Vaccine Briefs

HVTN 505 Trial Expanded to See if Vaccine Candidates Can Block HIV Acquisition

By Regina McEnery

The US National Institute of Allergy and Infectious Diseases (NIAID) is expanding a Phase II trial, known as HVTN 505, testing the safety and efficacy of a DNA/Ad5 prime-boost regimen to determine whether the two vaccine candidates developed at the Vaccine Research Center (VRC) at NIAID are capable of protecting against HIV infection.

The trial, which was launched in 2009, was initially designed based on a single endpoint—whether the prime-boost regimen was able to decrease set point viral load in volunteers who became HIV infected despite vaccination (see Vaccine Briefs, IAVI Report, July-Aug. 2009). Adding protection against infection as an additional endpoint will result in significant change in enrollment in the HVTN 505 trial. The trial was originally designed to enroll 1,350 circumcised, HIV-uninfected men who have sex with men (MSM) or transgendered women who have sex with men with no pre-existing immunity to adenovirus serotype 5 (Ad5), a commonly circulating strain of the cold virus that is used as a vector in one of the two vaccine candidates. Now investigators aim to enroll 2,200 participants—the number of volunteers that is estimated to be needed in order to determine whether the vaccine regimen is at least 50% effective at preventing HIV acquisition 18 months following immunization—at 21 sites in 18 US cities at an expected overall cost of between US$75million and $80 million. So far, investigators have already enrolled more than 1,173 volunteers.

The prime-boost regimen being tested in HVTN 505 involves three vaccinations with DNA encoding HIV clade B Gag, Pol, and Nef, and Env from HIV clades A, B, and C, followed by an Ad5 vector-based vaccine candidate encoding clade B Gag and Pol, and Env from clades A, B, and C.

Carl Dieffenbach, director of the Division of AIDS (DAIDS) at NIAID, says the expanded trial is a positive step for the field, but he cautioned observers to keep the scope of the trial and where it might lead in perspective. “We have to be careful that we continue to put this forward without trying to over-promise,” he says.

The evolution of the HVTN 505 trial reflects a dizzying series of changes that have largely been driven by the outcomes of two other efficacy trials: the STEP trial of Merck’s MRKAd5 candidate, another Ad5 vector-based vaccine that produced a disappointing outcome in the fall of 2007, and the RV144 trial that tested a canarypox vector-based candidate in combination with a protein boost and energized the AIDS vaccine field two years later when it yielded the first evidence of vaccine-induced protection against HIV.

A much earlier version of HVTN 505 known as PAVE 100 was slated to begin enrolling 8,500 HIV-uninfected men and women at multiple study sites in the Americas and southern and eastern Africa just a week after results showed that MRKAd5 failed to show any efficacy in the STEP trial. Further analysis of the STEP trial indicated that male volunteers who received the vaccine candidate had a higher risk of acquiring HIV if they were uncircumcised and had pre-existing immunity to the Ad5 vector. This prompted NIAID to shelve the original PAVE 100 design in favor of a smaller trial focused only on viral load set point, and to only enroll circumcised men with no pre-existing Ad5 immunity (see PAVEing the Way to a Smaller Trial, IAVI Report, July-Aug. 2008).

This trial, which became known as HVTN 505, faced additional challenges, however. Despite a much smaller enrollment target, the study struggled to find volunteers, prompting investigators to turn to social media sites and online classified sites such as craigslist to try and attract participants (see Vaccine Briefs, IAVI Report, Mar.-Apr. 2010).

Then, when the RV144 trial, jointly funded by NIAID and the US Army, delivered unexpectedly encouraging results, NIAID decided to take a closer look at the immune responses elicited by its other HIV vaccine candidates in clinical trials.

Results from a series of nonhuman primate studies influenced the decision to expand the HVTN 505 trial, says Dieffenbach. Animal data showed that about half of rhesus macaques given a simian immunodeficiency virus (SIV) vaccine regimen similar to the HIV vaccine regimen used in the HVTN 505 trial were protected against SIV following SIVsmE660 challenge, and that a low level of neutralizing antibodies to Env, and an Env-specific CD4+ T-cell response correlated with this protective effect (see Research Briefs, IAVI Report, May-June 2011).

Dieffenbach says the large number of animals (129 macaques) used in the study, and the fact that the protection occurred in the presence of robust cellular responses and low levels of SIV-neutralizing antibodies, suggested that the HVTN 505 regimen could have the capacity to prevent HIV acquisition in people. “You are only as good as the data you have in front of you,” says Dieffenbach, reflecting on the expansion of the HVTN 505 trial. “We [haven’t had] many efficacy trials and if we have the opportunity and there is plausibility, we need as a field to take a chance.”