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Therapeutic HIV Vaccine Boosts CD4/CD4 Ratio,
Cuts HIV DNA in PBMCs in 33-Person Trial
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Toward an HIV Cure Symposium, July 18-19, 2015, Vancouver
Mark Mascolini
VAC-3S, an immunotherapeutic vaccine that mimics a highly conserved motif in the HIV-1 gp41 envelope protein, proved immunogenic in a 32-week trial that involved 33 adults taking suppressive antiretroviral therapy [1]. Induction of anti-3S antibodies was associated with a climbing CD4/CD8 ratio and declining HIV in peripheral blood mononuclear cells (PBMCs), reported researchers from InnaVirVax and collaborators at medical centers in Paris.
The S3 motif in HIV's gp41 protein induces expression of NKp44L, a cellular ligand of the NK (natural killer) receptor NKp44, which makes uninfected CD4 cells vulnerable to NK lysis. The investigators noted previous in vitro, ex vivo human, and in vivo macaque data showing that NKp44L expression strongly correlates with falling CD4 counts, CD4-cell apoptosis, T-cell activation, and inflammation. SHIV-infected macaques immunized with a 3S vaccine garnered protection against CD4-cell depletion and chronic immune activation.
This phase 1, randomized, double-blind, placebo-controlled, dose-escalation trial assessed the safety and immunogenicity of VAC-3C administration at weeks 0, 4, and 8 at doses of 0.1, 1, 10, and 20 ug, followed by one booster at week 32 in the 1- and 10-ug arms. Study participants had an undetectable viral load on antiretroviral therapy and a CD4 count above 200. The researchers defined responders as participants with total anti-3S antibodies at or above 30 arbitrary units at week 12 in active arms. Nonresponders were participants with total anti-3S antibodies below 30 arbitrary units at week 12 in active arms. Twenty-four people got the VAC-3C vaccine and 9 got placebo.
Everyone in an active arm received all three VAC-3C doses, and 8 of 9 in the placebo group received three doses. Age averaged in the 40s across all five arms, and body mass index averaged about 24 kg/m2. The overall response rate was 33%, with responses in none of 6 in the 0.1-ug arm, 3 of 6 people in the 1-ug arm, 3 of 6 in the 10-ug arm, and 5 of 6 in the 20-ug arm.
Among responders percentage of CD8 cells fell significantly at week 24 (P = 0.027) while percentage of CD4 cells rose significantly (P = 0.031). The researchers found a negative correlation between change from baseline percentage of CD4+CD95+ cells and anti-S3 titers at week 24 (r = -0.59, P = 0.002), a result they believe suggests protective effects of anti-S3 antibodies against bystander apoptosis of CD4 cells.
The HIV reservoir in blood cells (measured as change from baseline HIV DNA copies per million PBMCs) correlated negatively with anti-3S titers at week 12 (r = -0.41, P = 0.023), week 36 (r = -0.31, P = 0.107), week 60 (r = -0.42, P = 0.018), and week 84 (r = -0.57, P = 0.03).
Estimated log10 change in HIV DNA per million PBMCs rose significantly from baseline to weeks 12 and 36 among nonresponders and placebo recipients while falling at week 60 (P = 0.07) and week 84 (P = 0.01) in responders. Change in HIV DNA per million PBMCs was nonsignificantly lower in responders than in the nonresponder/placebo group at week 60 (P = 0.29) and significantly lower in responders at week 84 (P = 0.029).
Vaccination did not significantly change serum inflammatory markers and did not increase residual viral replication as assessed by an ultrasensitive assay.
The researchers concluded that "VAC-3S is safe and immunogenic HIV immunotherapy at higher tested doses," although they did not detail safety findings in their report. A phase 2a trial in 90 participants is under way to confirm the safety and immunogenicity findings in people with a CD4 count between 200 and 500 [2].
References
1. Ho Tsong Fang R, Launay O, Rouzioux C, et al. VAC-3S, a safe immunotherapeutic HIV vaccine decreased total HIV DNA and increased CD4/CD8 ratio: phase I final results. Toward an HIV Cure. July 18-19, 2015. Vancouver. Abstract 3630.
2. Katlama C, Rockstroh JK, Gatell JM, et al. VAC-3S immunotherapeutic HIV vaccine combined with ART is immunogenic and safe. phase II initial analysis of the IPROTECT1 multicenter European study. IAS 2015. 8th Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2015. Vancouver. Abstract MOPEA038.
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