When the trial that came to be known as HVTN 505 began in 2009, it had a single endpoint: a decrease in the 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 in 2011 resulted in a 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). That is the commonly circulating strain of the cold virus that was used as to construct the vector bearing one of the two vaccine candidates.
The trial was expanded to include 2,200 participants because that many participants would be required to determine whether the vaccine regimen was at least 50% effective at preventing HIV acquisition 18 months following immunization. The trial is estimated to have cost between US$75million and $80 million.
The investigational HIV vaccine regimen involved a series of three immunizations over the course of eight weeks, beginning with a DNA-based vaccine designed to prime the immune system, followed by an Ad5 vector-based vaccine candidate. The vaccine regimen was designed to be broad-based, providing coverage across multiple subtypes or HIV clades. The DNA vaccine candidate included Gag, Pol, Nef and Env inserts from three major HIV subtypes–A, B and C. The Ad5 vector-based candidate included Gag and Pol inserts from HIV subtype B and Env from HIV subtypes A, B and C.
When the decision was made in 2011 to expand the trial, Carl Dieffenbach, director of the Division of AIDS (DAIDS) at NIAID, 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 said at the time.
The evolution of the HVTN 505 trial was 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. The latter study 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 statistically significant elevated 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 enroll only 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. 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. 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).
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 to researchers that the HVTN 505 regimen could have the capacity to prevent HIV acquisition in people.
But just like the vaccine candidate tested in the Step trial, which moved forward based in part on encouraging animal data, the regimen used in the HVTN 505 trial has also proved to be a disappointment.
It is unclear what the impact will be on ongoing AIDS vaccine trials, particularly ones that include adenovirus viral vector vaccine candidates. Most such trials are in the early stage of clinical development.
While the findings are a blow to the field, there are two other large efficacy trials in the works that are slated to begin around 2015. Those trials are being headed by the Military HIV Research Program, which was also an organizer of the RV144 trial of 16,000 participants in Thailand.
The PrEP factor
The HVTN 505 trial was also the first to have to grapple with the emerging use of a biomedical strategy known as pre-exposure prophylaxis or PrEP. The strategy involves the administration of antiviral drugs prior to exposure to reduce HIV transmission.
Several years ago, the results of a large-scale international study known as iPrEx, which was conducted in MSM, revealed that Truvada—a combination of the ARVs tenofovir and emtricitabine—was 44% effective in preventing HIV infection among nearly 2,500 men and transgendered women who have sex with men. The study, which was conducted in six countries including the US, prompted Truvada’s maker, Gilead Sciences, to apply for regulatory approval from the US Food and Drug Administration (FDA) to expand the use of ARV as a therapy to prevent HIV acquisition, making it the first antiretroviral drug to be considered for such use. Last July, the FDA approved the use of Truvada for HIV prevention.
Even before the FDA’s decision however, and shortly after the results of the iPrEx study were unveiled in November 2010, the HVTN consulted nearly 800 trial participants, scientists, community leaders, and other stakeholders to determine whether PrEP should be offered to some or all of the enrollees in the HVTN 505 trial and, if the drug were offered, how participants should be monitored during and after the trial.
While studying the effect of the vaccine candidate remained the main focus of the study, trial organizers decided to begin providing volunteers information about PrEP in periodic risk-reduction counseling sessions that are standard in HIV prevention trials. They also decided to monitor PrEP use among trial participants in two different ways. Trial participants who voluntarily chose to use PrEP were asked to report their PrEP use on a regular basis. To supplement this self-reporting tool, trial sites have also been analyzing the blood plasma levels of volunteers in order to obtain additional data on PrEP use among participants.
Those data will, presumably, also be released in the coming months.