Odilon Nouatin1, Ulysse Ateba Ngoa2, Javier Ibáñez3, Jean Claude Dejon-Agobe4, Benjamin Mordmüller5, Jean Ronald Edoa6, Fabrice Mougeni7, Sina Brückner8, Aurore Bouyoukou Hounkpatin4, Meral Esen9, Michael Theisen10, Kabirou Moutairou11, Stephen L Hoffman12, Saadou Issifou13, Adrian J F Luty14, Marguerite M Loembe15, Selidji Todagbé Agnandji16, Bertrand Lell17, Peter G Kremsner18, Ayôla Akim Adegnika19. 1. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon; Institut für Tropenmedizin, Universität Tubingen, Wilhelmstraβe 27, D-72074 Tübingen, Germany; Germany; German Centre for Infection Research (DZIF), Partner Site Tübingen, Germany; Département de Biochimie et de Biologie Cellulaire, Faculté des Sciences et Techniques, Université d'Abomey-Calavi, Cotonou, Benin. Electronic address: paterneodilon@gmail.com. 2. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon. Electronic address: ulyssus7000@gmail.com. 3. Institut für Tropenmedizin, Universität Tubingen, Wilhelmstraβe 27, D-72074 Tübingen, Germany. 4. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon; Institut für Tropenmedizin, Universität Tubingen, Wilhelmstraβe 27, D-72074 Tübingen, Germany. 5. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon; Institut für Tropenmedizin, Universität Tubingen, Wilhelmstraβe 27, D-72074 Tübingen, Germany; Germany; German Centre for Infection Research (DZIF), Partner Site Tübingen, Germany. Electronic address: benjamin.mordmueller@uni-tuebingen.de. 6. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon; Institut für Tropenmedizin, Universität Tubingen, Wilhelmstraβe 27, D-72074 Tübingen, Germany. Electronic address: j.ronaldedoa@cermel.org. 7. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon. 8. Institut für Tropenmedizin, Universität Tubingen, Wilhelmstraβe 27, D-72074 Tübingen, Germany. Electronic address: sinab@gmx.net. 9. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon; Institut für Tropenmedizin, Universität Tubingen, Wilhelmstraβe 27, D-72074 Tübingen, Germany; Germany; German Centre for Infection Research (DZIF), Partner Site Tübingen, Germany. Electronic address: meral.esen@uni-tuebingen.de. 10. Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark and Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, University of Copenhagen, and Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark. Electronic address: mth@ssi.dk. 11. Département de Biochimie et de Biologie Cellulaire, Faculté des Sciences et Techniques, Université d'Abomey-Calavi, Cotonou, Benin. Electronic address: kamoutairo@yahoo.fr. 12. Sanaria Inc, Rockville, MD 20850, USA. Electronic address: slhoffman@sanaria.com. 13. Fondation pour la Recherche Scientifique, 72 BP45 Cotonou, Benin. Electronic address: isaadou2002@yahoo.fr. 14. Centre d'Etude et de Recherche sur le Paludisme Associé à la Grossesse et à l'Enfance, Faculté des Sciences de la Santé, Université d'Abomey-Calavi, Cotonou, MERIT UMR D216, Benin; Université de Paris, MERIT, IRD, Paris, France. Electronic address: adrian.luty@ird.fr. 15. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon; Institut für Tropenmedizin, Universität Tubingen, Wilhelmstraβe 27, D-72074 Tübingen, Germany; Germany; German Centre for Infection Research (DZIF), Partner Site Tübingen, Germany. Electronic address: mmassingaloembe@cermel.org. 16. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon; Institut für Tropenmedizin, Universität Tubingen, Wilhelmstraβe 27, D-72074 Tübingen, Germany; Germany; German Centre for Infection Research (DZIF), Partner Site Tübingen, Germany. Electronic address: agnandjis@cermel.org. 17. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon; Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria. Electronic address: bertrand.lell@cermel.org. 18. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon; Institut für Tropenmedizin, Universität Tubingen, Wilhelmstraβe 27, D-72074 Tübingen, Germany; Germany; German Centre for Infection Research (DZIF), Partner Site Tübingen, Germany. Electronic address: peter.kremsner@uni-tuebingen.de. 19. Centre de Recherches Médicales de Lambaréné, BP: 242 Lambaréné, Gabon; Institut für Tropenmedizin, Universität Tubingen, Wilhelmstraβe 27, D-72074 Tübingen, Germany; Germany; German Centre for Infection Research (DZIF), Partner Site Tübingen, Germany; Leiden University Medical Centre (LUMC), 2333 ZA Leiden, the Netherlands. Electronic address: aadegnika@cermel.org.
Abstract
BACKGROUND: Despite appreciable immunogenicity in malaria-naive populations, many candidate malaria vaccines are considerably less immunogenic in malaria-exposed populations. This could reflect induction of immune regulatory mechanisms involving Human Leukocyte Antigen G (HLA-G), regulatory T (Treg), and regulatory B (Breg) cells. Here, we addressed the question whether there is correlation between these immune regulatory pathways and both plasmablast frequencies and vaccine-specific IgG concentrations. METHODS:Fifty Gabonese adults with lifelong exposure to Plasmodium spp were randomized to receive three doses of either 30 µg or 100 µg GMZ2-CAF01, or 100 µg GMZ2-alum, or control vaccine (rabies vaccine) at 4-week intervals. Only plasma and peripheral blood mononuclear cells isolated from blood samples collected before (D0) and 28 days after the third vaccination (D84) of 35 participants were used to measure sHLA-G levels and anti-GMZ2 IgG concentrations, and to quantify Treg, Breg and plasmablast cells. Vaccine efficacy was assessed using controlled human malaria infection (CHMI) by direct venous inoculation of Plasmodium falciparum sporozoites (PfSPZ Challenge). RESULTS: The sHLA-G concentration increased from D0 to D84 in all GMZ2 vaccinated participants and in the control group, whereas Treg frequencies increased only in those receiving 30 µg or 100 µg GMZ2-CAF01. The sHLA-G level on D84 was associated with a decrease of the anti-GMZ2 IgG concentration, whereas Treg frequencies on D0 or on D84, and Breg frequency on D84 were associated with lower plasmablast frequencies. Importantly, having a D84:D0 ratio of sHLA-G above the median was associated with an increased risk of P. falciparum infection after sporozoites injection. CONCLUSION: Regulatory immune responses are induced following immunization. Stronger sHLA-G and Treg immune responses may suppress vaccine induced immune responses, and the magnitude of the sHLA-G response increased the risk of Plasmodium falciparum infection after CHMI. These findings could have implications for the design and testing of malaria vaccine candidates in semi-immune individuals.
RCT Entities:
BACKGROUND: Despite appreciable immunogenicity in malaria-naive populations, many candidate malaria vaccines are considerably less immunogenic in malaria-exposed populations. This could reflect induction of immune regulatory mechanisms involving Human Leukocyte Antigen G (HLA-G), regulatory T (Treg), and regulatory B (Breg) cells. Here, we addressed the question whether there is correlation between these immune regulatory pathways and both plasmablast frequencies and vaccine-specific IgG concentrations. METHODS: Fifty Gabonese adults with lifelong exposure to Plasmodium spp were randomized to receive three doses of either 30 µg or 100 µg GMZ2-CAF01, or 100 µg GMZ2-alum, or control vaccine (rabies vaccine) at 4-week intervals. Only plasma and peripheral blood mononuclear cells isolated from blood samples collected before (D0) and 28 days after the third vaccination (D84) of 35 participants were used to measure sHLA-G levels and anti-GMZ2 IgG concentrations, and to quantify Treg, Breg and plasmablast cells. Vaccine efficacy was assessed using controlled humanmalaria infection (CHMI) by direct venous inoculation of Plasmodiumfalciparum sporozoites (PfSPZ Challenge). RESULTS: The sHLA-G concentration increased from D0 to D84 in all GMZ2 vaccinated participants and in the control group, whereas Treg frequencies increased only in those receiving 30 µg or 100 µg GMZ2-CAF01. The sHLA-G level on D84 was associated with a decrease of the anti-GMZ2 IgG concentration, whereas Treg frequencies on D0 or on D84, and Breg frequency on D84 were associated with lower plasmablast frequencies. Importantly, having a D84:D0 ratio of sHLA-G above the median was associated with an increased risk of P. falciparum infection after sporozoites injection. CONCLUSION: Regulatory immune responses are induced following immunization. Stronger sHLA-G and Treg immune responses may suppress vaccine induced immune responses, and the magnitude of the sHLA-G response increased the risk of Plasmodium falciparuminfection after CHMI. These findings could have implications for the design and testing of malaria vaccine candidates in semi-immune individuals.
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Authors: Odilon Nouatin; Javier Ibáñez; Rolf Fendel; Ayola A Adegnika; Benjamin Mordmüller; Ulysse A Ngoa; Freia-Raphaella Lorenz; Jean-Claude Dejon-Agobé; Jean Ronald Edoa; Judith Flügge; Sina Brückner; Meral Esen; Michael Theisen; Stephen L Hoffman; Kabirou Moutairou; Adrian J F Luty; Bertrand Lell; Peter G Kremsner Journal: Malar J Date: 2022-06-17 Impact factor: 3.469