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The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition against bnAb-sensitive viruses. HIV-1 viruses isolated from AMP participants who acquired infection during the study in the sub-Saharan African (HVTN 703/HPTN 081) and the Americas/European (HVTN 704/HPTN 085) trials represent a panel of currently circulating strains of HIV-1 and offer a unique opportunity to investigate the sensitivity of the virus to broadly neutralizing antibodies (bnAbs) being considered for clinical development. Pseudoviruses were constructed using envelope sequences from 218 individuals. The majority of viruses identified were clade B and C; with clades A, D, F and G and recombinants AC and BF detected at lower frequencies. We tested eight bnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10-1074 and 10E8v4) for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998-2010), the HVTN703/HPTN081 clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best against clade C viruses and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. Overall, the AMP placebo viruses represent a valuable resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs and highlight the need to update reference panels regularly. Our data also suggests that combining bnAbs in passive immunization trials would improve coverage of global viruses.

Abstract Adjuvants can alter the magnitude, characteristics, and persistence of the humoral response to protein vaccination. HIV vaccination might benefit from tailored adjuvant choice as raising a durable and protective response to vaccination has been exceptionally challenging. Analysis of trials of partially effective HIV vaccines have identified features of the immune response that correlate with decreased risk, including high titers of V1V2-binding IgG and IgG3 responses with low titers of V1V2-binding IgA responses and enhanced Fc effector functions, notably antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). However, there has been limited opportunity to compare the effect of different adjuvants on these activities in humans. Here, samples from the AVEG015 study, a phase 1 trial in which participants (n = 112) were immunized with gp120SF-2 and one of six different adjuvants or combinations thereof were assessed for antibody titer, biophysical features, and diverse effector functions. Three adjuvants, MF59 + MTP-PE, SAF/2, and SAF/2 + MDP, increased the peak magnitude and durability of antigen-specific IgG3, IgA, FcγR-binding responses and ADCP activity, as compared to alum. While multiple adjuvants increased the titer of IgG, IgG3, and IgA responses, none consistently altered the balance of IgG to IgA or IgG3 to IgA. Linear regression analysis identified biophysical features including gp120-specific IgG and FcγR-binding responses that could predict functional activity, and network analysis identified coordinated aspects of the humoral response. These analyses reveal the ability of adjuvants to drive the character and function of the humoral response despite limitations of small sample size and immune variability in this human clinical trial.

Passive transfer of monoclonal antibodies (mAbs) of human origin into Non-Human Primates (NHPs), especially those which function predominantly by a Fc-effector mechanism, requires an a priori preparation step, in which the human mAb is reengineered to an equivalent NHP IgG subclass. This can be achieved by changing both the Fc and Fab sequence while simultaneously maintaining the epitope specificity of the parent antibody. This Ab reengineering process, referred to as rhesusization, can be challenging because the simple grafting of the complementarity determining regions (CDRs) into an NHP IgG subclass may impact the functionality of the mAb. Here we describe the successful rhesusization of a set of human mAbs targeting HIV-1 envelope (Env) epitopes involved in potent Fc-effector function against the virus. This set includes a mAb targeting a linear gp120 V1V2 epitope isolated from a RV144 vaccinee, a gp120 conformational epitope within the Cluster A region isolated from a RV305 vaccinated individual, and a linear gp41 epitope within the immunodominant Cys-loop region commonly targeted by most HIV-1 infected individuals. Structural analyses confirm that the rhesusized variants bind their respective Env antigens with almost identical specificity preserving epitope footprints and most antigen-Fab atomic contacts with constant regions folded as in control RM IgG1s. In addition, functional analyses confirm preservation of the Fc effector function of the rhesusized mAbs including the ability to mediate Antibody Dependent Cell-mediated Cytotoxicity (ADCC) and antibody dependent cellular phagocytosis by monocytes (ADCP) and neutrophils (ADNP) with potencies comparable to native macaque antibodies of similar specificity. While the antibodies chosen here are relevant for the examination of the correlates of protection in HIV-1 vaccine trials, the methods used are generally applicable to antibodies for other purposes.

Despite antibody-dependent cellular cytotoxicity (ADCC) responses being implicated in protection from HIV-1 infection, there is limited evidence that they control virus replication. The high mutability of HIV-1 enables the virus to rapidly adapt, and thus evidence of viral escape is a very sensitive approach to demonstrate the importance of this response. To enable us to deconvolute ADCC escape from neutralizing antibody (nAb) escape, we identified individuals soon after infection with detectable ADCC responses, but no nAb responses. We evaluated the kinetics of ADCC and nAb responses, and viral escape, in five recently HIV-1-infected individuals. In one individual we detected viruses that escaped from ADCC responses but were sensitive to nAbs. In the remaining four participants, we did not find evidence of viral evolution exclusively associated with ADCC-mediating non-neutralizing Abs (nnAbs). However, in all individuals escape from nAbs was rapid, occurred at very low titers, and in three of five cases we found evidence of viral escape before detectable nAb responses. These data show that ADCC-mediating nnAbs can drive immune escape in early infection, but that nAbs were far more effective. This suggests that if ADCC responses have a protective role, their impact is limited after systemic virus dissemination. Author summary Reponses that clear or control viral replication in acute infection are considered important responses to elicit by vaccination. In the only HIV-1 vaccine trial to date to show any efficacy, antibody-dependent cellular cytotoxicity (ADCC)-mediating non-neutralizing antibodies (nnAbs) were correlated with reduced risk of infection. However, the role of ADCC-mediating antibodies in controlling replication in acute infection is not well understood. Viral escape provides evidence of the importance of immune responses, but there is very little evidence of HIV-1 immune escape from nnAbs to-date. We assessed the impact of early ADCC-mediating nnAbs on HIV-1 envelope evolution in infected individuals where we had early samples, prior to the detection of nAbs. We found evidence of escape from ADCC-mediating nnAbs, but in only one individual. In contrast, escape to nAbs was rapid and with or without resistance to ADCC-mediating antibodies. We identified escape pathways which were sensitive to neutralization but resistant to ADCC. These data show that ADCC-mediating nnAbs can drive immune escape in early infection, but to a lesser extent than nAbs, suggesting they may have a limited protective role after systemic virus dissemination.

Knowledge on how antibody responses have evolved is critical for the induction of protective immunity. Here the authors analyse, using high-throughput sequencing of both exon and intron regions, the mutation and lineage development of an HIV-neutralizing antibody to find an unexpected early emergence of broadly neutralizing species.

Summary: Antibodies that bind residue K169 in the V2 region of the HIV-1 envelope correlated with reduced risk of infection in the RV144 vaccine trial but were restricted to two ED-motif-encoding light chain genes. Here, we identify an HIV-infected donor with high-titer V2 peptide-binding antibodies and isolate two antibody lineages (CAP228-16H/19F and CAP228-3D) that mediate potent antibody-dependent cell-mediated cytotoxicity (ADCC). Both lineages use the IGHV5-51 heavy chain germline gene, similar to the RV144 antibody CH58, but one lineage (CAP228-16H/19F) uses a light chain without the ED motif. A cocrystal structure of CAP228-16H bound to a V2 peptide identified a IGLV3-21 gene-encoded DDxD motif that is used to bind K169, with a mechanism that allows CAP228-16H to recognize more globally relevant V2 immunotypes. Overall, these data further our understanding of the development of cross-reactive, V2-binding, antiviral antibodies and effectively expand the human light chain repertoire able to respond to RV144-like immunogens. : V2-directed antibodies from the RV144 vaccine trial correlated with reduced HIV-1 infection risk but exhibited restricted light chain gene usage. Here, van Eeden et al. isolate similar antibodies from an HIV-1-infected individual and identify a third V2-reactive light chain gene, increasing the antibody repertoire potentially elicited by vaccination. Keywords: HIV, V2 antibodies, K169, V2 structure, ED motif, CAP228, CH58, antibody evolution, ADCC, RV144 vaccine response

Rhesus macaques can be readily infected with chimeric simian-human immunodeficiency viruses (SHIV) as a suitable virus challenge system for testing the efficacy of HIV vaccines. Three Chinese-origin rhesus macaques (ChRM) were inoculated intravenously (IV) with SHIVC109P4 in a rapid serial in vivo passage. SHIV recovered from the peripheral blood of the final ChRM was used to generate a ChRM-adapted virus challenge stock. This stock was titrated for the intrarectal route (IR) in 8 ChRMs using undiluted, 1:10 or 1:100 dilutions, to determine a suitable dose for use in future vaccine efficacy testing via repeated low-dose IR challenges. All 11 ChRMs were successfully infected, reaching similar median peak viraemias at 1–2 weeks post inoculation but undetectable levels by 8 weeks post inoculation. T-cell responses were detected in all animals and Tier 1 neutralizing antibodies (Nab) developed in 10 of 11 infected ChRMs. All ChRMs remained healthy and maintained normal CD4+ T cell counts. Sequence analyses showed >98% amino acid identity between the original inoculum and virus recovered at peak viraemia indicating only minimal changes in the env gene. Thus, while replication is limited over time, our adapted SHIV can be used to test for protection of virus acquisition in ChRMs.