Boosting with AIDSVAX B/E Enhances Env Constant Region 1 and 2 Antibody-Dependent Cellular Cytotoxicity Breadth and Potency

Abstract

Induction of protective antibodies is a critical goal of HIV-1 vaccine development. One strategy is to induce nonneutralizing antibodies (NNAbs) that kill virus-infected cells, as these antibody specificities have been implicated in slowing HIV-1 disease progression and in protection. HIV-1 Env constant region 1 and 2 (C1C2) monoclonal antibodies (MAbs) frequently mediate potent antibody-dependent cellular cytotoxicity (ADCC), making them an important vaccine target. Here, we explore the effect of delayed and repetitive boosting of RV144 vaccine recipients with AIDSVAX B/E on the C1C2-specific MAb repertoire. It was found that boosting increased clonal lineage-specific ADCC breadth and potency. A ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-specific MAb showed that it bound a highly conserved Env gp120 epitope. Thus, boosting to affinity mature these types of IgG C1C2-specific antibody responses may be one method by which to make an improved HIV vaccine with higher efficacy than that seen in the RV144 trial. IMPORTANCE Over one million people become infected with HIV-1 each year, making the development of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human HIV-1 vaccine regimen is the only HIV-1 clinical trial to date to demonstrate vaccine efficacy. An area of focus has been on identifying ways by which to improve upon RV144 vaccine efficacy. The RV305 HIV-1 vaccine regimen was a follow-up boost of RV144 vaccine recipients that occurred 6 to 8 years after the conclusion of RV144. Our study focused on the effect of delayed boosting in humans on the vaccine-induced Env constant region 1 and 2 (C1C2)-specific antibody repertoire. It was found that boosting with an HIV-1 Env vaccine increased C1C2-specific antibody-dependent cellular cytotoxicity potency and breadth.

Recognition Patterns of the C1/C2 Epitopes Involved in Fc-Mediated Response in HIV-1 Natural Infection and the RV114 Vaccine Trial

“…Since the specificities of the RV144 antibodies were not characterized structurally, we performed a systematic analysis of their fine epitope specificities and compared them to those induced in natural infection. We also compared them to the anti-cluster A RV305 antibody DH677.3 (28). We were able to determine the crystal antigen complex structures of two RV144 antibodies, CH54 and CH55, and map the epitopes of five additional RV144 antibodies by FRET-FCS.…”

“…NCT01435135), in which a subset of RV144 vaccinees were immunized again with the same RV144 vaccine components, indicated that A32-like ADCC responses induced by ALVAC/ AIDSVAX B/E vaccine could be effectively boosted. Sera from RV305 subjects were capable of effective ADCC, and several isolated A32-like mAbs showed increased potency and breadth compared to those of A32 and mAbs isolated from RV144 subjects (28).…”

Improved killing of HIV-infected cells using three neutralizing and non-neutralizing antibodies

“…Infection of primary cells. The generation of infected cells was described previously (79). Here, 3 × 10 6 cells were infected with the appropriate dose of IMC or latent reservoir virus supernatant.…”

“…Scores obtained from PC1 account for 70% variability in the affinity of the antibodies toward the LRVs. This method of calculation of ADCC score was described by Easterhoff et al (79).…”

HIV-1 Vaccine Sequences Impact V1V2 Antibody Responses: A Comparison of Two Poxvirus Prime gp120 Boost Vaccine Regimens

“…Despite lower V2 response in HVTN 100 compared to HVTN 097, HVTN 100 elicited potent and cross-subtype binding antibody responses against HIV-1 envelope, with higher magnitude for multiple major epitopes compared to HVTN 097. Subsequent evaluation of the functions of the antibodies, including antibody Fc effector functions such as conformational C1-C2 antibody specificities that mediate ADCC 44 , elicited in these studies is needed to fully understand the differences in immunogenicity across these regimens. In addition, one of the objectives of testing RV144-like poxvirus-prime/ protein-boost vaccines in South Africa is to see whether the correlates of decreased HIV-1 risk identified in RV144 can be repeated by subtype C vaccines.…”