Synergistic malaria vaccine combinations identified by systematic antigen screening
| Autor: | Leyla Y. Bustamante, Pietro Cicuta, Yen-Chun Lin, Gareth T. Powell, Julian C. Rayner, Cécile Crosnier, Gavin J. Wright, Alison Kemp, Michael D. Macklin, Nicole Müller-Sienerth, Nadia Cross, Ogobara K. Doumbo, Peter D. Crompton, Theo Sanderson, Tuan M. Tran, Paula Cawkill, Boubacar Traore |
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| Přispěvatelé: | Cicuta, Pietro [0000-0002-9193-8496], Tran, Tuan M [0000-0002-1928-861X], Apollo - University of Cambridge Repository |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Erythrocytes Population Plasmodium falciparum Protozoan Proteins malaria Antibodies Protozoan Video microscopy Antigens Protozoan erythrocyte invasion Microbiology Cell Line 03 medical and health sciences Antigen vaccine parasitic diseases Malaria Vaccines Medicine Humans Prospective Studies Malaria Falciparum education Parasite genome education.field_of_study Multidisciplinary biology Malaria vaccine business.industry Biological Sciences biology.organism_classification medicine.disease 3. Good health antigen combinations 030104 developmental biology HEK293 Cells Immunology biology.protein Antibody business Malaria |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance Malaria still kills hundreds of thousands of children each year. Malaria vaccine development is complicated by high levels of parasite genetic diversity, which makes single target vaccines vulnerable to the development of variant-specific immunity. To overcome this hurdle, we systematically screened a panel of 29 blood-stage antigens from the most deadly human malaria parasite, Plasmodium falciparum. We identified several targets that were able to inhibit erythrocyte invasion in two genetically diverse strains. Testing these targets in combination identified several pairs that blocked invasion more effectively in combination than in isolation. Video microscopy and studies of natural immune responses to malaria in patients suggest that targeting multiple steps in invasion is more likely to produce a synergistic vaccine response. A highly effective vaccine would be a valuable weapon in the drive toward malaria elimination. No such vaccine currently exists, and only a handful of the hundreds of potential candidates in the parasite genome have been evaluated. In this study, we systematically evaluated 29 antigens likely to be involved in erythrocyte invasion, an essential developmental stage during which the malaria parasite is vulnerable to antibody-mediated inhibition. Testing antigens alone and in combination identified several strain-transcending targets that had synergistic combinatorial effects in vitro, while studies in an endemic population revealed that combinations of the same antigens were associated with protection from febrile malaria. Video microscopy established that the most effective combinations targeted multiple discrete stages of invasion, suggesting a mechanistic explanation for synergy. Overall, this study both identifies specific antigen combinations for high-priority clinical testing and establishes a generalizable approach that is more likely to produce effective vaccines. |
| Databáze: | OpenAIRE |
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