Large AIDS Vaccine Trial Shudders to a Halt
A large Phase IIb trial testing the safety and efficacy of a DNA/Ad5 prime-boost regimen of two vaccine candidates developed by the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID) has discontinued immunizations.
The HVTN 505 trial was launched in 2009 and then expanded in 2011, largely in response to results from a previous AIDS vaccine trial that did demonstrate efficacy (see Special Report: Thai Trial Results, IAVI Report, 2009). The study enrolled 2,504 men who have sex with men and transgendered women who have sex with men at 21 sites in 19 US cities. It was conducted by the HIV Vaccine Trials Network, and supported by NIAID.
HVTN 505 trial was the only trial currently underway that was designed to evaluate efficacy—an important determinant of whether a vaccine candidate is suitable for licensure . Researchers were hopeful of a result that might have moved the field forward in some way. Instead, what they learned from their Data Safety Monitoring Board (DSMB) following a scheduled interim review on April 22, was that the vaccine regimen did not lower infection rates in individuals who received the vaccine. Nor did it reduce the amount of virus in the blood of those who became infected despite having received the candidate vaccines.
The DSMB examined data from 1,250 volunteers who received the vaccine candidate and 1,244 who received the placebo. The primary analysis looked at volunteers who were diagnosed with HIV after having been in the study a minimum of 28 weeks. This was done to allow the vaccine regimen sufficient time to stimulate an immune response. In this analysis, 27 HIV infections occurred among the vaccine recipients, and 21 HIV infections occurred among the placebo recipients. The apparent increase in HIV risk in vaccine recipients was not, however, found to be statistically significant, NIAID said in a statement released on April 25. It is not clear why this occurred; further analysis and study is needed.
Ken Mayer, a principal investigator at the Fenway Community Health Center in Boston, which had enrolled 90 volunteers in the HVTN505 trial, said it would be premature to speculate whether the Ad5 vector, which was similar to the one used in Merck Step trial, might have driven the poor outcome in the HVTN505 trial. “These are still early days,” said Mayer. “We just don’t know. We have no data yet on whether there were differences in risk-taking behaviors. If more people in the vaccine arm had more unprotected anal sex, then their risk [for acquiring HIV] is much higher.”
Still, Mayer said, given the outcomes in both the Step and HVTN505 trials, it is likely that some Ad vectors will be entering a period of increased scrutiny. “We now have two studies that used somewhat different types of Ad5s in different combinations and in different populations associated with no protection.”
Among volunteers who became HIV-infected during the first 28 weeks of the study, 14 cases of HIV infection were recorded in those who received the vaccine candidate, and nine in placebo vaccine recipients. Overall, from the day of enrollment through the month 24 study visit, a total of 41 cases of HIV infection occurred in the volunteers who received the vaccine candidate and 30 among those who got the placebo.
Additionally, the DSMB found that the vaccine failed to reduce viral load among volunteers who acquired HIV infection at least 28 weeks after entering the study, and who had been followed for at least 20 weeks after diagnosis. There were 30 participants with measurable viral load (15 vaccine recipients and 15 placebo recipients).
Based on these findings, the DSMB recommended that no further vaccinations be administered. NIAID agreed. The agency will, however, continue detailed follow up studies on volunteers who received the candidate regimen.
Study investigators at each of the 21 clinical trial sites are now in the process of contacting study volunteers to inform them of the developments. Mayer said he was informed of the results several days ago and that the Fenway site—one of the largest in the study—has been busy notifying volunteers.
Volunteers are being asked to report to their specific clinic sites over the next few weeks to find out whether they received the investigational vaccines or a placebo. Individuals who became HIV-infected during the trial were referred to local services for appropriate medical care and treatment. The study investigators will continue following all study participants for five years from the time of enrollment. For a brief history of the birth and convoluted evolution of HVTN 505, see the accompanying post.