Sequential immunization with glycan-restored HIV-1 Env immunogens drives maturation of CD4-binding-site broadly neutralizing antibodies in primates
Inducing broadly neutralizing antibodies (bnAbs) by vaccination remains a major challenge for HIV-1 vaccine development, with few examples achieving >50% breadth in outbred standard vaccine-test species such as nonhuman primates (NHPs). Although the CD4-binding site (CD4bs) is a promising site of vulnerability, immunization with stabilized HIV-1 envelope (Env) trimers typically elicits antibodies with limited breadth. Here, we boosted NHPs primed with glycan-deleted Env trimers using sequential immunogens that progressively restored glycans surrounding the CD4-binding site. This regimen elicited cross-clade serum neutralization and yielded two vaccine-induced CD4bs antibody lineages with >50% neutralization breadth against a 208-isolate panel. Cryo-EM structures revealed distinct recognition modes that accommodate CD4bs-proximal glycans. Longitudinal analysis identified maturation events that increased recognition, occurring late in the A13V144-a lineage and midway in the A11V093-a lineage. Together, these results show that sequential Env immunization can drive maturation of diverse broadly neutralizing CD4bs antibodies.