CROI 2016 Abstract eBook

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Poster Abstracts

Results: Plasmablasts (PBs) frequency increased 1 wk after the last vaccination (p=0.0005) while the α4β7 subset decreased (p=0.0010) and the CXCR3 + did not changed. Serum antibodies titer to 1086 peaked at week 26 (>10^6) in vaccinated animals that did not became infected and maintained a title > then 10^4 up to 48 wks. Plasma Abs elicited were able to neutralize only tier 1 Clade C viruses. Mucosal antibodies to V2 were higher in the vaginal mucosa then in the rectal. PBs CXCR3 + correlated with antibodies to V1/V2 antigens. Surprisingly we observed no reduction in the risk of SHIV acquisition in the vaccinated animals, nor protection from high viral load, nor CD4 loss. However animals that were infected later had higher titer of Ab titer in plasma at wk 28 to 1086 Conclusions: The lack of vaccine effect was surprising given the efficacy observed in a similar vaccine tested in the SIVmac251 model. However the α4β7 plasmablasts frequency differed in the two vaccine regimens. This difference might be due to differences in the adjuvants used in the two vaccine regimes that might also influenced differences in vaccine efficacy. 318 Specific IgG Subclasses Induced in RV305: A Late Boost Vaccination of RV144 Subjects Siriwat Akapirat 1 ; SandhyaVasan 2 ; Punnee Pitisuttithum 3 ; Supachai Rerks-Ngarm 4 ; Nelson L. Michael 5 ; Jean-Louis Excler 6 ; Jerome H. Kim 7 ; Robert O’Connell 1 ; Nicos Karasavvas 1 ; for the RV305 Study Group 1 Armed Forces Rsr Inst of Med Scis, Bangkok, Thailand; 2 US Military HIV Rsr Prog, APO, AP, USA; 3 Mahidol Univ, Ratchathewi, Thailand; 4 Ministry of PH, Muang Nonthaburi, Thailand; 5 US Military HIV Rsr Prog, Bethesda, MD, USA; 6 Henry M. Jackson Fndn for the Advancement of Military Med, Inc, Bethesda, MD, USA; 7 Intl Vaccine Inst, Seoul, Republic of Korea Background: While RV144 vaccine-induced IgG3 to HIV-1 Env variable loops 1 and 2 (V1V2) correlated with decreased risk of HIV-1 acquisition, the responses were not durable. We studied IgG subclasses (IgG1-IgG4) in HIV-uninfected RV144 volunteers who completed their primary vaccination series 6-8 years earlier and were randomized to receive booster vaccinations with either ALVAC-HIV/AIDSVAX B/E (Gr1), AIDSVAX B/E (Gr2) or ALVAC-HIV (Gr3) at 0 and 6 months (RV305). Methods: ELISA IgG1-IgG4 to HIV gp120 A244gD, and gp70V1V2 scaffold proteins 92TH023 (subtype AE) and CaseA2 (subtype B) were assessed in plasma and cervico-vaginal mucus (CVM) at study entry, 2 weeks post 1 st and 2 nd boosts, and 6 and 12 months post 2 nd boost. Results: At study entry, geometric mean titers (GMT) of IgG to gp120 A244gD in plasma ranged from 50-67 in all groups. We did not detect a boosting effect of any IgG subclasses in plasma and CVM in Gr3. IgG1 GMT increased 2 weeks post 1 st boost in Gr1 and Gr2, but significantly declined (p<0.01) 6 months post 2 nd boost (Gr1=4850 and 255; Gr2=5279 and 252, respectively). They were significantly higher than those in RV144 at peak immunogenicity and 6 months post last injection (492 and 88, p<0.01). IgG3 GMT increased 2 weeks post 1 st boost (Gr1=168, Gr2=159), but not after the 2 nd boost, and were significantly lower than RV144 at peak immunogenicity (532, p<0.01). While IgG4 was undetected in RV144, it increased to 951 and 611 and to 800 and 588 2 weeks post 1 st and 2 nd boosts in Gr1 and Gr2, respectively. IgG1-IgG4 to gp70V1V2 scaffolds was not detected at study entry. IgG1 GMT to AE and B V1V2 were similar in Gr1 and Gr2 after the 1 st boost (Gr1-Gr2/AE=528-524 and Gr1-Gr2/B=50-43) but lower after the 2 nd boost (Gr1-Gr2/AE=146-147 and Gr1-Gr2/B=28-24). IgG4 to AE and B V1V2 were detected in Gr1 and Gr2 but not detected in RV144. RV144 IgG3 to V1V2 scaffolds were not boosted in Gr1 and Gr2, and IgG2 remained weak for all antigens tested. In CVM, most responses to gp120 A244gD were IgG1 and IgG4, while to scaffolds were mostly IgG1. Conclusions: Late boosts with AIDSVAX B/E, with or without ALVAC-HIV, induced plasma HIV-specific IgG responses that were predominantly IgG1 and IgG4, were significantly higher than RV144 responses, but did not improve magnitude nor durability of IgG3, and were similar to subtypes in CVM. These studies highlight the need for new strategies to durably boost HIV-specific, protective antibody responses observed in RV144. 319 Vaccine Targeting Protease Cleavage Sites Protects Cynomolgus Monkeys Against SIV Ma Luo 1 ; DavidTang 1 ; Rupert Capina 1 ; Xin-YongYuan 1 ; Jorge Correia-Pinto 2 1 Natl Microbiology Lab of Canada, Winnipeg, MB, Canada; 2 Univ of Santiago de Compostela, Santiago de Compostela, Spain Background: With the sobering results of the STEP and HVTN 505 HIV vaccine clinical trials, novel approaches to HIV vaccine development must be explored. The HIV protease is a 99-amino acid aspartic enzyme that mediates the cleavage of Gag, Gag-Pol and Nef precursor polyproteins. This process is a highly specific, temporally regulated and essential for the production of infectious viral particles. A total of 12 proteolytic reactions are required to generate an infectious virion, and a single impaired cleavage reaction can render the virus noninfectious. Thus, HIV vaccine-elicited responses targeting the protease cleavage sites (PCS) could be highly efficacious. Methods: We assess vaccine immunogenicity elicited against PCS immunogens using a modified Vesicular stomatitis virus (VSV) vector combined with a nanodelivery system. We then evaluate protective efficacy to disrupt SIV acquisition and disease progression using a Cynomolgus macaque ( Macaca facicularis , Philippines) and SIV MAC239 intrarectal challenge model. To examine whether the immune driven viral mutations surrounding the PCS were detrimental to the virus, we amplified and sequenced the plasma viruses by 454-pyrosequencing and correlated the amino acid mutations surrounding PCS with alterations in viral load and CD4 count. Results: PCS peptides expressed by rVSVs and packaged in nanoparticles are able to generate both antibody and T cell responses in macaques. The ability of macaques to withstand high dose SIV MAC239 challenge was significantly correlated with the antibody and antibody/T cell responses to the number of PCS peptides(p=0.0005, R=0.8005). This combination imparted resistance to all but the higher SIV doses that were required to infect vaccinnees (p=0.01). the vaccine group maintains significantly higher CD4 counts (p=0.0002). Amino acid mutations (SN or NS) surrounding PCS correlated significantly with reduced viral RNA levels (p<0.0001). Conclusions: We show here in a Cynomolgus macaque/SIV model that a candidate HIV vaccine focusing immunologic responses to the regions surrounding the SIV protease cleavage sites can force viral mutation resulting in impaired SIV fitness. Focused immune response to the PCS region enables the macaques to withstand multiple high dose pathogenic SIV MAC239 intrarectal challenges. Virus recovered from vaccinnees harbored mutations surrounding the protease cleavage region that correlated significantly with reduced viral load, and the maintenance of CD4+ T cells in vivo . 320 Shaping CTL ImmunodominanceWith Conserved HIV Vaccines After Early Treatment (BCN01) Beatriz Mothe 1 ; Christian Manzardo 2 ; Pep Coll 1 ; Sara Moron-Lopez 1 ; Lucy Dorrell 3 ; Bonaventura Clotet 4 ; Javier Martinez-Picado 1 ; Christian Brander 1 ;Tomás Hanke 5 ; for the BCN01 Study Group 1 IrsiCaixa Inst for AIDS Rsr, Badalona, Spain; 2 Hosp Clinic-IDIBAPS-Univ of Barcelona, Barcelona, Spain; 3 Univ of Oxford, Oxford, UK; 4 Lluita Contra la SIDA Fndn, Germans Trias i Pujol Univ Hosp, Barcelona, Spain; 5 The Jenner Inst, Oxford, UK Background: Therapeutic T-cell vaccines targeting the most conserved regions of the HIV-1 proteome have the potential to enhance host immune control and facilitate clearance of the latent reservoir. Methods: BCN01 (NCT01712425) is a phase I, multicenter trial to evaluate the safety, immunogenicity and impact on the latent reservoir of a combined ChAdV63-MVA.HIVconsv vaccine in early-treated individuals (<6m from HIV-1 infection, n=24) who initiated TDF/FTC/RAL 1 wk after diagnosis. Individuals received ChAdV63.HIVconsv (5x10 10 vp, im) and MVA.HIVconsv (2x10 8 pfu, im) 8 or 24 wk after (Short vs Long regimen) and were followed for 6 months. Immunogenicity to the HIVconsv vaccine insert and the rest of the HIV-1 proteome was assessed by IFNg ELISPOT in cryopreserved PBMC. 24 unvaccinated controls were included to compare viral reservoir decay during 1st year of early-treatment initiation. Proviral DNA was quantified in purified CD4+ T-cells by droplet digital PCR. Single-copy assay was performed to investigate potential viral reactivation during vaccinations. Results: 22 individuals (92%) induced HIVconsv de-novo Tcell responses during vaccination schedule (not detectable before cART initiation). Responses were increased in 50% participants after ChAdV63 prime and in 100% of participants after MVA booster vaccination (median of 938 SFC/10 6 PBMC, range 73-6,805 at peak, p=0.0001, Wilcoxon t-test compared to pre-vaccination). No significant expansion of T-cells targeting HIV-1 regions outside the vaccine insert was noted, reflective of an effective shift of CTL immunity towards conserved regions (48% of total HIV-1 T-cells being HIVconsv-specific). No significant differences in peak or longevity of induced T-cells were observed between Short and

Poster Abstracts


CROI 2016

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