An experimental therapeutic HIV vaccine regimen did not suppress the virus in patients whose ART was paused in a study testing the vaccine’s safety and efficacy, according to researchers.
The results suggest that a vaccine capable of controlling HIV viremia without ART remains elusive, the researchers wrote in Science Translational Medicine.
“Despite using a vaccination strategy designed to maximize immunogenicity in a population of individuals who began ART during acute or early HIV infection, we were unable to demonstrate a beneficial effect of vaccination on maintaining suppression of HIV viremia after interruption of ART or on the size of the HIV reservoir of persistently infected CD4+ T cells,” researcher Michael C. Sneller, MD, of the National Institute of Allergy and Infectious Diseases Laboratory of Immunoregulation, and colleagues wrote.
The trial included patients who started ART early in their infections and were recruited between September 2013 and February 2015 in the United States and Canada. In all, 14 patients were randomly assigned to receive the vaccine regimen, and 15 received a placebo vaccine.
The experimental regimen included priming injections of an HIV multiantigen DNA vaccine, along with a DNA plasmid encoding human interleukin proteins. In addition, patients received a booster with an attenuated live viral vector containing the HIV gag gene.
Injections of the experimental vaccine and placebo took place at the study’s start, then at 4 weeks, 12 weeks, 24 weeks, 36 weeks and 48 weeks. The patients’ ART regimens were interrupted from week 56 to week 72 of the study.
Surprisingly, the researchers said, four of the 15 patients receiving placebo (26%) had viral suppression of less than 400 copies/mL at the end of the ART interruption period, compared with just two of the 14 (14%) who received the vaccine.
The vaccine also had “no observable effect on the size of the HIV reservoir, as measured in peripheral blood CD4+ T cells,” Sneller and colleagues said. They concluded that development of a therapeutic HIV vaccine independent of ART would require more research.
“It remains to be established whether therapeutic vaccination alone can produce sustained suppression of HIV replication in the absence of ART,” they wrote. “Future studies of therapeutic vaccination will likely need to incorporate other immune-based interventions into the vaccine regimens if sustained suppression of HIV replication in the absence of ART is to be achieved.”
In a related commentary, Col. Nelson L. Michael, MD, PhD, director of the U.S. Military HIV Research Program at the Walter Reed Army Institute of Research, wrote that the findings provide valuable insight into HIV therapy.
One simply must look beyond the vaccine’s overall ineffectiveness, he concluded.
“All too often, colleagues will look at the result of an infectious disease clinical research trial where the experimental arm fails to show a positive impact on acquisition or control of infection and simply declare that the study ‘failed,’” Michael contended. “Sneller [and colleagues] elegantly show us how misguided that thinking is in four ways. First, the specific [prime and boost] vaccine therapy was shown not to be effective. That is helpful as it excludes this approach in this HIV clinical setting.”
Michael went on to point out specific findings in the study that could guide future efforts to improve HIV therapy.
“Second, this study continues to build the case that CD8+ T cell responses against the HIV-1 Gag protein are likely key to early HIV-1 virologic control. Third, the authors made the decision to allow viral load to rise higher than just enough to declare treatment failure, which enabled them to discriminate between the active vaccine and placebo arms, thus contributing to a debate in the field about when to reinitiate ART after analytic treatment interruptions.”
Michael also added that the study design was useful.
“Fourth, the demonstration of the power of randomization and the use of a placebo control was critical to interpreting the results of the study,” he wrote. “Thus, the volunteers in this study were asked to assume some degree of risk, and the volunteerism was accompanied by advancing the field in both a specific and a general fashion.”
By Joe Green