Stabilized HIV-1 envelope immunization induces neutralizing antibodies to the CD4bs and protects macaques against mucosal infection.

A successful HIV-1 vaccine will require induction of a polyclonal neutralizing antibody (nAb) response, yet vaccine-mediated induction of such a response in primates remains a challenge. We found that a stabilized HIV-1 CH505 envelope (Env) trimer formulated with a Toll-like receptor 7/8 agonist induced potent HIV-1 polyclonal nAbs that correlated with protection from homologous simian-human immunodeficiency virus (SHIV) infection. The serum dilution that neutralized 50% of virus replication (ID₅₀ titer) required to protect 90% of macaques was 1:364 against the challenge virus grown in primary rhesus CD4⁺ T cells. Structural analyses of vaccine-induced nAbs demonstrated targeting of the Env CD4 binding site or the N156 glycan and the third variable loop base. Autologous nAb specificities similar to those elicited in macaques by vaccination were isolated from the human living with HIV from which the CH505 Env immunogen was derived. CH505 viral isolates were isolated that mutated the V1 to escape both the infection-induced and vaccine-induced antibodies. These results define the specificities of a vaccine-induced nAb response and the protective titers of HIV-1 vaccine–induced nAbs required to protect nonhuman primates from low-dose mucosal challenge by SHIVs bearing a primary transmitted/founder Env. Analyzing antibodies: A challenge for HIV-1 vaccine development is the need to induce a polyclonal neutralizing antibody (nAb) response in vaccine recipients. Here, Saunders et al. vaccinated rhesus macaques with a stabilized HIV-1 envelope trimer mixed with a Toll-like receptor 7/8 agonist with the goal of eliciting such nAbs. The authors observed that vaccinated macaques developed potent nAbs that targeted multiple sites on the envelope, including the CD4 binding site. This translated into protection against mucosal simian-human immunodeficiency virus challenge in the macaques. These results support further development of this vaccine as a strategy to induce nAbs in humans. [ABSTRACT FROM AUTHOR]