First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria.

Background: Malaria in pregnancy has major impacts on mother and child health. The current strategy to prevent pregnancy-associated malaria (PAM) comprises intermittent preventive treatment and use of impregnated bednets. To complement existing interventions, we developed a malaria vaccine candidate aiming at reducing sequestration of asexual "blood-stage" parasites in the placenta, the major virulence mechanism in PAM.

Methods: PAMVAC is a vaccine candidate based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Healthy, adult malaria-naive volunteers were immunized with three intramuscular injections of 20 μg (n=9) or 50 μg (n=27) PAMVAC, adjuvanted either with Alhydrogel, or with Glucopyranosyl Lipid Adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation to the three formulations was random and double-blind. Vaccines were given every four weeks. Volunteers were observed for six months following last immunization.

Results: All PAMVAC formulations were safe and well tolerated. Altogether, 262 adverse events (AE) occurred in 36/36 volunteers, 94 (ten Grade 2, two Grade 3) at least possibly related to the vaccine. No Serious AE occurred. Distribution and severity of AE were similar in all arms. PAMVAC was immunogenic in all participants. PAMVAC-specific antibody levels were highest with PAMVAC-GLA-SE. The antibodies inhibited binding of VAR2CSA expressing P. falciparum-infected erythrocytes to CSA in a standardized functional assay.

Conclusions: PAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well-tolerated and induced functionally active antibodies. PAMVAC will next be assessed in women before first pregnancies in an endemic area.