CROI 2016 Abstract eBook
Long vaccination regimens. Levels and decay of proviral DNA after cART were not associated with vaccine-induced immunogenicity nor differed from non-vaccinated individuals. Viral reactivation was not observed during vaccinations. Conclusions: Heterologous vaccination with ChAdV63 and MVA.HIVconsv was a safe strategy to induce new and shift pre-existing immune response towards conserved regions of HIV-1 in a cohort of early-treated individuals. Reservoir decay during first year of early-treatment was not further impacted by vaccinations. This is the first therapeutic vaccine trial able to demonstrate a refocusing of the CTL immunodominance pattern towards conserved regions of HIV-1 and may provide the base for effective kick and kill strategies. 321 DNA/rTV/Protein Vaccination Protects Against Acquisition of SHIV162P3 Challenges Xuan He ; Zhou Zhang;Ying Liu;Yanling Hao; Li Ren; Kunxue Hong;Yiming Shao Natl Cntr for AIDS/STD Control and Prevention, Chinese CDC, Beijing, China Background: We have previously reported that replication-competent Tiantan vaccinia (rTV) is a promising vaccine vector, and rTV-based HIV-1 vaccine with DNA primer provided protection from SHIV challenge. To further improve vaccine-induced immunity and protection, we combined DNA vaccine with boosts of both rTV and proteins in the recent study.
Methods: Eight Chinese rhesus macaques were intramuscularly primed with DNA vectors expressing HIV Env/ Gag/Pol/Nef and SIV Gag, followed by intradermal boost with rTV vectors expressing HIV gp145 and SIV Gag, and final intramuscular boost with proteins HIV gp140 and SIV Gag. Another eight macaques received sham vaccines. Animals were then challenged twelve times by intrarectal route with low dose of heterologous, neutralization- resistant virus SHIV162P3. Results: DNA/rTV/protein vaccination induced high-titer HIV Env-specific antibodies, and modest cytotoxic CD8 T-cell responses. In the vaccinated group, half macaques were completely protected from SHIV acquisition, whereas three macaques exhibited transient acute viremia and later became elite controllers with undetectable viral loads. Chronic viremia was observed in one vaccinated macaque. In contrast, all 8 sham controls were systemically infected (setpoint viral loads: 2.00-4.44 log SHIV RNA copies/ml), with peak plasma viremia levels ranging from 6.00 to 6.98 log SHIV RNA copies/ml, which were significantly higher than that in the vaccinated group that became infected, with peak viremia ranging from 3.82 to 5.54 log SHIV RNA copies/ml (p=0.004). No significant differences were observed among all immunized animals in terms of vaccine-induced neutralizing antibodies and cytotoxic CD8 T-cell responses, though the protected macaques and elite controllers showed modestly higher HIV Env-specific humoral response than viremia uncontrolled one. Dominantly higher titer of vaccine-induced binding antibodies to variable regions 1 and 2 (V1V2) of HIV-1 Env was observed in the protected animals (V1V2 titer: 4.40-5.01 log) and elite controllers (V1V2 titer: 4.10-5.01 log) compared with viremia uncontrolled macaque (V1V2 titer: 3.8 log). Conclusions: The protective efficacy of DNA/rTV/protein vaccines against acquisition of neutralization-resistant SHIV infection in rhesus macaques in the study has important implications for HIV-1 vaccine development. Moreover, our immunologic correlates analyses suggest that Env-specific V1V2 antibodies may be critical for blocking acquisition of SHIV challenges. Poly-ICLC, a TLR Agonist, Is Safe and Tolerable in HIV-Infected Individuals Elizabeth A. Miller 1 ; Rachel Sabado 1 ; Andres Salazar 2 ; Melissa LaMar 3 ; Martin Markowitz; Nina Bhardwaj 1 1 Icahn Sch of Med at Mount Sinai, New York, NY, USA; 2 Oncovir, Inc, Washington, DC, USA; 3 Aaron Diamond Aids Rsr Cntr, New York, NY, USA
Background: Safe and effective adjuvants will likely be a key component of successful therapeutic vaccines for HIV. Toll-like receptor (TLR) agonists are promising investigational adjuvants that may enhance vaccine immunogenicity, and based on preclinical data may stimulate viral expression from latent HIV reservoirs. Poly-ICLC is a synthetic dsRNA complex that is a potent agonist of TLR3, as well as cytoplasmic sensors including MDA5. Methods: We have undertaken a phase I/II, randomized, placebo-controlled, double-blinded, trial in cART-suppressed subjects with HIV infection (NCT02071095). Participants were randomized 3:1 to receive 2 consecutive daily doses of Poly-ICLC (1.4mg SQ) versus placebo. The primary outcome is safety and tolerability, in addition to multiple secondary immune and virologic endpoints. Transcriptional analysis of subjects’ PBMCs was performed using NanoString Technologies (nCounter® gene expression panel, human inflammation kit). Results: Fifteen participants have received both injections and have completed ≥ 4 weeks of follow up. Enrollment has closed, though the study remains blinded. Thus far, the injections have been safe and well-tolerated with only Grade 1/2 adverse events (AEs) attributed to the study agent, with the exception of one Grade 3 transient neutropenia without clinical sequelae. Injection site reactions (ISR) have been the most frequent AE, all of which were Grade 1. Pain has been the most common ISR, occurring at 66% of injection sites. Erythema was present at 16% of injection sites. Fever has also been common (33%), lasting 24-48 hours. Other frequently reported AEs include chills, myalgias, fatigue, malaise, and headache. Plasma viral control has been maintained in these cART-treated individuals. Transcriptional analyses have revealed that in subjects with injection site reactions, multiple innate immune pathways are significantly upregulated in subjects PBMCs, including strong interferon (IFN) signaling. These responses generally peaked ~24 hours after injection and returned to baseline by day 8. Conclusions: Poly-ICLC injections appear safe and tolerable, are associated with mild injection site reactions and transiently stimulate innate immune responses during treated HIV infection, indicating promise as an adjuvant for HIV therapeutic vaccines. Additional assays currently underway will better define the immunologic and virologic effects of TLR stimulation during HIV infection. 323 TLR-9 Signaling Rescues Defects in B-Cell Response in Needle-Free Immunization Prabhu S Arunachalam 1 ; Ria Mishra 1 ; Sravan Payeli 2 ; Deepak Selvam 1 ; Richard R. Stout 3 ; Udaykumar Ranga 1 1 Jawaharlal Nehru Cntr for Advanced Scientific Rsr, Bangalore, India; 2 Bmom Fertility and Rsr Cntr, Bangalore, India; 3 Bioject Med Technologies, Inc, Tigard, OR, USA Background: The intradermal immunization (ID), unlike the intramuscular immunization (IM), can target diverse subsets of dendritic cells (DC) in the skin offering a great advantage especially with the DNA vaccines. We, therefore, compared in mice the ID immunization using a needle-free (NF) device with the traditional IM administration. The NF administration is also safe as it is a non-invasive technique. Methods: BALB/c and C57BL/6 mice were immunized through the IM or ID routes using comparable quantities of plasmid vectors encoding HIV-1 Gag, Tat, Firefly or Gaussia luciferase under the CMV promoter. The T- and B-cell responses were measured from the splenocytes/PBMC and sera, respectively. The frequencies of the antigen-specific and activated T-cells expressing IFN-γ and TNF-α, manifesting the proliferation or degranulation phenotypes were determined using the multi-parametric flow analysis. The in vivo antigen expression was evaluated using luciferase assay and confocal microscopy. Results: The IM and ID immunizations elicited comparable T-cell responses with 0.55 ± 0.12 and 0.52 ± 0.12% CD8 T-cells manifesting the p24-specific IFN-γ+TNF-α double positive phenotype, respectively. At a dose as low as 2 μg, the ID route was superior to the IM route eliciting a 3 fold higher magnitude of the double positive cells. Surprisingly, although the IgM antibody titres were comparable between the routes of immunization, the IgG response was significantly diminished in the ID immunization. The mean IgG
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