Trials Planned to Confirm Efficacy of Tenofovir Microbicide Gel
Following the results from the recent Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial, which demonstrated the first statistically significant reduction in HIV infection from a microbicide candidate, researchers are planning two confirmatory trials that could lead to licensure of the gel.
At the International AIDS Conference in Vienna in July, researchers reported that vaginal application of a 1% gel formulation of the antiretroviral (ARV) tenofovir in 889 South African women ages 18-40 at high risk of HIV infection reduced HIV incidence by 39% after 30 months of use, with efficacy as high as 50% after 12 months (seeMicrobicides Finally Gel, Securing Spotlight at the International AIDS Conference, IAVI Report, July-Aug. 2010). Researchers also found that the tenofovir-based microbicide gel reduced the incidence of herpes simplex virus (HSV)-2 by 51% in a subset of women who weren’t already infected with HSV-2 at the start of the study.
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 confirmatory trial known as FACTS 001, which is still pending approval by South African regulatory authorities, will evaluate the same BAT24 dosing regimen tested in the CAPRISA 004 trial—women are counseled to apply the gel up to 12 hours before sex and as soon as possible following intercourse but within 12 hours. 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. FACTS 001 would also add prevention of HSV-2 as an endpoint. 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 considered with the aim of determining whether two doses are necessary to reduce the risk of HIV infection or whether a single dose around the time of intercourse is sufficient. This trial, referred to as MDP 302, will compare the efficacy of the CAPRISA 004 BAT24 dosing regimen with a simplified regimen of one dose of tenofovir gel right before sexual intercourse or, failing that, as soon as possible after intercourse. Some clinicians and public health researchers in South Africa are concerned that a stricter dosing schedule may prove to be impractical in a real-world setting, undercutting the effectiveness of this intervention. There was some indication that adherence to the BAT24 regimen waned over the course of the CAPRISA 004 trial. The single-dose regimen is also less expensive. Plans are to enroll 3,750 women from up to five African countries, among them, 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 be providing the bulk of the funding for the FACTS 001 trial. “There’s still a shortfall so there’s an ongoing effort to raise those funds,” says Karim. The MDP 302 trial will be partly funded by the Medical Research Council in the UK, with other funding sources to be determined.
Additionally, researchers are planning two follow-up studies to determine the best way to deliver the microbicide gel and the effects of tenofovir gel use on the safety and effectiveness of oral tenofovir when used to treat HIV. —Regina McEnery
Phase I Trial of Adenovirus-based Prime-boost Regimen Begins in Boston
A Phase I trial to test the safety and immunogenicity of an adenovirus (Ad) serotype 35 vector-based vaccine candidate with an Ad26 serotype vector-based candidate in a prime-boost combination is now underway at Brigham and Women’s Hospital in Boston. Both of the candidates express HIV clade A env genes. The Ad26.ENVA.01 candidate was developed by Dan Barouch, an associate professor of medicine at the Beth Israel Deaconness Medical Center (BIDMC) and Harvard Medical School, and manufactured by the Dutch biopharmaceutical company Crucell. The Ad35-ENV candidate was developed by IAVI and manufactured by the French biopharmaceutical company Transgene. Volunteers will receive two injections, administered either three or six months apart, of Ad26.ENVA.01 as a prime followed by Ad35-ENV as a boost or vice versa, or repeated vaccinations with one of the two vaccine candidates.
Vaccinations of volunteers in the trial in Boston, 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.
“[This] will be the first-in-human evaluation of homologous and heterologous Ad26 and Ad35 regimens in multiple regions of the world, including target populations in Africa,” says Barouch, who leads the Integrated Preclinical/Clinical AIDS Vaccine Development program (IPCAVD) team that is developing novel Ad vectors as HIV vaccine candidates. A heterologous Ad26/Ad5 prime-boost vaccine regimen was shown to enhance the magnitude and breadth of cellular immune responses as compared with a homologous regimen in nonhuman primates (Nature 457, 87, 2009). Nonhuman primate studies show the Ad35/Ad26 prime-boost regimen induces a high frequency of antibody and T-cell responses, according to Barouch, who said data from protective efficacy studies in monkeys is expected early next year.
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. Preliminary results of IAVI B001, a double-blind, placebo-controlled, randomized Phase I trial involving 56 volunteers showed that combined vaccination with the clade A Ad35-ENV and an Ad35 vector expressing a fusion protein consisting of parts of HIV subtype A genes gag, reverse transcriptase, integrase, and nef (referred to as GRIN) at three different doses was safe and immunogenic, according to Michael Keefer, the principal investigator of B001. In Atlanta, Barouch presented preliminary results of a Phase I trial called IPCAVD 001, which is testing the safety and immunogenicity of Ad26.ENVA.01 in 60 volunteers in Boston. He says results so far suggest that “the vector is safe and immunogenic at all doses tested.”
According to Barouch, the Ad26 and Ad35 vectors to be used in IAVI B003/IPCAVD-004 are biologically very different from Ad5, the vector used in the MRKAd5 vaccine candidate, developed by Merck, which failed to induce any protection or control of virus in the Phase IIb STEP trial. Results from the STEP trial showed that uncircumcised, vaccinated male volunteers who had preexisting antibody immunity to naturally circulating Ad5 were at increased risk of HIV acquisition (see A Change of Tune, page 4). Individuals with preexisting immunity to Ad26 or Ad35 will be eligible to enroll in B003, according to IAVI. “Given the major biological differences among these Ad vectors, it is not at all clear whether findings with Ad5 from the STEP study will be applicable for biologically very different Ad vectors such as Ad26 and Ad35,” Barouch says. In addition, fewer people have preexisting immunity to Ad26 and Ad35 and at lower titers than to Ad5, he adds. The B003 trial will only enroll individuals at low risk of HIV infection, said IAVI’s Chief Medical Officer Pat Fast, and the goal of the trial is to advance the development of a vaccine applicable to the general population.
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, the HIV Vaccine Trials Network (HVTN) and Crucell. It is funded by the HVTN, NIAID’s Division of AIDS, the Ragon Institute, and IAVI. —Andreas von Bubnoff
Gates Foundation Announces New Round of CAVD Grants
The Collaboration for AIDS Vaccine Discovery (CAVD), an international network launched in 2006 by the Bill & Melinda Gates Foundation to accelerate the development of an AIDS vaccine, recently issued a new request for proposals (RFP).
The HIV vaccine approaches being considered within this RFP include: HIV vaccines for containment at portal of entry, novel HIV vaccines to elicit protective antibodies, replicating viral vectors for an HIV vaccine, and passive immunization with human monoclonal antibodies for HIV prevention. The CAVD awards will range from US$500,000 to $3 million per year, per grant, over approximately three years. Additional funding may be awarded to successful projects that are on a clear product development pathway.
Letters of inquiry can be submitted through March 31, 2011. Grants will be awarded from June 2011 through June 2012. For more information on the grants, visit www.cavd.org. —Regina McEnery
NIAID Unveils Plans for CHAVI 2.0
At the AIDS Vaccine Research Subcommittee Meeting of the US National Institutes of Health (NIH), which was held Sep. 21-22 in Rockville, Maryland, plans were unveiled for the second iteration of the Center for HIV/AIDS Vaccine Immunology (CHAVI), a virtual research consortium established five years ago by NIAID to coordinate research and promote big science efforts to overcome roadblocks to HIV vaccine development.
The second iteration of CHAVI, called CHAVI Immunogen Design (ID), will focus on understanding why broadly neutralizing antibodies are not readily induced, dissecting the interplay between innate and adaptive immune responses, rapidly translating new knowledge into novel immunization approaches, and finally moving these approaches into clinical trials. “Clearly the focus is on prevention of acquisition [of HIV],” said Peggy Johnston, director of the Vaccine Research Program in NIAID’s Division of AIDS.
NIAID is seeking US $31.5 million for CHAVI-ID in 2012, including up to $20 million in direct costs for the first fiscal year, though this amount could change based on the final NIAID budget. This is about $15 million less in total costs ($10 million less in direct costs) than what was allocated annually to CHAVI beginning in 2005. Still, the award is the largest single grant administered by NIAID for AIDS vaccine research.
CHAVI-ID will be awarded for seven years, but this time it may be divided into two awards. NIAID says the decision about whether to fund one or two awards will be made during the peer review process of the CHAVI-ID applications. NIAID says a new request for applications (RFA) for the second generation CHAVI should be formally announced within six to eight months.
The current CHAVI is led by Barton Haynes, who also directs the Human Vaccine Institute at Duke University. CHAVI’s network is comprised of more than 60 investigators at 28 institutions in Africa, Europe, Australia, and North America. —Kristen Jill Kresge