Description

Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies

Bryan Briney^1,2,3,*, Devin Sok^1,2,3,*, Joseph G. Jardine^1,2,3,*, Daniel W. Kulp^1,2,3,*, Patrick Skog,^1,* Sergey Menis^1,2,3, Ronald Jacak², Oleksandr Kalyuzhniy^1,2,3, Natalia de Val^2,3,4, Fabian Sesterhenn^1,2,3, Khoa M. Le^1,2,3, Alejandra Ramos^1,2,3, Meaghan Jones^1,2,3, Karen L. Saye-Francisco,^1,2,3, Tanya R. Blane¹, Skye Spencer^1,2,3, Erik Georgeson^1,2,3, Xiaozhen Hu^1,2,3, Gabriel Ozorowski^2,3,4, Yumiko Adachi^1,2,3, Michael Kubitz^1,2,3, Anita Sarkar^2,3,4, Ian A. Wilson^2,3,4,5, Andrew B. Ward^2,3,4, David Nemazee¹, Dennis R. Burton^1,2,3,6, William R. Schief^1,2,3,6

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.