability (in those who were randomly assigned and received at least one vaccination). The trial was registered in the Pan African Clinical Trial Registry (PACTR202404598604620).

Findings

On March 20, April 15, and May 9, 2024, 34 participants (15 males, 19 females) received their vaccinations (n=17 ProC6C-AlOH/MM and n=17 control vaccine). The vaccinations were well tolerated, with 13 (76%) of 17 ProC6C-AlOH/MM recipients experiencing at least one adverse event, almost all of which were mild, compared with three (18%) of 17 control vaccine recipients. On Aug 11, 2024, 94 days after the last dose of vaccine, 32 of 34 participants underwent CHMI, of whom 19 (59%) developed P falciparum parasitaemia by day 28 post-CHMI initiation (13 of 16 in the control group and six of 16 in the ProC6C-AlOH/MM group). In those that became parasitaemic, the median time to positivity was delayed in ProC6C-AlOH/MM recipients by 2 days (14 days ProC6C-AlOH/MM, 12 days control; p=0·049). In the per-protocol time-to-event analysis, vaccine efficacy was 76% (95% CI 36–91, p=0·0022). By proportional analysis (1 – risk ratio) the vaccine efficacy was 54% (95% CI 9–77, p=0·029).

Interpretation

This is the first clinical trial of an anti-PfCSP subunit vaccine that has shown greater than 50% vaccine efficacy against CHMI at 12 weeks after the last vaccine dose, associated with a novel, strong, and mechanistically plausible correlate of protection. Following age de-escalation, future phase 2 studies with ProC6C should therefore assess vaccine efficacy against naturally acquired clinical malaria and onward transmission in the target population, preschool-aged and primary-school-aged children.

Funding

European & Developing Countries Clinical Trials Partnership (EDCTP2 programme) and Gates Foundation.

Source: 

Link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(25)00664-4/abstract?rss=yes

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