STI Quarterly: U.S. HIV vaccine trial halts shots — What is the next step in research?
Shot unsuccessful at preventing healthy subjects from contracting HIV
The National Institute of Allergy and Infectious Diseases (NIAID) is halting the administration of injections in the clinical trial of an investigational HIV vaccine regimen after a scheduled interim review data indicated the regimen did not prevent HIV infection, nor did it reduce viral load among vaccine recipients who became infected with HIV. [On April 26, 2013, Contraceptive Technology Update issued an e-bulletin on the study shutting down. To receive breaking news as it occurs, provide your email address to AHC Media customer service at email@example.com or (800) 688-2421.]
The study began testing in 2009 the prime-boost vaccine regimen developed by NIAID’s Vaccine Research Center. Conducted by the NIAID-funded HIV Vaccine Trials Network (HVTN), the Phase IIb study, known as HVTN 505, was designed to determine whether the vaccine regimen could prevent HIV infection and/or reduce the amount of virus in the blood of vaccine recipients who became infected with HIV. (To read more about the trial, see “Initiative for HIV vaccine research funded — Quest for a shot persists,” STI Quarterly supplement, December 2012, p. 1, and “New research may boost AIDS vaccine research,” CTU, October 2010, p. 118.)
The trial was looking at the safety and efficacy of a two-part HIV vaccine regimen consisting of one vaccine designed to prime the immune system, followed by another vaccine designed to boost the immune response. Investigators had enrolled 2,504 HIV-negative men who have sex with men and transgender people who have sex with men at 21 sites in 19 U.S. cities to conduct the study.
“This trial has provided a clear, swift answer about a specific vaccine strategy,” said Mitchell Warren, executive director of AVAC, a New York City-based advocacy and education organization. “It’s not the answer we hoped for, but the search doesn’t end here.”
There are other approaches that must be pursued, and the findings from the HVTN 505 trial will help to focus and guide those efforts, said Warren in a statement following the NIAID announcements. “Researchers need to further investigate the data from the HVTN 505 trial to understand more about why this strategy didn’t prevent infection,” Warren noted.
Take a closer look
The HVTN 505 vaccine regimen involved three immunizations over eight weeks, beginning with a DNA-based vaccine designed to prime the immune system. The DNA priming vaccine was designed with genetic material expressing antigens representing proteins from the surface and internal structures of HIV. Shots of the priming vaccine were followed by a single injection at week 24 with a recombinant vaccine based on a weakened adenovirus type 5 (Ad 5). The adenovirus was used as a vector, or carrier, of genetic material expressing a matching set of HIV antigens. Structures from all three major HIV clades, or subtypes, were included.
Safety experts in an April 22, 2013, independent panel review looked at information gathered from 1,250 volunteers who received the investigational vaccine regimen and 1,244 volunteers who received the placebo vaccine. The primary analysis looked at volunteers who were diagnosed with HIV infection after having been in the study a minimum of 28 weeks. This approach allowed enough time for the vaccine regimen to be given and stimulate an immune response.
In the April 22 analysis, data indicated 27 HIV infections occurred among vaccine recipients, and 21 HIV infections were recorded among those receiving the placebo shot. Among volunteers who became HIV-infected during the first 28 weeks of the study, 14 cases of HIV infection occurred among those who received the investigational vaccine regimen, and nine HIV infections were found among those getting the placebo shot. Looking at all data from the day of enrollment through the month 24 study visit, 41 cases of HIV infection occurred in the volunteers who received the investigational vaccine regimen, and 30 cases of HIV infection occurred among the placebo vaccine recipients.
The safety experts also 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. The analysis found 30 participants with measurable viral load; 15 were vaccine recipients and 15 received the placebo shot.
Researchers are contacting all participants to inform them of the review board’s findings and NIAID’s decision to halt injections. Study 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 placebo injections. Researchers will continue following each participant for five years after their enrollment in the trial. Those who became HIV-infected during the trial have been referred to local health services for appropriate care and treatment.
What’s the next step?
What is the next step in HIV vaccine research, given this new development?
“I view of the early stopping of the HVTN 505 HIV vaccine trial, it is imperative to better define the immune responses that can protect humans from HIV infection and control infection, and then learn how to design a vaccine that can elicit these responses,” says Timothy Mastro, MD, FACP, DTM&H, group director of global health, population & nutrition at FHI 360 in Durham, NC. FHI 360 serves as the coordinating and operations center for the HIV Prevention Trials Network.
Science may be yielding new clues on possible HIV vaccine approaches. In an advance for HIV vaccine research, scientists have now determined how both the virus and a resulting strong antibody response co-evolved in one HIV-infected individual.1 Such findings could help investigators specify which proteins to use to induce antibodies capable of preventing infection from an array of HIV strains. The research team was led by Barton Haynes, MD, director of the Duke Human Vaccine Institute in Durham, NC, and John Mascola, MD, acting director of the National Institutes of Health Vaccine Research Center in Bethesda.
This discovery occurred after scientists identified one of the some 20% of HIV-infected individuals who naturally develop broadly neutralizing antibodies to the virus after several years of infection. The individual was a volunteer in an African study in which participants gave weekly blood samples beginning early in the course of infection. The volunteer joined the study just four weeks after infection and was followed for more than three years.
Because researchers were able to follow the participant from such an early stage, they were able to identify the particular “founder” virus that triggered the immune system to make an immature broadly neutralizing antibody against HIV, as well as the cell from which that antibody emerged. Analyses of the weekly samples also enabled investigators to see the series of changes that the virus and antibody underwent over 2.5 years until the antibody matured to a form capable of potently neutralizing the virus.1
With data in hand, researchers are developing a vaccine that harmlessly mimics the virus at key points in the observed process to generate broadly neutralizing HIV antibodies, first in uninfected animals and then in uninfected people.
“The next step is to use that information to make sequential viral envelopes and test them as experimental vaccines,” said Haynes in statement accompanying the publication of research. “This is a process of discovery, and we’ve come a long way with regard to understanding what the problem has been.”
1. Liao HX, Lynch R, Zhou T, et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 2013; 496(7446):469-476.