Odilon Nouatin1,2,3, Juliana Boex Mengue2, Jean Claude Dejon-Agobé1,4, Rolf Fendel1,2,5, Javier Ibáñez2, Ulysse Ateba Ngoa1, Jean Ronald Edoa1, Bayodé Roméo Adégbité1,4,6, Yabo Josiane Honkpéhédji1,6,7, Jeannot Fréjus Zinsou1,6,7, Aurore Bouyoukou Hounkpatin1,2, Kabirou Moutairou3, Andreas Homoet1,2, Meral Esen2,5, Andrea Kreidenweiss1,2,5, Stephen L Hoffman8, Michael Theisen9,10,11, Adrian J F Luty12,13, Bertrand Lell1,14, Selidji Todagbé Agnandji1,2,5, Ghyslain Mombo-Ngoma1,2,15, Michael Ramharter1,15, Peter Kremsner1,2,5, Benjamin Mordmüller1,2,5,16, Ayôla Akim Adegnika1,2,5,6,7. 1. Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon. 2. Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany. 3. Département de Biochimie et de Biologie Cellulaire, Faculté des Sciences et Techniques, Université d'Abomey-Calavi, Cotonou, Bénin. 4. Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Amsterdam University Medical Centers, Amsterdam Infection & Immunity, Amsterdam Public Health, University of Amsterdam, Amsterdam, The Netherlands. 5. German Center for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany. 6. Fondation pour la Recherche Scientifique, Cotonou, Bénin. 7. Department of Parasitology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands. 8. Sanaria, Inc., Rockville, Maryland, United States of America. 9. Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. 10. Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. 11. Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 12. Centre d'Etude et de Recherche sur le Paludisme Associé à la Grossesse et à l'Enfance, Calavi, Bénin. 13. Université de Paris, MERIT, IRD, Paris, France. 14. Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria. 15. Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine & I, Department of Medicine, University Medical Centre, Hamburg-Eppendorf, Hamburg, Germany. 16. Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands.
Abstract
BACKGROUND: Helminths can modulate the host immune response to Plasmodium falciparum and can therefore affect the risk of clinical malaria. We assessed here the effect of helminth infections on both the immunogenicity and efficacy of the GMZ2 malaria vaccine candidate, a recombinant protein consisting of conserved domains of GLURP and MSP3, two asexual blood-stage antigens of P. falciparum. Controlled human malaria infection (CHMI) was used to assess the efficacy of the vaccine. METHODOLOGY: In a randomized, double-blind Phase I clinical trial, fifty, healthy, lifelong malaria-exposed adult volunteers received three doses of GMZ2 adjuvanted with either Cationic Adjuvant Formulation (CAF) 01 or Alhydrogel, or a control vaccine (Rabies) on days (D) 0, D28 and D56, followed by direct venous inoculation (DVI) of 3,200 P. falciparum sporozoites (PfSPZ Challenge) approximately 13 weeks after last vaccination to assess vaccine efficacy. Participants were followed-up on a daily basis with clinical examinations and thick blood smears to monitor P. falciparum parasitemia for 35 days. Malaria was defined as the presence of P. falciparum parasites in the blood associated with at least one symptom that can be associated to malaria over 35 days following DVI of PfSPZ Challenge. Soil-transmitted helminth (STH) infection was assessed by microscopy and by polymerase chain reaction (PCR) on stool, and Schistosoma infection was assessed by microscopy on urine. Participants were considered as infected if positive for any helminth either by PCR and/or microscopy at D0 and/or at D84 (Helm+) and were classified as mono-infection or co-infection. Total vaccine-specific IgG concentrations assessed on D84 were analysed as immunogenicity outcome. MAIN FINDINGS: The helminth in mono-infection, particularly Schistosoma haematobium and STH were significantly associated with earlier malaria episodes following CHMI, while no association was found in case of coinfection. In further analyses, the anti-GMZ2 IgG concentration on D84 was significantly higher in the S. haematobium-infected and significantly lower in the Strongyloides stercoralis-infected groups, compared to helminth-negative volunteers. Interesting, in the absence of helminth infection, a high anti-GMZ2 IgG concentration on D84 was significantly associated with protection against malaria. CONCLUSIONS: Our results suggest that helminth infection may reduce naturally acquired and vaccine-induced protection against malaria. Vaccine-specific antibody concentrations on D84 may be associated with protection in participants with no helminth infection. These results suggest that helminth infection affect malaria vaccine immunogenicity and efficacy in helminth endemic countries.
RCT Entities:
BACKGROUND: Helminths can modulate the host immune response to Plasmodium falciparum and can therefore affect the risk of clinical malaria. We assessed here the effect of helminth infections on both the immunogenicity and efficacy of the GMZ2malaria vaccine candidate, a recombinant protein consisting of conserved domains of GLURP and MSP3, two asexual blood-stage antigens of P. falciparum. Controlled humanmalaria infection (CHMI) was used to assess the efficacy of the vaccine. METHODOLOGY: In a randomized, double-blind Phase I clinical trial, fifty, healthy, lifelong malaria-exposed adult volunteers received three doses of GMZ2 adjuvanted with either Cationic Adjuvant Formulation (CAF) 01 or Alhydrogel, or a control vaccine (Rabies) on days (D) 0, D28 and D56, followed by direct venous inoculation (DVI) of 3,200 P. falciparum sporozoites (PfSPZ Challenge) approximately 13 weeks after last vaccination to assess vaccine efficacy. Participants were followed-up on a daily basis with clinical examinations and thick blood smears to monitor P. falciparum parasitemia for 35 days. Malaria was defined as the presence of P. falciparum parasites in the blood associated with at least one symptom that can be associated to malaria over 35 days following DVI of PfSPZ Challenge. Soil-transmitted helminth (STH) infection was assessed by microscopy and by polymerase chain reaction (PCR) on stool, and Schistosoma infection was assessed by microscopy on urine. Participants were considered as infected if positive for any helminth either by PCR and/or microscopy at D0 and/or at D84 (Helm+) and were classified as mono-infection or co-infection. Total vaccine-specific IgG concentrations assessed on D84 were analysed as immunogenicity outcome. MAIN FINDINGS: The helminth in mono-infection, particularly Schistosoma haematobium and STH were significantly associated with earlier malaria episodes following CHMI, while no association was found in case of coinfection. In further analyses, the anti-GMZ2 IgG concentration on D84 was significantly higher in the S. haematobium-infected and significantly lower in the Strongyloides stercoralis-infected groups, compared to helminth-negative volunteers. Interesting, in the absence of helminth infection, a high anti-GMZ2 IgG concentration on D84 was significantly associated with protection against malaria. CONCLUSIONS: Our results suggest that helminth infection may reduce naturally acquired and vaccine-induced protection against malaria. Vaccine-specific antibody concentrations on D84 may be associated with protection in participants with no helminth infection. These results suggest that helminth infection affect malaria vaccine immunogenicity and efficacy in helminth endemic countries.