Boosters of a therapeutic HIV-1 vaccine induce divergent T cell responses related to regulatory mechanisms

AbstractTherapeutic human immunodeficiency virus (HIV) vaccines aim to reduce disease progression by inducing HIV-specific T cells. Vacc-4x are peptides derived from conserved domains within HIV-1 p24 Gag. Previously, Vacc-4x induced T cell responses in 90% of patients which were associated with reduced viral loads. Here we evaluate the effects of Vacc-4x boosters on T cell immunity and immune regulation seven years after primary immunization. Twenty-five patients on effective antiretroviral therapy received two Vacc-4x doses four weeks apart and were followed for 16 weeks. Vacc-4x T cell responses were measured by proliferation (CFSE), INF-γ, CD107a, Granzyme B, Delayed-Type Hypersensitivity test (DTH) and cytokines and chemokines (Luminex). Functional regulation of Vacc-4x-specific T cell proliferation was estimated in vitro using anti-IL-10 and anti-TGF-ß monoclonal antibodies.Vacc-4x-specific CD8+ T cell proliferation increased in 80% after either the first (64%) or second (16%) booster. Only 40% remained responders after two boosters with permanently increased Vacc-4x-specific proliferative responses (p=0.005) and improved CD8+ T cell degranulation, IFN-γ production and DTH. At baseline, responders had higher CD8+ T cell degranulation (p=0.05) and CD4+ INF-γ production (p=0.01), whereas non-responders had higher production of proinflammatory TNF-α, IL-1α and IL-1ß (p<0.045) and regulatory IL-10 (p=0.07).Notably, IL-10 and TGF-ß mediated downregulation of Vacc-4x-specific CD8+ T cell proliferation increased only in non-responders (p<0.001). Downregulation during the study correlated to higher PD-1 expression on Vacc-4x-specific CD8+ T cells (r=0.44, p=0.037), but was inversely correlated to changes in Vacc4x-specific CD8+ T cell proliferation (r=−0.52, p=0.012).These findings show that Vacc-4x boosters can improve T cell responses in selected patients, but also induce vaccine-specific downregulation of T cell responses in others. Broad surveillance of T cell functions during immunization may help to individualize boosting, where assessment of vaccine-related immune regulation should be further explored as a potential new parameter

Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial.

BackgroundPresent combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1.MethodsBetween July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load &lt;50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov, number NCT00659789.Findings174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23,100 copies per mL Vacc-4x vs 71,800 copies per mL placebo; p=0·025) and week 52 (median 19,550 copies per mL vs 51,000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations.InterpretationThe proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies.FundingNorwegian Research Council GLOBVAC Program and Bionor Pharma ASA

The urban heat island effect in Austin : current trends and opportunities for further mitigation

This report explores issues surrounding the Urban Heat Island (UHI) effect and its mitigation, while focusing on UHI in Austin, Texas. It presents current trends in American cityscapes, namely the increases in impervious surface cover and decreases in urban green spaces. The report contextualizes these losses in green space through a review of the extensive health and societal benefits provided by urban trees and vegetation. Moreover, the report covers the human health implications and socioeconomic disparities associated with urban heat. It examines climate change projections as they relate to changes in extreme heat events. Furthermore, the report touches on the main types of UHI mitigation approaches and utilizes the City of Los Angeles as a case study. This report presents Austin’s UHI mitigation approaches as found in the city’s plans and policies. Next, it analyzes the spatial distribution of surface temperature, tree canopy coverage, and a variety of vulnerability factors for residents in Austin. Finally, this report provides recommendations for further UHI mitigation efforts in Austin and research areas for future studyCommunity and Regional Plannin