Amy K Bei1,2,3, Ambroise D Ahouidi2, Jeffrey D Dvorin1,4, Kazutoyo Miura5, Ababacar Diouf5, Daouda Ndiaye3, Zul Premji6,7, Mahamadou Diakite8, Souleymane Mboup2,9, Carole A Long5, Manoj T Duraisingh1. 1. Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. 2. Laboratory of Bacteriology and Virology, Le Dantec Hospital, Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, Senegal. 3. Laboratory of Parasitology and Mycology, Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, Senegal. 4. Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Massachusetts. 5. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. 6. Department of Parasitology and Medical Entomology, Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania. 7. Department of Pathology, Aga Khan University Hospital, Nairobi, Kenya. 8. Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Odontostomatology, University of Science, Techniques and Technologies of Bamako, Mali. 9. Institut de Recherche en Santé, de Surveillance Epidemiologique et de Formations, Dakar, Senegal.
Abstract
Background: Plasmodium falciparum reticulocyte-binding protein homologue 2b (PfRh2b) is an invasion ligand that is a potential blood-stage vaccine candidate antigen; however, a naturally occurring deletion within an immunogenic domain is present at high frequencies in Africa and has been associated with alternative invasion pathway usage. Standardized tools that provide antigenic specificity in in vitro assays are needed to functionally assess the neutralizing potential of humoral responses against malaria vaccine candidate antigens. Methods: Transgenic parasite lines were generated to express the PfRh2b deletion. Total immunoglobulin G (IgG) from individuals residing in malaria-endemic regions in Tanzania, Senegal, and Mali were used in growth inhibition assays with transgenic parasite lines. Results: While the PfRh2b deletion transgenic line showed no change in invasion pathway utilization compared to the wild-type in the absence of specific antibodies, it outgrew wild-type controls in competitive growth experiments. Inhibition differences with total IgG were observed in the different endemic sites, ranging from allele-specific inhibition to allele-independent inhibitory immune responses. Conclusions: The PfRh2b deletion may allow the parasite to escape neutralizing antibody responses in some regions. This difference in geographical inhibition was revealed using transgenic methodologies, which provide valuable tools for functionally assessing neutralizing antibodies against vaccine-candidate antigens in regions with varying malaria endemicity.
Background: Plasmodium falciparum reticulocyte-binding protein homologue 2b (PfRh2b) is an invasion ligand that is a potential blood-stage vaccine candidate antigen; however, a naturally occurring deletion within an immunogenic domain is present at high frequencies in Africa and has been associated with alternative invasion pathway usage. Standardized tools that provide antigenic specificity in in vitro assays are needed to functionally assess the neutralizing potential of humoral responses against malaria vaccine candidate antigens. Methods: Transgenic parasite lines were generated to express the PfRh2b deletion. Total immunoglobulin G (IgG) from individuals residing in malaria-endemic regions in Tanzania, Senegal, and Mali were used in growth inhibition assays with transgenic parasite lines. Results: While the PfRh2b deletion transgenic line showed no change in invasion pathway utilization compared to the wild-type in the absence of specific antibodies, it outgrew wild-type controls in competitive growth experiments. Inhibition differences with total IgG were observed in the different endemic sites, ranging from allele-specific inhibition to allele-independent inhibitory immune responses. Conclusions: The PfRh2b deletion may allow the parasite to escape neutralizing antibody responses in some regions. This difference in geographical inhibition was revealed using transgenic methodologies, which provide valuable tools for functionally assessing neutralizing antibodies against vaccine-candidate antigens in regions with varying malaria endemicity.
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