However, findings from the study may provide a roadmap for future analyses of immune-based interventions seeking to relieve HIV patients of the lifelong burden of daily medication intake and enhance viral suppression.
A therapeutic vaccination protocol designed to maximize immunogenicity in antiretroviral therapy (ART)-experienced patients following acute or early HIV infection failed to maintain suppression of viremia or reduce the size of the reservoir of “persistently infected” CD4+ T cells, 2 key markers for its efficacy, a study published December 6, 2017, in the journal Science Translational Medicine (STM) confirmed.
However, notable findings of the research project, led by a team of scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and clinicians from across North America, may provide a roadmap for future analyses of immune-based interventions seeking to relieve HIV patients of the lifelong burden of daily medication intake—an important consideration given the long-term toxicity associated with ART regimens—and enhance viral suppression.
Study co-author Tae-Wook Chun, PhD, Chief, HIV Immunovirology Unit at NIAID/NIH told Contagion® that the observations made from the patients enrolled in the study could ultimately help identify “types of immune-based interventions aimed at augmenting vaccine-induced anti-HIV T cell responses [including] combining therapeutic vaccination with immune checkpoint inhibitors—such as anti-PD1 or anti-PD1 ligand—or immune stimulants such as Toll-like receptor 7 antagonists.
For the STM study, Dr. Chun and colleagues tested a strategy featuring a plasmid DNA vaccine containing genes encoding multiple HIV proteins—including clade B gag/pol and nef/tat/vif and env—which was then boosted with a live attenuated viral vector containing the HIV gag gene. A total of 31 HIV-positive adults from the United States and Canada were enrolled in the study, and 30 completed the vaccine phase of the project, with roughly half receiving the study vaccine and the other half receiving a placebo; an additional study subject was lost to follow-up.
As part of the protocol, 14 study subjects in the vaccine group and 15 in the placebo group discontinued ART at week 56 of the study. Although the vaccine was generally well tolerated—with the only adverse events reported being grade 1 injection site pain or tenderness and mild-to-moderate fatigue, myalgia, and arthralgia—the authors found that the therapeutic vaccine had “no significant effect on the kinetics or magnitude of viral rebound” following ART interruption.
Indeed, the median plasma viral loads were 4932 and 3170 copies/ml in the vaccine and placebo groups, respectively, and 5 study subjects in the vaccine group and 1 in the placebo group met the study criteria for restarting ART at study week 72. Furthermore, in post hoc analyses, the authors identified no significant differences between the 2 groups in terms of time from ART interruption to viral loads of ≥40 copies/ml (median 28 days in both groups) and to viral loads of ≥400 copies/ml (median 28 vs 30 days in the vaccine and placebo groups, respectively).
In the 26 participants in whom immunologic analyses were performed, the study authors observed increases in IFN-γ- and/or IL-2-expressing CD3+CD4+ T cells to the Gag 1 peptide pool in 7 of 13 participants in the vaccine group compared to none of the 13 in the placebo group. They also observed increases in IFN-γ- and/or IL-2-expressing CD3+CD4+ T cells to the Env 1 peptide pool in 4 of 12 participants in the vaccine group compared to none of the 13 in the placebo group. They also noted that the vaccine was less effective at inducing increases in IFN-γ- and/or IL-2-expressing CD3+CD8+ T cells in response to individual HIV-1 antigens or boosting T cell responses to Pol or Nef antigens. Finally, the authors observed “no significant changes in the frequency of CD4+ T cells carrying HIV proviral DNA, cell-associated HIV RNA, or replication-competent virus” in the vaccine and placebo groups over the study period, which they believe indicates “that the therapeutic vaccine regimen had no observable effect on the size of the HIV reservoir, as measured in peripheral blood CD4+ T cells.”
Still, their work to find solutions to the vexing problem of achieving “durable suppression of HIV replication” following ART discontinuation is far from over. “We are currently pursuing several non-vaccine approaches, [including] therapy with broadly neutralizing monoclonal anti-HIV antibodies that target the virus gp120 protein and using a specific monoclonal antibody (vedolizumab) that targets alpha4beta7, a T cell surface protein that regulates T cell trafficking to the gut and HIV entry into T cells,” said Dr. Chun. “Both of these approaches have shown promise in non-human primate models of HIV infection.”
Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.