Journal
IMMUNITY
Volume 54, Issue 2, Pages 324-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2020.12.014
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Funding
- Intramural Research Program of the Vaccine Research Center, NIAID, NIH
- NIH [P01-AI104722]
- NIAID, Division of AIDS, Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) [5UM1 AI100645]
- Bill and Melinda Gates Foundation [OPP1162123]
- US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]
- Bill and Melinda Gates Foundation [OPP1162123] Funding Source: Bill and Melinda Gates Foundation
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This study demonstrates that vaccine-induced VRC01-class bnAbs with >50% breadth can be matured by sequential immunization from unmutated ancestors. Crystal structures of representative bnAbs revealed the same mode of recognition as known VRC01-class bnAbs, and structure-function studies pinpointed key mutations and their induction with specific immunizations.
Vaccine elicitation of broadly neutralizing antibodies (bnAbs) is a key HIV-research goal. The VRC01 class of bnAbs targets the CD4-binding site on the HIV-envelope trimer and requires extensive somatic hypermutation (SHM) to neutralize effectively. Despite substantial progress, vaccine-induced VRC01-class antibodies starting from unmutated precursors have exhibited limited neutralization breadth, particularly against viruses bearing glycan on loop D residue N276 (glycan276), present on most circulating strains. Here, using sequential immunization of immunoglobulin (Ig)-humanized mice expressing diverse unmutated VRC01-class antibody precursors, we elicited serum responses capable of neutralizing viruses bearing glycan276 and isolated multiple lineages of VRC01-class bnAbs, including two with >50% breadth on a 208-strain panel. Crystal structures of representative bnAbs revealed the same mode of recognition as known VRC01-class bnAbs. Structure-function studies further pinpointed key mutations and correlated their induction with specific immunizations. VRC01-class bnAbs can thus be matured by sequential immunization from unmutated ancestors to >50% breadth, and we delineate immunogens and regimens inducing key SHM.
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