By Regina McEnery
Grants Awarded to Establish New Nonhuman Primates Consortia
Researchers from Emory University and the Beth Israel Deaconess Medical Center (BIDMC) were recently selected to lead a five-year, US$60 million effort to use nonhuman primate (NHP) models to better understand events that occur during the earliest stages of mucosal HIV infection. More than 90% of all HIV infections worldwide are sexually transmitted. But, as is likely obvious, studying the earliest stages of HIV transmission is difficult, if not impossible, in humans. So instead, researchers are relying on studying simian immunodeficiency virus (SIV) infection in rhesus macaques.
The US National Institute of Allergy and Infectious Diseases (NIAID) solicited applications for the Consortia for AIDS Vaccine Research in Nonhuman Primates in April 2010 with the goal of establishing a collaborative, multidisciplinary research program to investigate viral and host events at the earliest stages of mucosal infection of NHPs with SIV, and to identify vaccines and vaccine-induced immune responses that can block initial infection, prevent establishment of systemic infection, or significantly reduce the pathogenic effects of SIV. The initial request for applications was for one to two applicants eligible to receive a total of $5 million a year over five years. Then in August 2010, NIAID upped the ante to $8.5 million a year for five years. The grants were then raised again to $12 million a year for five years after NIAID was able to obtain additional funds.
The BIDMC consortium, which comprises nine institutions and will receive about $36 million, is being led by Dan Barouch, chief of the Division of Vaccine Research at BIDMC and R. Paul Johnson, associate professor of medicine at the New England Primate Research Center. The collaborating institutions include Oregon Health & Science University (OHSU), The Scripps Research Institute, the University of Minnesota, the University of Pennsylvania, the Florida-based Vaccine & Gene Therapy Institute at OHSU, the University of Massachusetts Medical School, and SAIC Frederick Inc.
The consortium will work on five projects and six cores designed to elucidate the mechanisms of protection against SIV and an SIV/HIV hybrid known as SHIV in rhesus macaques following administration of vector-based, protein-based, or live-attenuated virus vaccines, as well as monoclonal antibodies.
“The overall goal of our grant is to look at the very early events of acute mucosal SIV infection in monkeys and how different vaccine technologies might be able to block and impede those events,” says Barouch. “No one has looked at such an early point at exactly how vaccines work—whether there are antibodies at the site of inoculation, whether there are mucosal T cells at the site of inoculation, what types of immune responses can block or inhibit the virus, or what kinds of immune responses fail to block the virus.”
Barouch says the BIDMC consortium will not be developing new vaccine technologies but will be investigating the earliest phases of infection at a level of detail and sophistication that has never been done before.
The Emory consortium, which consists of seven institutions and is receiving $26 million, is being led by Eric Hunter, co-director of the Emory Center for AIDS Research and professor of pathology and laboratory medicine at Emory’s School of Medicine. The research will be conducted primarily at the Yerkes National Primate Research Center at Emory. Other collaborators include Louisiana State University Health Science Center, the Mount Sinai School of Medicine, the La Jolla Institute for Allergy & Immunology, and the Nebraska Center for Virology at the University of Nebraska.
The Emory consortium is working on four projects that examine the immunological mechanisms by which adjuvants can enhance SIV-based vaccine candidate induced protection. Hunter says researchers will be looking at two different adjuvants. The first, granulocyte-macrophage colony-stimulating factor (GM-CSF)—a cytokine produced by macrophages, neutrophils, and other immune cells—has already shown promise and is being used in a DNA/MVA-based AIDS vaccine candidate by Georgia-based GeoVax Inc. The other uses toll-like receptor ligands delivered in a novel synthetic nanoparticle formulation. Both are thought to stimulate a more effective immune response through different arms of the innate immune system, though the mechanisms involved are unclear.
Hunter says identifying adjuvants that might enhance the responses of existing vector-based vaccine candidates would be a significant breakthrough for the field, citing the relatively modest 31.2% efficacy observed in the RV144 trial in Thailand as an example. “If one could increase the efficacy of that significantly through adjuvants or modifications in the viral-vector systems, then I think that could really be important in moving the field forward,” he says.
While the BIDMC and Emory consortiums will conduct separate projects, they will be looking for areas of synergy, according to both Hunter and Barouch. “The two are distinct, but there will be close interactions,” says Barouch.
Hormonal Contraception Raises HIV Infection Risk, According to New Study
Results from a study of 3,790 serodiscordant couples from southern Africa provides the strongest evidence thus far that the use of hormonal contraception may also elevate the risk of HIV acquisition, in some instances dramatically (1).
The study, led by investigators from the University of Washington, found the use of both oral and injectable hormonal contraceptives was associated with a doubling of the risk of HIV infection among women, as well as doubling the HIV transmission risk from women to men. While women in the study received either oral or injectable forms of hormonal contraception, the long-lasting, injectable methods were the most commonly used in this study population. Sub-group analyses of just the women who received injectable contraception had a significantly increased HIV infection risk, while an analysis of women using oral contraception showed a non-significant increase in HIV infection risk.
This study isn’t the first to find a link between hormonal contraception and an increased risk of HIV acquisition. “We went into this analysis knowing the previous data had not provided a clear picture,” says study investigator Jared Baeten. “There had been some suggestion of increased risk but not all studies showed this, so we were not sure what we would find.”
The World Health Organization (WHO) will convene a meeting in January to consider whether the evidence suggesting hormonal contraception increases HIV infection and/or transmission risk is now strong enough for them to issue a warning to women.
According to the Guttmacher Institute, a New York City-based non-profit that advances sexual and reproductive health through research, policy analysis, and education, about 12 million women in sub-Saharan Africa use injectable contraceptives and eight million use oral contraceptives. Another 11 million use condoms, sterilization, or intrauterine devices as contraception. Baeten says in some HIV prevention studies of vaccines and other interventions like pre-exposure prophylaxis (PrEP), contraception is “often part of the clinical counseling and clinical repertoire of services,” and he expects hormonal contraception would continue to be offered in these trials. “I think we would be remiss to say that contraception should not be part of clinical care,” adds Baeten.
The serodiscordant couples that were followed in the prospective study were initially enrolled in either the Partners in Prevention HSV/HIV Transmission Study—a randomized, placebo-controlled trial testing whether suppressing herpes simplex virus type 2 (HSV-2) with daily acyclovir prevented HIV transmission among 3,408 serodiscordant couples from Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia—or a parallel immune correlates of protection study, which involved an additional 485 serodisordant couples from Uganda and South Africa.
Baeten says the cohort they followed was much larger than those from previous studies, making the findings more robust. Focusing on serodiscordant couples, according to Baeten, also allowed them to better track HIV transmission between both men and women. This is thought to be the first prospective study to show increased HIV risk in the male partners of HIV-infected women.
But the study was limited by the fact that contraception use was self-reported and investigators didn’t record the specific brand of contraception used, preventing them from being able to draw any conclusions on differences in HIV risk with specific forms of contraceptives. Baeten says preclinical studies have not been able to determine how hormonal contraceptives enhance the risk of HIV, adding that the recent findings were not intended to undermine the importance of contraception.
1. Lancet Infec. Dis. 2011, doi: 1016/S1473-3099(11)70247-X
New Data on How Tenofovir Protects Against Herpes Simplex
The results of the CAPRISA 004 trial, reported in July 2010, showed that a vaginal microbicide gel containing 1% of the antiretroviral tenofovir reduced the risk of HIV infection among women by 39%, and also reduced the incidence of herpes simplex virus (HSV)-2 by 51% in a subset of 450 women from CAPRISA 004, who were not already HSV-2 infected at the start of the trial (see Microbicides Finally Gel, Securing Spotlight at the International AIDS Conference, IAVI Report, July-Aug. 2010). Now, researchers have reported a possible mechanism by which tenofovir inhibits HSV-2 (1).
In the study, researchers tested a 1% tenofovir gel in tissue samples taken from women infected with HSV-2. These experiments showed that tenofovir gel inhibited HSV-2 replication in cells found in epithelial or connective tissue from women, and decreased HSV-2 replication by as much as 99% in lymphoid and cervicovaginal tissue samples. In tissues from mice infected with HSV-2, 1% tenofovir gel also delayed the formations of lesions and even death. Researchers concluded that the active metabolite of tenofovir inhibited both HSV-2 DNA polymerase and HIV reverse transcriptase.
1. Cell Host Microbe 10, 379, 2011
Gates Foundation Names New Head of Global Health Program
Trevor Mundel, the global head of development for Novartis Pharma AG in Switzerland, was named the new director of global health at the Bill & Melinda Gates Foundation, overseeing a portfolio that has awarded more than US$14.7 billion in grants thus far.
Mundel, who assumes his new post Dec. 1, will lead the foundation’s efforts to develop and deliver drugs, vaccines, and other tools to fight diseases such as HIV/AIDS, tuberculosis, and malaria, and to continue progress toward polio eradication. Mundel replaces Tachi Yamada, who retired in June as head of the global health program and is now senior executive in residence at the Seattle-based venture capital firm Frazier Healthcare.
Mundel has been a senior executive and scientist with Novartis since 2003. While at Novartis, he oversaw some 140 clinical projects, a budget of $3 billion, and more than 7,500 employees.
Oral Tenofovir Arm of VOICE Trial Discontinued Early
One arm of the multi-arm Phase IIb test-of-concept VOICE trial designed to test the safety, efficacy, and acceptability of one topical and two oral pre-exposure prophylaxis (PrEP) regimens in more than 5,000 women was discontinued in September after the trial’s independent data safety monitoring board (DSMB) concluded that the study would be unable to show any difference between a daily dose of the antiretroviral (ARV) pill tenofovir (TDF) and placebo in preventing HIV infection.
The remaining arms of the trial, one of which is testing daily administration of Truvada (the single pill combination of TDF and the ARV emtricitabine, or FTC), and another testing the topical administration of a 1% tenofovir gel, will continue in order to determine if they are safe and effective HIV prevention measures for women compared to pill or gel placebo groups. Unlike other large-scale PrEP trials that were recently completed or still ongoing, the VOICE study is the first to evaluate both oral and topical PrEP regimens in the same trial.
The US National Institute of Allergy and Infectious Diseases (NIAID), the primary funder of the trial projected to cost US$100 million, noted that the DSMB found no safety concerns with oral TDF, which is currently used to treat HIV. The VOICE trial is sponsored by NIAID, the Microbicide Trials Network, Gilead Sciences (the manufacturer of tenofovir and Truvada), and CONRAD, a Virginia-based research institute developing contraceptive products and options to prevent HIV and other sexually transmitted infections.
The VOICE trial, which is being conducted at 15 clinical sites in South Africa, Zimbabwe, and Uganda, began in September 2009 and completed enrollment of 5,029 women in June. About 1,000 of the volunteers were randomized to the oral TDF arm.
Michael Chirenje, associate professor in the department of obstetrics and gynecology at the University of Zimbabwe and a principal investigator of the trial, says interpreting the recent results from the oral TDF arm would be a matter of speculation at this point. The trial is due to conclude in June and the study unblinded shortly after, at which point investigators will be able to determine whether volunteers in the oral TDF arm were less adherent to the daily dose of tenofovir than women in the Truvada or microbicide arms.
Still, Chirenje says it is perplexing oral TDF did not seem to work any better than placebo in the VOICE study. A previous trial involving serodiscordant couples found the same regimen was 62% effective at reducing HIV infection risk in men and women. One possible reason for the difference in outcomes for these two studies is demographics, according to Chirenje. HIV-uninfected women enrolled in the VOICE study tended to be in their early 20s and unmarried, perhaps making them less inclined to take their pills faithfully compared to the women in the serodiscordant couples study, whose average age was 36 and who were aware their partners were HIV infected.
“Obviously we are all disappointed and perplexed by the recent results,” says Chirenje. “But in science, we have to accept reality.” Three other trials have found both oral tenofovir and oral Truvada to be effective at preventing HIV infection in serodiscordant couples (see Treatment Is Prevention, IAVI Report July-Aug. 2011) and men who have sex with men. However, another trial, known as FemPrEP, evaluating oral Truvada in women, was discontinued ahead of schedule after the DSMB concluded that it would be highly unlikely to demonstrate any efficacy (see April 18, 2011 IAVI Report blog, Oral PrEP Trial in Women Stopped Early).