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

Abstract

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 (ID 50 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.

Vaccine induction of CD4-mimicking broadly neutralizing antibody precursors in macaques

“…Peripheral blood B cell sorting was performed as described previously 57,58 . Briefly, cryopreserved PBMC were stained with viability dye, CD14, CD16, CD20, CD3, CD27, IgD, fluorophore-labeled Man 5 GlcNAc 2 -enriched CH505.M5.G458Y, and fluorophore-labeled Man 5 GlcNAc 2 -enriched CH505.M5.G458Y.N280D Env Trimer.…”

“…Epitope-Specific Single B Cell Sorting. Peripheral blood B cell sorting was performed as described previously 57,58 . Briefly, cryopreserved PBMC were stained with viability dye, CD14, Rhesus Immunoglobulin RT-PCR.…”

“…Briefly, cryopreserved PBMC were stained with viability dye, CD14, Rhesus Immunoglobulin RT-PCR. Immunoglobulin genes were amplified as previously described 57,58 . Immunoglobulin genes from a single B cell were reverse transcribed with Superscript III (ThermoFisher) and constant region-specific reverse primers.…”

Mutation-Guided Vaccine Design: A Strategy for Developing Boosting Immunogens for HIV Broadly Neutralizing Antibody Induction

“…to the study of antibody evolution and have informed HIV-1 vaccine design strategies for induction of bnAbs (2,3,5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The inferred unmutated common ancestor (UCA) at the root of a bnAb clonal tree is a representation of the original B cell progenitor of the bnAb B cell clone, and recent successes in designing immunogens that can engage B cell germlines and expand bnAb precursor B cells have been reported (6,11,(20)(21)(22)(23)(24)(25)(26). However, a major roadblock following germline targeting of bnAb precursor B cells is lack of a strategy to design boosting immunogens to select for required improbable functional mutations (2,6,20).…”

Time is of the essence for vaccine success

“…Mechanistically this involves increasing numbers of T follicular helper cells and antigen retention 4 , both crucial for GC response size and longevity 6 . They 5 and others 7 have also shown how adjuvants that specifically engage Toll-like receptors markedly affect the antibody response. Lee et al 2 have now combined antigen, adjuvant and delivery schedule to induce long-lasting GC responses in nonhuman primates that are active for at least 6 months.…”