期刊
IMMUNITY
卷 54, 期 12, 页码 2859-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2021.10.017
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资金
- Ragon Institute of MGH
- MIT
- Harvard
- Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID)
- U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]
This study demonstrates the use of repeat antigens to evade immune responses and the successful improvement of a highly effective anti-malarial antibody in a mouse model, showcasing the potential of using vaccination and bioinformatic analysis to enhance protective capacity.
Repeat antigens, such as the Plasmodium falciparum circumsporozoite protein (PfCSP), use both sequence degeneracy and structural diversity to evade the immune response. A few PfCSP-directed antibodies have been identified that are effective at preventing malaria infection, including CIS43, but how these repeat -targeting antibodies might be improved has been unclear. Here, we engineered a humanized mouse model in which B cells expressed inferred human germline CIS43 (iGL-CIS43) B cell receptors and used both vaccination and bioinformatic analysis to obtain variant CIS43 antibodies with improved protective capacity. One such antibody, iGL-CIS43.D3, was significantly more potent than the current best-in-class PfCSP-directed antibody. We found that vaccination with a junctional epitope peptide was more effective than full-length PfCSP at recruiting iGL-CIS43 B cells to germinal centers. Structure-function analysis revealed multiple somatic hypermutations that combinatorically improved protection. This mouse model can thus be used to understand vaccine immunogens and to develop highly potent anti-malarial antibodies.
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