CROI 2020 Abstract eBook
1 CAPRISA, Durban, South Africa, 2 University of Rochester, Rochester, NY, USA, 3 Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 4 NIH, Bethesda, MD, USA, 5 Duke Human Vaccine Institute, Durham, NC, USA, 6 University of Lausanne, Lausanne, Switzerland, 7 EuroVacc Foundation, Amsterdam, Netherlands, 8 GlaxoSmithKline, Rixensart, Belgium Background: After RV144, the Pox Protein Public Private Partnership initiated multiple trials to evaluate a clade C bivalent protein (TV1.C and 1086.C gp120) vaccine with different adjuvants and priming agents to optimize the design of future vaccine regimens. We showed that substituting DNA (DNA-HIV-PT123) for ALVAC can improve immune responses. The aim of HVTN 108, a phase 1/2a randomized, placebo-controlled trial, was to evaluate the safety and immunogenicity of the DNA vaccine with several protein/MF59/AS01B adjuvant combinations. Methods: We randomly allocated 334 HIV-uninfected participants from the US and South Africa to 7 intervention groups (T1-T7) or placebo. We assessed DNA prime at months (M)0, 1 with DNA/protein/adjuvant boosts at M3 and 6 (T1– T3), DNA/protein/adjuvant co-administration at M0, 1 and 6 (T4-6), and only low dose protein/AS01B at M0, 1 and 6 (T7). Protein was either adjuvanted with MF59 or AS01B. Safety was assessed by collecting reactogenicity and adverse events (AEs). We measured humoral and cellular immunogenicity at M6.5 by binding antibody multiplex assay and ex vivo intracellular cytokine staining. Results: Blinded safety data revealed 48 grade 3, and three grade 4 reactogenicity events in 39 persons, and 30 mild or moderate related AEs. All intervention groups had high IgG response rates (>89%) and high magnitude responses to HIV-1 Env gp120 and gp140 proteins. Response rates for the AS01B-adjuvanted groups approached 100%. V1V2 IgG response magnitude, the correlate of decreased HIV risk in RV144, was higher in the AS01B group (Figure 1). Additionally, there was evidence of a higher IgG3 Env response rate in the AS01B group. CD4+ T-cell response rates and magnitudes to all Env peptide pools were higher in the AS01B-adjuvanted than MF59-adjuvanted regimens (all p<0.01), except for Env-2-ZM96. Furthermore, the AS01B-adjuvanted lower protein dose elicited higher magnitude responses than the higher protein dose regimen. Conclusion: DNA/protein/adjuvant combinations demonstrated acceptable safety profiles, with unblinded analysis pending. All groups showed high IgG response rates to gp140 and gp120, and robust responses to Env V1V2. AS01B-adjuvanted groups showed improved CD4+ T cell, V1V2 IgG and Env IgG3 responses. Assessments of durability and antibody Fc effector functions are underway. These data highlight that substituting the MF59 adjuvant with AS01B could further enhance both humoral and cellular responses.
HIV Research Program, Silver Spring, MD, USA, 4 Mahidol University, Bangkok, Thailand, 5 Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand, 6 SEARCH, Bangkok, Thailand, 7 Sanofi Pasteur, Swiftwater, PA, USA, 8 International Vaccine Institute, Seoul, South Korea Background: The majority of HIV-1 infections occur across mucosal surfaces, hence mucosal immune responses including CTL, T-helper cells and IgA- secreting plasmablasts (PB) are part of the initial defense against infection. RV144 is still the only vaccine trial that demonstrated modest efficacy; however, mucosal responses were not characterized. Here we assess mucosal immune responses elicited after the ALVAC-HIV/AIDSVAX B/E prime boost regime used in RV144 followed by additional late boost strategies. Methods: Sigmoid biopsies were collected two weeks after final vaccinations, either after the RV144 regimen, or after late boosts at 12, 15 or 18 months (mo) with ALVAC-HIV and/or AIDSVAX B/E. TH023- and Gag-specific CD4 and CD8 T cell responses as well as B cell responses were assessed by flow cytometry. Vaccine-specific IgG and IgA was measured in rectal secretions by binding antibody ELISA. Results: Mucosal TH023- and Gag-specific T cell responses were readily observed with TNFa as the predominant cytokine produced followed by IFNg and IL-2. After the RV144 regimen, 30% of vaccine recipients developed TH023- specific CD4 T cell TNFa responses, which increased after the late boosts to 63% (12mo), and 100% (15/18mo). Similarly, the magnitude of TH023-specific CD4 T cell TNFa responses increased with a delayed boost interval from 0.01% post RV144, to 0.09% at 12mo, 0.98% at 15mo and 0.92% at 18mo boosts (p=0.007 by Kruskal-Wallis). Additionally, magnitude of mucosal TH023-specific CD8 T cell TNFa responses increased with later boost intervals (post RV144: 0.12%, 12mo: 0.09%, 15mo: 0.58%, 18mo: 0.83%; p=0.03 by Kruskal-Wallis). This is in contrast to univariate peripheral responses that were mainly CD4-mediated, appeared already after the RV144 regimen and were maintained after the late boosts. Although vaccine-specific IgA was not detected in rectal secretions, an increase in mucosal IgA-producing PB was observed with increasing late boost intervals (post RV144: 8.6%, 12mo: 7.7%, 15mo: 17.4%, 18mo: 17.0%; p=0.04 by Kruskal-Wallis). Conclusion: Late boosts with ALVAC-HIV and/or AIDSVAX B/E induce robust mucosal vaccine-specific CD4 and CD8 T cell responses and increase the frequency of mucosal IgA-producing PB. These responses differ in quality and kinetics from peripheral responses, highlighting potentially different mucosal mechanisms in contributing to the defense against HIV-1 after vaccination. 290 CANDIDATE IMMUNOGENS DIFFERENTIALLY ENGAGE HIV BROADLY NEUTRALIZING PLASMA ANTIBODIES Irene Abela 1 , Teja Turk 1 , Nikolas Friedrich 1 , Claus Kadelka 1 , Matthias Gloegl 1 , Brano Ivan 1 , Peter Rusert 1 , Merle Schanz 1 , Roger Kouyos 1 , Huldrych F. Günthard 2 , Alexandra Trkola 1 , for the Swiss HIV Cohort Study 1 University of Zurich, Zurich, Switzerland, 2 University Hospital Zurich, Zurich, Switzerland Background: Deciphering factors that drive broadly neutralizing antibodies (bnAbs) induction remains critical to guide HIV-1 vaccine development. Including 4,484 patients with detailed demographic data alongside plasma samples, the Swiss 4.5K Screen had unique means to distinguish positive, independent drivers of breadth (viral load, infection length, viral diversity, black ethnicity) (Rusert et al. 2016). Here we report on the XbnAb cohort, a sub-cohort of the Swiss 4.5K Screen that includes bnAb inducers and matched non-neutralizing (nnAb) controls. Using the controlled setting of the XbnAb cohort we compared the capacity of candidate immunogens in binding naturally occurring Abs and assess their efficacy in predicting bnAb activity. Methods: We defined within the Swiss 4.5K Screen the XbnAb cohort, which comprises all identified bnAb inducers (N=304) and matched nnAb controls (N=304; matched for HIV-1 subtype, length of infection, host demographics). Patient plasmas were assessed for binding antibodies (IgG1,2,3) against 47 HIV-1 envelope (Env) antigens (including 29 stabilized soluble Env trimer variants and candidate immunogens provided by lead investigators in the field) and 2 Gag proteins using an in-house Luminex bead assay. EC 50 plasma Ab binding activity was established for each antigen and the prediction potential of antigens to distinguish bnAb activity assessed by univariate conditional logistic regressions. Results: Confirming work from the Swiss 4.5K Screen (Kadelka et al. 2018) we found that IgG1 Env trimer reactivity is generally higher among bnAb inducers. However, levels of significance varied considerably (p=10-3to p=10-16), highlighting substantial differences among candidate immunogens in engaging
289 MUCOSAL T AND B CELL RESPONSES INDUCED BY ALVAC-HIV/AIDSVAX B/E LATE BOOST STRATEGIES Alexandra Schuetz 1 , Siriwat Akapirat 2 , Michael A. Eller 3 , Yuwadee Phuang- Ngern 2 , Punnee Pitisutthithum 4 , Sorachai Nitayaphan 2 , Suwat Chariyalertsak 5 , Nittaya Phanuphak 6 , Carlos A. Diazgranados 7 , Jerome H. Kim 8 , Merlin L. Robb 3 , Nelson L. Michael 3 , Robert J. O'Connell 2 , Sandhya Vasan 1 , for the RV306 Study Group 1 US Military HIV Research Program in Thailand, Bangkok, Thailand, 2 Armed Forces Research Institute of Medical Sciences in Bangkok, Bangkok, Thailand, 3 US Military
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