Comparison of carrier proteins to conjugate malaria transmission blocking vaccine antigens,Pfs25 and Pfs230 |
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| Affiliation: | 1. Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA;2. Fina Biosolutions LLC, Rockville, MD, USA;1. Trudeau Institute, Inc., Saranac Lake, NY, USA;2. Infectious Disease Research Institute, Seattle, WA, USA;3. University of Connecticut School of Medicine, Department of Immunology and Center on Aging, Farmington, CT, USA;1. Infectious Disease Research Institute, Seattle, WA 98102, USA;2. Department of Global Health, University of Washington, Seattle, WA 98105, USA;1. Center for Virology & Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA;2. Infectious Disease Research Institute, Seattle, WA 98102, USA;3. Crucell, 2301 CA Leiden, The Netherlands;4. Division of Molecular Medicine, Children''s Hospital, Boston, MA 02115, USA;5. Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA;6. Ragon Institute of MGH, MIT and Harvard, Boston, MA 02114, USA;2. Pasteur Institut, Paris, France;3. IDRI, Seattle, USA;4. Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland;1. Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso;5. INSERM, Institut de Santé Publique, Pôle de Recherche Clinique, Paris, France;10. Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands;6. AP HP, Hôpital Cochin, Plateforme d’immuno-monitoring vaccinal, Laboratoire d’Immunologie, Paris, France;7. INSERM U970, Paris, France;8. AP-HP, Hôpital Européen Georges Pompidou, Service d’Immunologie Biologique, Paris, France;1. Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso;2. INSERM SC10-US19, Villejuif, France;3. INSERM CIC 1417, F-CRIN, I-REIVAC, Paris, France;4. Assistance Publique –Hôpitaux de Paris (AP HP), Hôpital Cochin, CIC Cochin-Pasteur, Paris, France;9. European Vaccine Initiative (EVI), Heidelberg, Germany;6. AP HP, Hôpital Cochin, Plateforme d’immuno-monitoring vaccinal, Laboratoire d’Immunologie, Paris, France;7. INSERM U970, Paris, France;8. AP-HP, Hôpital Européen Georges Pompidou, Service d’Immunologie Biologique, Paris, France;10. Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands;11. Université Paris Descartes; Sorbonne Paris-Cité, Paris, France;1. Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands;1. Department of Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands;3. Department for Health Evidence, Biostatistics Section, Radboud University Medical Center, Nijmegen, Netherlands;4. Department of Intensive Care, Radboud University Medical Center, Nijmegen, Netherlands;5. Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands;6. Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands;7. PATH''s Malaria Vaccine Initiative, PATH, Seattle, WA, USA;8. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA;9. Human Immunology Laboratory, Imperial College London, London, UK;10. TropIQ Health Sciences, Nijmegen, Netherlands;11. Institut für Tropenmedizin, Universitätsklinikum Tübingen, Tübingen, Germany;12. Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon |
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| Abstract: | Malaria transmission blocking vaccines (TBV) target the sexual stage of the parasite and have been pursued as a stand-alone vaccine or for combination with pre-erythrocytic or blood stage vaccines. Our efforts to develop TBV focus primarily on two antigens, Pfs25 and Pfs230. Chemical conjugation of these poorly immunogenic antigens to carrier proteins enhances their immunogenicity, and conjugates of these antigens to Exoprotein A (EPA) are currently under evaluation in clinical trials. Nonetheless, more potent carriers may augment the immunogenicity of these antigens for a more efficacious vaccine; here, we evaluate a series of proteins to identify such a carrier. Pfs25 and Pfs230 were chemically conjugated to 4 different carriers [tetanus toxoid (TT), a recombinant fragment of tetanus toxin heavy chain (rTThc), recombinant CRM197 produced in Pseudomonas fluorescens (CRM197) or in E. coli (EcoCRM®)] and compared to EPA conjugates in mouse immunogenicity studies. Conjugates of each antigen formulated in Alhydrogel® elicited similar antibody titers but showed differences in functional activity. At a 0.5 µg dose, Pfs230 conjugated to TT, CRM197 and EcoCRM® showed significantly higher functional activity compared to EPA. When formulated with the more potent adjuvant GLA-LSQ, all 4 alternate conjugates induced higher antibody titers as well as increased functional activity compared to the EPA conjugate. IgG subclass analysis of Pfs230 conjugates showed no carrier-dependent differences in the IgG profile. While Alhydrogel® formulations induced a Th2 dominant immune response, GLA-LSQ formulations induced a mixed Th1/Th2 response. |
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| Keywords: | Malaria Transmission-blocking vaccine Pfs25 Pfs230 Carrier protein |
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