Gamblers, poker players, and Las Vegas casino visitors all have their schemes for when to hold their cards, when to fold, and which cards are keepers or losers. In medical research, those decisions belong mainly to a Data and Safety Monitoring Board (DSMB), an independent group of statistical and clinical experts who monitor patient safety and treatment efficacy data during a clinical trial. A DSMB can halt a trial if periodic assessments show safety concern or no efficacy.
This week’s NEJM includes the interim results of a trial, known as HVTN 505, that was halted early because of lack of efficacy. This phase 2B study was evaluating the efficacy of a DNA prime–recombinant adenovirus type 5 boost (DNA/rAd5) vaccine regimen in US residents at increased risk for HIV-1 infection. The vaccine was designed to elicit HIV-specific, multifunctional responses in CD4+ and CD8+ T cells and antibodies to envelopes of the major HIV viral strains. However, there was no evidence of efficacy, and development of an effective HIV vaccine remains an elusive and difficult challenge.
The candidate vaccine was a multi gene, multi-clade DNA prime-recombinant adenovirus type 5 vector boost (DNA/rAd5) vaccines that was found safe and immunogenic in preclinical work and early-phase clinical studies. The dual primary endpoints for the study were diagnosis of HIV infection and viral-load set point, which was the HIV-1 RNA level 10 to 20 weeks after diagnosis. The 6-plasmid DNA vaccine was administered at initial visit, followed by doses four and eight weeks later. The rAd5 vector boost was administered at week 24. Patients enrolled in the study were men or transgender women who have sex with men.
Dr. Scott Hammer from Columbia University and his colleagues reported HIV diagnoses in 27 vaccine recipients and 21 participants in the placebo arm; vaccine efficacy was -25.0% ( 95% confidence interval, −121.2 to 29.3).The study had sought a vaccine efficacy of 50%. Mean viral load set points were virtually identical. A difference of 1.0 log10 was the goal for mean viral load. The authors reported the vaccine induced cellular and humoral responses that weren’t protective.That lack of efficacy prompted the DSMB recommendation to stop the trial. Dr. Hammer and his co-authors noted that “30 years after the discovery of HIV, a safe and effective vaccine is still not in sight.”
The DSMB recommendation to stop the study came when two-thirds of the total predicted person-years of follow-up had been completed. In short, the DSMB made the decision to fold. HIV vaccines are especially difficult to develop because the HIV virus continually evolves in infected persons. A successful vaccine will have to show efficacy against that moving target of evolving viral infection.
See also a new Perspective article:
The Quest for an HIV-1 Vaccine
The challenges in the development of a prophylactic HIV-1 vaccine are unprecedented in the history of vaccinology. But there are reasons for optimism, and indeed, several promising vaccine concepts are currently moving toward clinical efficacy trials.