Boosting with ALVAC-HIV and AIDSVAX B/E enhances Env constant region 1 and 2 antibody-dependent cellular cytotoxicity

Abstract

Significance 26Over one million people become infected with HIV-1 each year making the development 27 of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human 28 HIV-1 vaccine-regimen is the only HIV-1 clinical trial to date to demonstrate vaccine- 29 efficacy. An area of focus has been on identifying ways by which to improve upon 30 RV144 vaccine-efficacy. The RV305 HIV-1 vaccine-regimen was a follow-up boost of 31 RV144 vaccine-recipients that occurred 6-8 years after the conclusion of RV144. Our 32 2 studies focused on the effect of delayed boosting in humans on the vaccine-induced 33 antibody repertoire. It was found that boosting with a HIV-1 Env vaccine increased 34 antibody-mediated effector function potency and breadth. 35Abstract 36 Induction of protective antibodies is a critical goal of HIV-1 vaccine development. One 37 strategy is to induce non-neutralizing antibodies that kill virus-infected cells as these 38 antibody specificities have been implicated in slowing HIV-1 disease progression and in 39 protection. HIV-1 Env constant region 1 and 2 (C1C2) antibodies frequently contain 40 potent antibody dependent cellular cytotoxicity (ADCC) making them a vaccine target. 41Here we explore the effect of delayed and repetitive boosting of RV144 vaccinee 42 recipients with ALVAC/AIDSVAX B/E on the C1C2-specific antibody repertoire. It was 43 found that boosting increased clonal lineage specific ADCC breadth and potency. A 44 ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-45 specific antibody showed that it bound a highly conserved Env gp120 epitope. Thus, 46 rationally designed boosting strategies to affinity mature these type of IgG C1C2-47 specific antibody responses may be one method by which to make an improved HIV 48 vaccine with higher efficacy than seen in the RV144 trial. 49 INTRODUCTION 50CD4-inducible (CD4i) epitopes within HIV-1 envelope (Env) constant regions 1 and 51 2 (C1C2) are targets for antibodies that mediate antibody dependent cellular cytotoxicity 52 (ADCC) [1]. C1C2-specific antibody epitopes have been termed Cluster A [1] and defined 53 by two Env-targeted monoclonal antibodies (mAbs), A32 [2] and C11 [1]. Structural 54 analyses of antigen complexes formed by A32, A32-like [3-5] and C11-like antibodies [6] 55 3 indicate that these antibodies bind distinct Env epitopes. The A32 epitope involves a 56 discontinuous sequence within layers 1 and 2 of the inner domain [4, 5] while the C11 57 epitope maps to the inner domain eight-stranded β sandwich [6]. Importantly, both 58 antibodies are non-neutralizing for tier 2 HIV strains, but are capable of broad and potent 59 ADCC [1, 2]. 60 The secondary analysis of HIV-1 infection risk in RV114 (NCT00223080) 61 indicated that ADCC in the presence of low anti-Env IgA responses correlated with 62 decreased HIV-1 acquisition [7]. While antibodies representative of the Env variable 63 region 2 (V2) response inversely correlated with HIV-1 acquisition [7], we previously 64 demo...

Effects of gp120 Inner Domain (ID2) Immunogen Doses on Elicitation of Anti-HIV-1 Functional Fc-Effector Response to C1/C2 (Cluster A) Epitopes in Mice

“…Interestingly, the results from the recent RV144 follow up study, RV305, indicated that A32-like ADCC responses can be effectively boosted. Sera from RV305 subjects were capable of effective ADCC with increased potency and breadth compared to C1/C2 mAbs isolated from RV144 subjects [ 48 , 49 ]. Our structural analyses RV144 and RV305 mAbs confirmed their Cluster A specificity [ 50 ].…”