HVTN 505: “A hard blow”
It’s probably a bit of an understatement to say vaccine researchers were disappointed yesterday, when they heard about the discontinuation of HVTN 505, a clinical trial that tested the efficacy of a DNA/Ad5 prime-boost vaccine regimen in about 2,500 people. When the trial was stopped, there was no significant difference in HIV infections between those who received the candidate vaccines and the placebo recipients. Beyond that, there was a—statistically insignificant—trend towards more infections among the vaccinated (see previous blog postby Regina McEnery).
“It’s a hard blow,” said Scott Hammer of Columbia University, the principal investigator of the trial. “There is no sugarcoating it, it’s a disappointment, but I think we got a clear cut answer to the questions asked. We need to be humble in this field. We need to modulate our responses both to positive results and negative results, take the science and move on.”
Others involved in the trial were as crestfallen. “It’s a very disappointing result, and a surprising result for me, because I really thought there’d be more biological activity,” said Barney Graham of the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID), who has been working on the project for 11 years. “It’s one of the big things I came here to the VRC to work on.”
The trend towards more infections among vaccine recipients raises questions. “People will look at the increased numbers of infections in the vaccine arm and say, is this statistically insignificant finding truly insignificant, or is it really telling us something?” Hammer said.
NIAID director Anthony Fauci echoed that concern. “The trend is the issue that’s a little bit disturbing,” he said. The HVTN 505 vaccine regimen used a DNA prime, and a boost that employed adenovirus serotype 5 (Ad5) as a vector. Ad5 was also used in Merck’s MRKAd5 vaccine in the Step trial, which led to an increased risk of HIV acquisition in a subgroup of vaccinees who were uncircumcised and had pre-existing Ad5 antibody immunity.
But the reasons for the trend in HVTN 505 are likely different from those responsible for the phenomenon in the Step trial, researchers said. That’s because the kinds of individuals who showed a higher risk of infection in Step were excluded in HVTN 505. “We took precautions given the Step results to enroll people who were not at any increased risk,” Hammer said.
This, he said, raises a question: what else could be responsible for the trend towards more infections among vaccine recipients in 505. “Is that a signal that there is some mechanism going on that we haven’t figured out? Is there a problem with an Ad5 vector in an Ad5 negative population which we didn’t expect?”
It also raises questions about the use of Adenovirus-based vectors in general. “I think we would have to seriously say that we can’t go any further with Adeno 5 vectors,” Fauci said. “What impact it’s going to have on other Adeno vectors is going to depend on what we find out regarding studying and following up on these [HVTN 505] patients.”
To be sure, there were many differences between the vaccine regimens used in Step and HVTN 505: Unlike MRKAd5, the HVTN 505 vaccine regimen involved a DNA prime preceding the Ad5 boost, and used an Ad5 that caused less Ad5-specific immune responses.
And unlike MRKAd5, the HVTN 505 candidate contained HIV Envelope as an immunogen. This, researchers had hoped, might enable the HVTN 505 candidate regimen to induce protection against HIV. Previous studies, Hammer said, have shown that the HVTN 505 candidate produces a lot of Env-binding antibodies but is weak on broadly cross-reactive neutralizing antibodies.
The negative result of HVTN 505 now suggests that this was insufficient to induce protection. “Having Envelope-binding antibodies per se is not enough,” Hammer said. “It puts the focus again on not just any antibody, but antibodies that will neutralize or be involved in other immune-defensive things like ADCC [antibody-dependent cellular cytotoxicity].”
The negative 505 result will likely bolster those in the field who advocate the use of immunogens that elicit broadly neutralizing antibody responses, even as it weakens advocates of vectors that induce T-cell responses, a direction the field has taken already, said Nelson Michael, director of the US Military HIV Research Program, who was not involved in the 505 study.
The work to better understand the results of HVTN 505 is only just beginning. For example, it will be interesting to study how immune responses correlate with infection risk after just the DNA primes versus after the Ad5 boost, Michael said. Studying the immune responses in 505 might also give clues to whether there are certain immune responses that aren’t as important for protection. “That might tell us that there are immune responses we should probably not be as enthusiatic about,” Michael said. A so-called sieve analysis will also be interesting, Hammer said, because it will tell researchers if the vaccine put any pressure on the kinds of viruses that were able to infect vaccine recipients.