First-in-human, Randomized, Double-blind Clinical Trial of Differentially Adjuvanted PAMVAC, A Vaccine Candidate to Prevent Pregnancy-associated Malaria.

Benjamin Mordmüller,Mihály Sulyok,Meral Esen,Mafalda Resende,Helle Holm Smedegaard,Odile Leroy,Ali Salanti,Philippe Deloron,Sophie Houard,Javier Ibáñez,Carlos Lamsfus Calle,Charlotte Dyring,Annette Knoblich,Lars Poulsen,Saadou Issifou,Willem A De Jongh ,Steven G Reed ,Sisse B Ditlev ,Randall F Howard ,Diane Egger‐Adam ,Max Søgaard ,Thor G Theander ,Adrian J F Luty ,Nicaise Tuikue Ndam ,Peter G Kremsner ,M Jensen ,Morten A Nielsen

doi:10.1093/cid/ciy1140

Abstract

BackgroundMalaria in pregnancy has major impacts on mother and child health. To complement existing interventions, such as intermittent preventive treatment and use of impregnated bed nets, we developed a malaria vaccine candidate with the aim of reducing sequestration of asexual “blood-stage” parasites in the placenta, the major virulence mechanism.MethodsThe vaccine candidate PAMVAC is 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 3 intramuscular injections of 20 μg (n = 9) or 50 μg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation was random and double blind. The vaccine was given every 4 weeks. Volunteers were observed for 6 months following last immunization.ResultsAll PAMVAC formulations were safe and well tolerated. A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine. No serious AEs occurred. Distribution and severity of AEs 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.ConclusionsPAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well tolerated, and induced functionally active antibodies. Next, PAMVAC will be assessed in women before first pregnancies in an endemic area.Clinical Trials RegistrationEudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.

Highlights

First-in-human, Randomized, Double-blind Clinical Trial of Differentially Adjuvanted PAMVAC, A Vaccine Candidate to Prevent Pregnancy-associated Malaria
A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine
PAMVAC-specific antibody levels were highest with PAMVAC-glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE)

Summary

Methods

The vaccine candidate PAMVAC is based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Adult malaria-naive volunteers were immunized with 3 intramuscular injections of 20 μg (n = 9) or 50 μg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Eligible volunteers were immunized with PAMVAC, adjuvanted with Alhydrogel, GLA-SE, or GLA-LSQ 3 times at 4-week intervals. Neither the clinical team nor the volunteers were aware of allocation to the Alhydrogel, GLA-SE, or GLA-LSQ arm. Vaccinations started in 3 sentinel volunteers, receiving 20 μg PAMVAC adjuvanted with Alhydrogel, GLA-SE, or GLA-LSQ, respectively, followed by 2 volunteers in each group 1 day later (n = 3 per arm). Volunteers were contacted actively by the clinical team 1 and 14 days following each vaccination. The team was available 24 hours, 7 days a week

Results

Discussion

Conclusion