Following the encouraging results from the recent Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial that demonstrated that vaginal application of a microbicide gel containing 1% of the antiretroviral tenofovir, which is used in the treatment of HIV, reduced the HIV incidence in 889 South African women by 39%, researchers are planning two confirmatory trials that could potentially lead to licensure of the microbicide candidate (see VAX September 2010 Spotlight article, Microbicides Finally Gel, Securing Spotlight in Vienna).

Researchers now hope to be able to replicate the results of CAPRISA 004 in a confirmatory trial involving 3,000 women enrolled at six clinical research centers in South Africa. The trial known as FACTS 001 will evaluate the same dosing regimen tested in the CAPRISA 004 trial, pending approval by South African regulatory authorities. Women in CAPRISA 004 received regular HIV prevention counseling and were instructed to apply the gel up to 12 hours before sex and as soon as possible following sex, but within 12 hours, a regimen referred to as BAT24. Eligibility criteria for enrollment in the FACTS 001 trial will be expanded to include girls ages 16 and 17 because they are considered to be at high risk of HIV infection through heterosexual sex. Salim Abdool Karim, director of CAPRISA, says he hopes to begin the confirmatory trial in early 2011, with results expected in 2013.

A second confirmatory trial is also being planned to determine whether a single dose of the microbicide gel around the time of intercourse is sufficient to protect against HIV. A trial referred to as MDP 302 will compare the efficacy of the CAPRISA 004 BAT24 dosing regimen with one dose of tenofovir gel right before sexual intercourse or, failing that, as soon as possible after intercourse. Plans are to enroll 3,750 women from up to five African countries, including Uganda, Tanzania, and Mozambique.

The South African Department of Science and Technology and the US Agency for International Development (USAID), which together funded CAPRISA 004, will provide most of the funding for FACTS 001. The MDP 302 trial will be partly funded by the Medical Research Council in the UK, with other funding sources to be determined.

Other follow-up studies will determine the best way to deliver the microbicide and how tenofovir gel use impacts the safety and effectiveness of oral tenofovir for HIV treatment. —Regina McEnery

A Phase I trial designed to test the safety of two vaccine candidates and their ability to induce immune responses to HIV recently began at Brigham and Women’s Hospital in Boston. Vaccinations of volunteers in the trial, known as IAVI B003/IPCAVD-004, began in October, following approval by the US Food and Drug Administration and Harvard’s institutional review board. Pending regulatory approval, investigators will also enroll additional volunteers for the trial in Africa. The overall goal is to enroll approximately 212 HIV-uninfected individuals at low risk of HIV infection at as many as six clinical research centers.

The two vaccine candidates use different types of adenovirus (Ad26 and Ad35), a common cold virus, as a vector to deliver non-infectious HIV genes into the body with the goal of inducing an immune response against HIV. The two candidates will be tested either in combination or alone. One candidate, referred to as Ad26.ENVA.01, was developed by Dan Barouch, an associate professor of medicine at the Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, and manufactured by the Dutch biopharmaceutical company Crucell. The other, referred to as Ad35-ENV, was developed by IAVI and manufactured by the French biopharmaceutical company Transgene.

Data from ongoing clinical trials that were presented at the recent AIDS Vaccine 2010 conference in Atlanta suggest that both Ad26 and Ad35 candidate vaccines are safe and immunogenic.

The trial is a joint effort by IAVI, BIDMC, the Ragon Institute, Harvard University, Massachusetts Institute of Technology, the National Institute of Allergy and Infectious Diseases’ (NIAID) Division of AIDS (DAIDS), the HIV Vaccine Trials Network (HVTN), and Crucell. It is funded by the HVTN, DAIDS, the Ragon Institute, and IAVI. —Andreas von Bubnoff

Researchers are looking at new methodologies to make late-stage efficacy trials more flexible and faster

Before AIDS vaccine candidates can be approved and licensed for use, their safety and efficacy must be demonstrated in a series of animal and human studies. The process begins with animal studies and then small Phase I clinical trials that are primarily conducted to assess the safety of the vaccine candidate in humans.

The most promising candidates are eventually tested in larger clinical trials that are designed to determine the efficacy of the vaccine candidate. These trials are typically Phase IIb test-of-concept trials or even larger Phase III efficacy trials (see VAX September 2005 Primer on Understanding Test-of-Concept Trials). Only a handful of efficacy trials have been conducted for HIV vaccine candidates so far, and until recently, none of them yielded positive results. This changed in 2009 when the results from the RV144 trial in Thailand, involving 16,000 volunteers, provided the first evidence of protection against HIV infection through vaccination.

Following these results, many AIDS vaccine researchers and advocates are calling for more clinical trials and more efficient ways of conducting them. The Global HIV Vaccine Enterprise, a research alliance formed in 2003 to accelerate development of an AIDS vaccine, called for the exploration of new approaches to conducting clinical trials in its 2010 Scientific Strategic Plan, launched this September. And at the recently held AIDS Vaccine 2010 conference in Atlanta, there was extensive discussion about alternate clinical trial designs. One approach being promoted by the HIV Vaccine Trials Network, a leading sponsor of AIDS vaccine trials around the world, is a so-called adaptive clinical trial design that can test multiple candidates simultaneously, comparing them to the same placebo group in a randomized, blinded, Phase IIb trial to see if they are able to prevent HIV infection (see VAX October-November 2007Primer on Understanding Randomized, Controlled Clinical Trials). Adaptive trials allow investigators to modify the trial while it’s underway, giving them more flexibility to drop candidates that don’t seem to be working. This type of trial design would not allow for a direct comparison of different vaccine candidates, but it would allow investigators to rank the different candidates based on how well they work.

More nimble trials

So how would the methodology used in adaptive trials differ from that used in earlier AIDS vaccine efficacy trials? In the late-stage vaccine trials conducted thus far, such as RV144 or the STEP trial, a Phase IIb trial of Merck’s HIV vaccine candidate MRKAd5, the efficacy of each vaccine regimen was evaluated by comparing its effectiveness among vaccinated volunteers to that of placebo recipients. The trials were blinded—meaning volunteers were not aware during the trial whether they had received the vaccine or the placebo—but Data Safety Monitoring Boards (DSMB) collected and analyzed safety and efficacy data at pre-specified time points during the course of the trials and could then determine whether the trials should continue or be stopped either for safety reasons or for futility if there was no evidence the vaccine candidate was working. An interim analysis conducted during the STEP trial is what led the trial’s DSMB to recommend stopping immunizations because the data suggested the vaccine candidate was not effective.

But aside from halting a study for safety or futility reasons, AIDS vaccine researchers have had limited ability to respond immediately to any of the interim data. This means that every trial has gone to completion, or near completion in the case of the STEP trial. However, with adaptive clinical trials, more frequent interim analyses could allow investigators to identify promising candidates more quickly and weed out those with no apparent benefit.

If the interim data indicates that a vaccine candidate is clearly not meeting pre-determined efficacy levels, researchers have the flexibility to shrink or drop that arm of the study while continuing the others. For instance, in a trial population with a 4% annual HIV incidence rate and 2,000 volunteers per group, it would be possible to reach a decision point on whether a vaccine candidate is working in approximately 20 months, as long as volunteers are rapidly enrolled in the trial. If this type of adaptive trial design was employed in past efficacy trials, RV144 could have been stopped two-and-a-half years earlier and the STEP trial could have been stopped nine months earlier, according to researchers.

One important caveat of adaptive clinical trials is that they are not suitable for licensure. That means that the results from an adaptive clinical trial could not be submitted to a regulatory body to serve as the basis of getting the vaccine licensed for use. The more frequent interim data analyses that are conducted in adaptive trials, and the flexibility that researchers will have to respond to the data, reduce the overall power of the study, making it more difficult to interpret the results. For that reason, adaptive trials are meant to serve more as a research tool that allows investigators to rapidly prioritize candidates for further study. Those that show promise could then be tested in much larger, more stringently designed clinical trials that could serve as the basis for licensure.