Highlights from the HIV Research for Prevention Conference (R4P),: 17-21 October 2016, Chicago, IL, USA.

Introduction

The HIV prevention research community gathered in Chicago, Illinois, USA for the second biennial HIV R4P, the only scientific conference dedicated to biomedical HIV prevention research. The conference highlighted advances in preventive HIV vaccines, updates on oral PrEP, advances in mucosal immunology and sequencing, and updates on the role of monoclonal antibodies in pathogenesis and transmission. Finally, a satellite meeting on systems biology and vaccines highlighted the systems-based approaches utilised to accelerate vaccine development.

HIV preventative vaccines

Sandhya Vasan

The HIV Research for Prevention Conference (R4P) showcased many advances in preventive HIV vaccines. Several trials built upon RV144, the only trial to date to demonstrate partial efficacy of a preventative HIV vaccine [1]. The RV305 trial in Thailand administered two boosts of ALVAC-HIV, AIDSVAX® B/E protein, the combination, or placebo, 6–8 years post initial vaccination of RV144 vaccine recipients, whereas RV306 enrolled naive participants in Thailand to receive the RV144 regimen or placebo, followed by boosting in various intervals. Siriwat Akapirat presented data demonstrating that IgG binding titers to gp120 A244, gp120 MN, and V1V2 scaffolds increased with boosting in RV306 both in plasma [2], cervicovaginal, rectal and seminal secretions [3], accompanied by increases in Tier 1 neutralisation responses in RV305 and RV306 presented by Lindsay Wieczorek [4] and HIV-1 Env-specific IgG producing plasmablasts in RV306, presented by Alexandra Schuetz [5]. While these responses were equivalent in subjects boosted with either AIDSVAX® B/E protein alone or in combination with ALVAC-HIV, Carolina Herrera found that transcriptional responses to cervical explants from RV305 vaccines differed between these groups [6]. In addition to cellular and humoral responses, innate mechanisms may play a role. Michael Eller [7] described natural killer cell activation following late boosting in RV305. Stephen Kent emphasised not only the role of antibody-dependent cellular cytotoxicity (ADCC) in protection in RV144, but the importance of interactions of antibodies with other molecules such as neutrophils [8]. Building from the work in Thailand, the Pox Protein Public Private Partnership (P5) is moving forward to test a similar subtype C-based pox-protein regimen in southern Africa. Georgia Tomaras [9] reviewed immunogenicity results from HVTN100, which demonstrated that anti-gp120 humoral and cellular responses were equivalent or superior to those in RV144, passing all four go/no go criteria to advance this regimen into an efficacy trial, HVTN702. Nicole Frahm [10] suggested that the polyfunctionality of Env-specific CD4 T cells as quantified by combinatorial polyfunctionality analysis of antigen-specific T-cell subsets (COMPASS) scores was inversely associated with risk of HIV acquisition [11].

Data from HVTN 096/EV04 presented by Giuseppe Pantaleo [12] demonstrated that simultaneous co-administration of either NYVAC or DNA vaccines expressing subtype C Env, Gag and Pol-Nef with the AIDSVAX® B/E protein affords a more rapid induction of immune responses, which would be important for early coverage of high-risk individuals. The magnitude or humoral and cellular responses and durability of humoral responses was also improved, findings corroborated in studies of DNA-protein vaccine co-administration in HVTN105 were presented by Nadine Rouphael [13] and in non-human primates (NHP) were presented by Barbara Felber [14].

Several trials utilised the DNA-prime, modified vaccinia Ankara (MVA)-boost regimen. Agricola Joachim [15] presented data showing that multi-plasmid DNA prime followed by HIV-MVA-CMDR boost in Tanzanian volunteers induced frequent and durable antibody and T cell responses. A trial in Mozambique presented by Edna Viegas determined that delivery of the DNA prime via intradermal electroporation did not increase the magnitude of responses over intradermal (ID) injection alone. Incorporation of the GLA adjuvant, a TLR4 agonist, improved binding antibody responses, and boosting with MVA improved Tier 1 homologous neutralising antibody responses [16]. Utilisation of the GM-CSF adjuvant in the GeoVax DNA/MVA vaccine regimen preferentially improved durability of anti-gp41 antibodies over gp120 antibodies in HVTN094 [17]. In contrast, UK HVC 033, a DNA/MVA clinical trial with different inserts and GLA adjuvant showed preferential anti-V3 responses over gp41 [18]. Thus, inserts, schedule and adjuvants all play a role in influencing the immunogenicity of various vaccine regimens. Finally, Bonnie Philips presented the exploration of a potential paediatric DNA/MVA vaccine regimen that induced HIV env-specific antibodies particularly in an extended interval group [19]. The goal is to target infants of HIV-infected mothers to protect from oral breastmilk transmission.

Lindsay Baden presented data from a Phase 1 trial evaluating two MVA constructs with mosaic inserts that spanned bioinformatically engineered HIV-1 sequences designed to maximise global coverage across HIV-1 subtypes. Vaccines were administered to healthy adults who were either naive or who had received adenovirus type 26 (Ad26) EnvA 4–6 years earlier, who had persistent detectable anti-Env responses. All vaccines were safe and well-tolerated, and MVA elicited cross-clade ELISPOT and ELISA responses in both groups [20]. A similar NHP study presented by Frank Wegmann evaluated the relative efficacy of Ad26 mosaic regimens with or without MVA mosaic vaccines and/or Clade C gp140 protein against intrarectal SHIV162p3 challenge. Groups receiving Ad26 had higher HIV-1 specific IFNγ ELISPOT responses, whereas groups receiving the gp140 protein boost had higher anti-gp140 ELISA responses. Overall, Ad26 prime, AD26+gp140 boost showed the highest efficacy at 66% full protection after six challenges [21]. Other novel vaccine regimens in the pipeline include intranasal Sendai virus vector followed by intramuscular adenovirus-35 (Ad35) in humans [22], replicating cytomegalovirus vector (CMV) [23] in NHP, and full length single chain gp 129-cd4 (FLSC), a fusion protein consisting of a modified full-length gp120 protein, linked to the first two domains of human CD4, in NHP [24]. In addition to novel vaccines, Sudhir Kasturi suggested that the TLR 7/8 ligand 3M052, when used as an adjuvant alone or in combination with GLA, improved the magnitude and durability of humoral and T-follicular helper cell responses to an HIV-Env protein antigen in NHP [25].