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

TY - JOUR

T1 - First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria

AU - Mordmüller, Benjamin

AU - Sulyok, Mihály

AU - Egger-Adam, Diane

AU - Resende, Mafalda

AU - de Jongh, Willem A

AU - Jensen, Mette H.

AU - Smedegaard, Helle Holm

AU - Ditlev, Sisse B

AU - Soegaard, Max

AU - Poulsen, Lars

AU - Dyring, Charlotte

AU - Calle, Carlos Lamsfus

AU - Knoblich, Annette

AU - Ibáñez, Javier

AU - Esen, Meral

AU - Deloron, Philippe

AU - Ndam, Nicaise

AU - Issifou, Saadou

AU - Houard, Sophie

AU - Howard, Randall F

AU - Reed, Steven G

AU - Leroy, Odile

AU - Luty, Adrian J F

AU - Theander, Thor G

AU - Kremsner, Peter G

AU - Salanti, Ali

AU - Nielsen, Morten A

N1 - © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

PY - 2019/10/15

Y1 - 2019/10/15

N2 - 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.

AB - 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.

U2 - 10.1093/cid/ciy1140

DO - 10.1093/cid/ciy1140

M3 - Journal article

C2 - 30629148

SN - 1058-4838

VL - 69

SP - 1509

EP - 1516

JO - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

JF - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

IS - 9

ER -