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

Abstract

BACKGROUND:

Malaria 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.

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). 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.

RESULTS:

All 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.

CONCLUSIONS:

PAMVAC 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 REGISTRATION:

EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.

• Authors: Benjamin Mordmüller, Mihály Sulyok, Diane Egger-Adam, Mafalda Resende, Willem A de Jongh, Mette H Jensen, Helle Holm Smedegaard, Sisse B Ditlev, Max Soegaard, Lars Poulsen, Charlotte Dyring, Carlos Lamsfus Calle, Annette Knoblich, Javier Ibáñez, Meral Esen, Philippe Deloron, Nicaise Ndam, Saadou Issifou, Sophie Houard, Randall F Howard, Steven G Reed, Odile Leroy, Adrian J F Luty, Thor G Theander, Peter G Kremsner, Ali Salanti, Morten A Nielsen
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 69 Issue 9 Pg. 1509-1516 (10 15 2019) ISSN: 1537-6591 [Electronic] United States
• PMID: 30629148 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

Chemical References

• Liposomes
• Malaria Vaccines
• Aluminum Hydroxide
• Chondroitin Sulfates

Topics

• Adult
• Aluminum Hydroxide (chemistry)
• Chondroitin Sulfates (metabolism)
• Double-Blind Method
• Female
• Humans
• Injections, Intramuscular
• Liposomes (chemistry)
• Malaria Vaccines (administration & dosage, therapeutic use)
• Plasmodium falciparum (immunology, pathogenicity)
• Pregnancy
• Young Adult