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

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  • Benjamin Mordmüller
    Institut für Tropenmedizin, Universitätsklinikum Tübingen and Deutsches Zentrum für Infektionsforschung, Germany
  • Mihály Sulyok
    Institut für Tropenmedizin, Universitätsklinikum Tübingen and Deutsches Zentrum für Infektionsforschung, Germany
  • Diane Egger-Adam
    Institut für Tropenmedizin, Universitätsklinikum Tübingen and Deutsches Zentrum für Infektionsforschung, Germany
  • Mafalda Resende
    Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital
  • Willem A de Jongh
    ExpreS2ion Biotechnologies, Horsholm, Denmark
  • Mette H Jensen
    Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital
  • Helle Holm Smedegaard
    Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital
  • Sisse B Ditlev
    Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital
  • Max Soegaard
    ExpreS2ion Biotechnologies, Horsholm, Denmark
  • Lars Poulsen
    ExpreS2ion Biotechnologies, Horsholm, Denmark
  • Charlotte Dyring
    ExpreS2ion Biotechnologies, Horsholm, Denmark
  • Carlos Lamsfus Calle
    Institut für Tropenmedizin, Universitätsklinikum Tübingen and Deutsches Zentrum für Infektionsforschung, Germany
  • Annette Knoblich
    Institut für Tropenmedizin, Universitätsklinikum Tübingen and Deutsches Zentrum für Infektionsforschung, Germany
  • Javier Ibáñez
    Institut für Tropenmedizin, Universitätsklinikum Tübingen and Deutsches Zentrum für Infektionsforschung, Germany
  • Meral Esen
    Institut für Tropenmedizin, Universitätsklinikum Tübingen and Deutsches Zentrum für Infektionsforschung, Germany
  • Philippe Deloron
    Mère et Enfant face aux Infections Tropicales, Institut de Recherche pour le Développement, Université Paris 5, Sorbonne Paris Cité, France
  • Nicaise Ndam
    Mère et Enfant face aux Infections Tropicales, Institut de Recherche pour le Développement, Université Paris 5, Sorbonne Paris Cité, France
  • Saadou Issifou
    Fondation pour la Recherche Scientifique and Institut de Recherche Clinique du Bénin, Cotonou
  • Sophie Houard
    European Vaccine Initiative, Heidelberg, Germany
  • Randall F Howard
    Infectious Disease Research Institute, Seattle, Washington
  • Steven G Reed
    Infectious Disease Research Institute, Seattle, Washington
  • Odile Leroy
    European Vaccine Initiative, Heidelberg, Germany
  • Adrian J F Luty
    Mère et Enfant face aux Infections Tropicales, Institut de Recherche pour le Développement, Université Paris 5, Sorbonne Paris Cité, France
  • Thor G Theander
    Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital
  • Peter G Kremsner
    Institut für Tropenmedizin, Universitätsklinikum Tübingen and Deutsches Zentrum für Infektionsforschung, Germany
  • Ali Salanti
    Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital
  • Morten A Nielsen
    Centre for Medical Parasitology at Department of Immunology and Microbiology, University of Copenhagen and Department of Infectious Diseases, Copenhagen University Hospital

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<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Clinical Trials Registration</jats:title> <jats:p>EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.</jats:p> </jats:sec>

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