Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies
Bryan Briney1,2,3,*, Devin Sok1,2,3,*, Joseph G. Jardine1,2,3,*, Daniel W. Kulp1,2,3,*, Patrick Skog,1,* Sergey Menis1,2,3, Ronald Jacak2, Oleksandr Kalyuzhniy1,2,3, Natalia de Val2,3,4, Fabian Sesterhenn1,2,3, Khoa M. Le1,2,3, Alejandra Ramos1,2,3, Meaghan Jones1,2,3, Karen L. Saye-Francisco,1,2,3, Tanya R. Blane1, Skye Spencer1,2,3, Erik Georgeson1,2,3, Xiaozhen Hu1,2,3, Gabriel Ozorowski2,3,4, Yumiko Adachi1,2,3, Michael Kubitz1,2,3, Anita Sarkar2,3,4, Ian A. Wilson2,3,4,5, Andrew B. Ward2,3,4, David Nemazee1, Dennis R. Burton1,2,3,6, William R. Schief1,2,3,6
1Department of Immunology and Microbial Science, The Scripps Research Institute; 2IAVI Neutralizing Antibody Center; 3Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute; 4Department of Integrative Structural and Computational Biology, The Scripps Research Institute; 5Skaggs Institute for Chemical Biology, The Scripps Research Institute; 6Ragon Institute of MGH, MIT and Harvard
Induction of broadly neutralizing antibodies (bnAbs) is a primary goal of HIV vaccine development. VRC01-class bnAbs are important vaccine leads because their precursor B cells targeted by an engineered priming immunogen are relatively common among humans. This priming immunogen has demonstrated the ability to initiate a bnAb response in animal models, but recall and maturation toward bnAb development has not been shown. Here, we report the development of boosting immunogens designed to guide the genetic and functional maturation of previously primed VRC01-class precursors. Boosting a transgenic mouse model expressing germline VRC01 heavy chains produced broad neutralization of near-native isolates (N276A) and weak neutralization of fully native HIV. Detailed single-cell analysis of vaccine-responsive B cells indicate that the boosted mAbs encoded by these B cells are consistent with partially mature VRC01-class antibodies and place them on a maturation trajectory that leads toward mature VRC01-class bnAbs. The results show how reductionist sequential immunization can guide maturation of HIV bnAb responses.
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