Phase II Prime-Boost Trial Begins in the US
A Phase II trial testing the safety and efficacy of a DNA/Ad5 prime-boost regimen of two vaccine candidates developed at the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID) recently began enrolling volunteers. The trial, which is sponsored by NIAID and is being conducted by the HIV Vaccine Trials Network (HVTN), is referred to as HVTN 505. Researchers aim to enroll 1,350 men who have sex with men (MSM) at 15 sites in 12 US cities.
The VRC prime-boost regimen involves three vaccinations with DNA encoding HIV clade B Gag, Pol, and Nef, and Env from HIV clades A, B, and C, followed by a vaccination with an adenovirus serotype 5 (Ad5) vector encoding clade B Gag and Pol, and Env from clades A, B, and C. The HVTN 505 trial will evaluate the safety of the prime-boost regimen, as well as its ability to decrease set point viral load in volunteers who become HIV infected despite vaccination.
The study is not powered to detect whether the prime-boost regimen can prevent HIV infection altogether. The VRC candidates being evaluated in HVTN 505 were originally slated to be tested in a much larger Phase IIb test-of-concept trial known as PAVE 100, involving 8,500 HIV-uninfected men and women from North and South America and Africa. But in 2007, after another Ad5-based candidate developed by Merck—known as MRKAd5—failed to prevent transmission of HIV or slow disease progression in vaccinated volunteers, the start of PAVE 100 was postponed. The protocol for this trial then went through a number of revisions before NIAID settled on the current version.
Results 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 antibodies against the Ad5 vector as compared to placebo recipients with the same characteristics. Based on these results, only circumcised MSM with no pre-existing antibodies against Ad5 will be eligible to enroll in HVTN 505. “We are deeply committed to the population that we are hoping to recruit for this trial,” says Scott Hammer, study chair of the HVTN 505 trial. “We know we are asking a major commitment of them and we will do our part to provide them with counseling and education about vaccines and make sure that they are fully aware of the STEP trial results.”
Alan Fix, chief of the Vaccine Clinical Research Branch at the US National Institutes of Health, says there are a number of differences between the regimen being assessed in HVTN 505 and MRKAd5. In the STEP trial, volunteers received three doses of the Ad5-based vaccine candidate, whereas in HVTN 505 they will receive only one dose of the Ad5 candidate as a boost, following three immunizations with the DNA candidate. And MRKAd5 did not contain HIV Env, whereas the VRC’s DNA and Ad5 candidates both encode HIV Env. There are also differences between the Ad5 vectors used in the STEP and HVTN 505 trials, not just the immunogens. “We don’t know if this vaccine, with its similarities and differences from the Merck vaccine, will behave the same way,” says Fix, which is why researchers have decided to restrict the study population for HVTN 505. The prime-boost regimen is not being evaluated for future commercial licensure, according to Fix.
The Fenway Community Health Center in Boston is one of the research centers now screening volunteers for the HVTN 505 trial. Ken Mayer, principal investigator at this site, says the informed consent documents include information about the STEP trial results and community information forums are being held to help potential participants understand the trial and put the results in their proper context. “While we hope to be vaccinating people very soon, it’s been an intense screening process,” says Mayer. Other sites are also holding town hall meetings in the coming months to clarify any questions regarding participation in HVTN 505. —Regina McEnery
South African AIDS Vaccine Initiative Launches Phase I Trial
The South African AIDS Vaccine Initiative (SAAVI) commemorated the launch of the South African arm of a Phase I AIDS vaccine trial at the Emavundleni Prevention Centre in Cape Town on July 20. The purpose of the trial is to evaluate the safety and immunogenicity of a prime-boost regimen, comprised of a DNA plasmid vaccine candidate followed by a modified vaccinia Ankara (MVA) vector-based candidate, developed by researchers in South Africa.
The trial, known as SAAVI102/HVTN 073, is being conducted in collaboration with the HIV Vaccine Trials Network (HVTN) and the National Institute of Allergy and Infectious Diseases (NIAID) at the US National Institutes of Health (NIH).
Researchers plan to enroll 36 volunteers at two clinical research centers in South Africa—the Emavundleni Prevention Centre and Chris Hani Baragwanath Hospital in Soweto. Twelve volunteers have already been successfully enrolled and vaccinated in the US arm of the study, which is being conducted at the Fenway Community Health Center in Boston.
The DNA vaccine candidate was constructed in South Africa using a plasmid provided by the Vaccine Research Center at NIAID and the MVA candidate was developed by researchers at the University of Cape Town with funding from SAAVI and the NIH. Both candidates were manufactured in the US and carry HIV clade C antigens. “We wanted to have a vaccine based on the subtype of the virus that circulates in South Africa,” said Anna-Lise Williamson, of the University of Cape Town, who led the development of the vaccine candidates and remarked on the significance of this. “We’re seen as the place to test vaccines, now we’ve developed one,” she said. “It usually happens the other way around.”
SAAVI is the lead program of the South African Medical Research Council (MRC) and was established by the South African government and the energy supply company Eskom in 1999 to coordinate the development of an HIV vaccine for southern Africa. Anthony Mbewu, president of the MRC, called the launch of this trial a “scientific milestone,” which he said “ensures that South Africa will be better able to design and develop vaccines against infectious agents in the future.”
Anthony Fauci, director of NIAID, said that scientists in South Africa received more NIAID funding last year than any other country outside the US. “You have the intellectual capital and people who are passionate about health, especially in the arena of HIV/AIDS,” he said. Fauci also mentioned the “extensive challenges” facing AIDS vaccine researchers.
Despite these challenges, many speakers noted the importance of continuing AIDS vaccine research. “The cost of [HIV] treatment is very high,” said Naledi Pandor, the South African Minister of Science and Technology. “I therefore cannot overstate the importance of the development of a vaccine for the South African population.”
“While we have the biggest antiretroviral roll out program in the world, vaccines are the best way to control infectious diseases,” said Williamson. —Kristen Jill Kresge
Tracking Spending on Vaccine, Microbicide, and PrEP Research and Development
Funding levels for AIDS vaccine research declined last year for the first time since 2000, most notably within the pharmaceutical industry, according to the HIV Vaccine and Microbicide Resource Tracking Working Group, which released a report at the 5th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention, held July 19-22 in Cape Town. The resource tracking group says, however, that over the past nine years investment in all experimental biomedical prevention strategies, including vaccines, has increased. The AIDS Vaccine Advocacy Coalition (AVAC), the Alliance for Microbicide Development, the Joint United Nations Programme on HIV/AIDS, and IAVI helped collect the figures and compile the report, which is available online atwww.hivresourcetracking.org.
According to the report, US$1.2 billion was spent in 2008 on HIV prevention research—$868 million for AIDS vaccine research and development, $244 million for microbicides, and close to $44 million for the study of pre-exposure prophylaxis (PrEP)—administration of antiretrovirals in an effort to block HIV infection. Spending on AIDS vaccine research fell 10% from 2007, while research for microbicides and PrEP rose by 8% and 13% respectively. The report cites shifts in scientific priorities and the likely influence of the global financial downturn as contributing factors to the decline in vaccine research and development funding. The cessation of immunizations in late 2007 in the STEP and Phambili trials, which were testing a candidate vaccine developed by Merck, ended one of the pharmaceutical company partnerships for HIV vaccine research and development.
Kevin Fisher, policy director at AVAC, says the estimates were drawn from a range of sources, including one-on-one interviews and publicly available information on clinical trials and spending by public agencies like the National Institute of Allergy and Infectious Diseases that support research and trials. —Regina McEnery