CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

Background: The late boosts with AIDSVAX B/E with or without ALVAC-HIV (RV305) induced higher HIV binding antibody responses in RV144 vaccine recipients who completed the primary vaccination series 6-8 years earlier. We studied HIV binding antibodies in HIV-uninfected RV305 vaccine and placebo recipients who received additional boost of AIDSVAX B/E 18-30 months post RV305 vaccinations. Methods: ELISA IgG and IgA to HIV gp120 A244gD- (CRF01_AE) and MNgD- (subtype B), and gp70V1V2 scaffold proteins 92TH023 (CRF01_AE) and CaseA2 (subtype B) were assessed in plasma at weeks 0, 1, 2 and 24 post additional boost of AIDSVAX B/E. Results: At the pre-additional boost timepoint, geometric mean titers (GMT) of IgG to gp120 A244gD- and MNgD- were detected in all groups (ALVAC-HIV/ AIDSVAX B/E [Gr1]-AIDVAX B/E [Gr2]-ALVAC-HIV [Gr3]-Placebo [PLB]/A244gD- =1459-1313-105-67; MNgD-=1925-1767-105-84), indicating durability of RV305 IgG binding antibodies. IgG GMT to gp70V1V2 scaffolds ranged from 50-115 at the pre-additional boost timepoint in all groups. IgG GMT to all proteins were significantly increased 2 weeks post additional boost in all groups (p<0.001, GMT range/A244gD-=23340-54245; MNgD-=37050-60887; 92TH023=5320- 13405; CaseA2=1106-3901) but significantly declined 24 weeks post additional boost (p<0.001, GMT range/A244gD-=4271-5991; MNgD-=4631-8903; 92TH023=189-459; CaseA2=76-159). Only IgG responses to CaseA2 2 weeks post additional boost were significantly higher (p<0.005) than those 2 weeks post 1st and 2nd boosts in all groups. Though IgG GMT to all proteins declined 24 weeks post additional boost, they were higher than those 24 weeks post 1st and 2nd boost, except IgG to A244gD- (Gr1) and 92TH023 (Gr1 and Gr2; fold changes range/A244gD-=0-75; MNgD-=0-79; 92TH023=0-6; CaseA2=1-2). IgA to gp120 (all groups) and 92TH023 (Gr1, Gr3 and PLB) significantly increased (p<0.05) 2 weeks post additional boost but declined to initial levels (GMT=50) 24 weeks post additional boost. We did not detect an additional boosting effect of IgA to CaseA2 in any group. Conclusion: An additional boost of AIDSVAX B/E increased plasma HIV-specific IgG antibodies. IgG to gp70V1V2 CaseA2 which inversely correlated with HIV infection risk in RV144, increased preferentially over IgA, a direct correlate of HIV infection risk. These findings support the hypothesis that administration of late recombinant protein boosts may be a strategy to enhance and extend preventive vaccine efficacy observed in RV144. 307 INCREASE IN B CELL RESPONSES UPON LATE BOOST STRATEGIES OF ALVAC-HIV/AIDSVAX B/E Alexandra Schuetz 1 , Siriwat Akapirat 2 , Weerawan Chuenarom 2 , Punnee Pitisutthithum 3 , Sorachai Nitayaphan 2 , Suwat Chariyalertsak 4 , Jaranit Kaewkungwal 3 , Sanjay Phogat 5 , Faruk Sinangil 6 , Merlin L. Robb 7 , Nelson L. Michael 7 , Jerome H. Kim 8 , Mark de Souza 9 , Robert J. O’Connell 1 , Sandhya Vasan 1 1 US Military HIV Research Program in Thailand, Bangkok, Thailand, 2 Armed Forces Research Institute of Medical Sciences in Bangkok, Bangkok, Thailand, 3 Mahidol University, Bangkok, Thailand, 4 Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand, 5 Sanofi Pasteur, Swiftwater, PA, USA, 6 Global Solutions for Infectious Diseases, San Francisco, CA, USA, 7 US Military HIV Research Program, Silver Spring, MD, USA, 8 International Vaccine Institute, Seoul, South Korea, 9 SEARCH, Bangkok, Thailand Background: Memory B cells, along with terminally differentiated plasmablasts (PB), are responsible for long-term persistence of humoral immunity elicited by most vaccines. In RV144, high V1V2-specific IgG antibodies were identified as an inverse correlate for risk, highlighting the potential importance of B cells. Methods: In RV306 HIV-uninfected volunteers received the ALVAC-HIV/ AIDSVAX B/E prime-boost regimen used in RV144 followed by different one-year late boosts with ALVAC-HIV/AIDSVAX B/E. B cell ELISpots detecting gp120 A244Δ11gDneg-specific IgG-producing PB and long-lived memory B cells using peripheral mononuclear cells (PBMC) were performed pre-immunization (wk0), post ALVAC-HIV/AIDSVAX B/E prime-boost regime (wk26) and post different late boosts at wk50, wk62 or wk74, and at wk96. A244Δ11gDneg-specific plasma antibodies were assessed by ELISA. Results: No B cell responses were detected at wk0 or in placebo recipients at any time-point. At wk26 23/58 (40%) and 52/58 (90%) showed PB and memory responses, respectively. With no late boost 3/9 (33%) maintained PB and 7/9 (78%) memory responses. With ALVAC-HIV/AIDSVAX B/E late boost at wk50 12/14 (86%) showed PB and 14/14 (100%) memory responses. Following a late boost at wk62 and wk74 11/11 (100%) showed PB and memory responses,

multivariate models were further developed to define the common correlates from the comprehensive antibody profiles. Results: Using a unsupervised multivariate analysis, we observed the distinct humoral profiles induced by different vaccine regimens, and the evolution of the humoral profiles skewing along vaccine priming and boosting. To connect between elicited antibody-mediated responses and protective efficacy, the immunological correlates that associated to vaccine protection in each of the NHP trials were defined by a supervised multivariate analysis. Importantly, we further developed a multiple-string model which ranked the antibody features from each of the studies, and defined the common correlates shared between two studies, including antibody polyfunctionality and breadth, indicating a potential core humoral response mechanism linked to protective efficacy, regardless of different antigens vaccinated in the two trials. Significantly, based on the communal correlates, the supervised multivariate model was able to robustly cross-predict the protective efficacy in these two independent trials with > 80% accuracy. Conclusion: Taken together, this predictive model built based on robust immunological correlates provides the first framework to evaluate protective immunity and define novel immunological correlates for the development of future human HIV vaccine trials. 305 VACCINATION WITH MF59 INDUCES DISTINCT VACCINE-SPECIFIC ANTIBODY FUNCTIONALITY Carolyn Boudreau , Todd J. Suscovich, Galit Alter Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA Background: In the search for an HIV vaccine, novel adjuvants such as MF59 provide a promising strategy boost vaccine responses, both through their capacity to improve antibody titers but also by improving antibody antiviral activity. Analyses of RV144 vaccinees showed that high IgG3 antibody responses, with links to antibody functions like antibody-dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and complement deposition (ADCD) were correlates of protection from HIV infection. However, whether adjuvants can boost both the neutralizing activity and Fc-functional activity of the vaccine-induced immune response remains unclear. In the imminent phase 2/3 RV144-follow up vaccine trial (HVTN702) underway, adjuvants MF59 and alumwill be compared. Thus, understanding the humoral immune effects of MF59, an oil-in-water emulsion, will provide vital clues related to the specific opportunities by which antibodies may provide resistance to HIV infection. Methods: Using Systems Serology, we evaluated the impacts of MF59 and alum on antibody effector profiles in an influenza vaccine study, using a potential pandemic influenza strain to which few individuals have pre-existing immunity. Results: Strikingly, MF59 induced remarkably distinct antibody effector profiles compared to alum-based vaccination. MF59 induced higher levels of ADCP, neutrophil phagocytosis (ADNP), natural killer cell degranulation, and ADCD. MF59 also induced longer lasting antibodies capable of inducing ADCP and ADCD. Moreover, this increase in functional humoral response was linked to an increase in the most functional subclass of antibodies, IgG3, previously linked to protection from HIV acquisition in the RV144 vaccine trial. Conclusion: Thus, these results from a pandemic influenza vaccine trial indicate that MF59 is an attractive adjuvant to boost both protective immune responses and functional antibody subclasses that may drive enhanced immunity to HIV. 306 ADDITIONAL BOOST OF AIDSVAX B/E FURTHER INCREASED RV305 IGG BUT NOT IGA ANTIBODIES Siriwat Akapirat 1 , Sandhya Vasan 2 , Supachai Rerks-Ngarm 3 , Punnee Pitisutthithum 4 , Kirsten S. Smith 1 , Surawach Rittiroongrad 1 , Jiraporn Puangkaew 1 , Sanjay Phogat 5 , Faruk Sinangil 6 , Nelson L. Michael 7 , Jean-Louis Excler 8 , Jerome H. Kim 8 , Nicos Karasavvas 9 , Robert J. O’Connell 1 1 Armed Forces Research Institute of Medical Sciences in Bangkok, Bangkok, Thailand, 2 US Military HIV Research Program in Thailand, Bangkok, Thailand, 3 Ministry of Pubic Health, Nonthaburi, Thailand, 4 Mahidol University, Bangkok, Thailand, 5 Sanofi Pasteur, Swiftwater, PA, USA, 6 Global Solutions for Infectious Diseases, San Francisco, CA, USA, 7 US Military HIV Research Program, Silver Spring, MD, USA, 8 International Vaccine Institute, Seoul, South Korea, 9 Walter Reed Army Institute of Research, Silver Spring, MD, USA

Poster Abstracts

CROI 2018 107