Phase I Trial of Novel HIV Vaccine Candidate Prime-boost Regimen Starts in Africa
Vaccinations in a Phase I clinical trial known as B002 that is designed to test the safety and immune responses induced by two HIV vaccine candidates administered either simultaneously or in a prime-boost regimen began in February at a clinical research center run by the Kenya AIDS Vaccine Initiative (KAVI) in Nairobi. The two vaccine candidates being tested in this double-blind, placebo-controlled, randomized trial are an adenovirus (Ad) serotype 35 vector-based candidate expressing HIV subtype A genes gag, reverse transcriptase, integrase, and nef(referred to as Ad35-GRIN), and an adjuvanted protein vaccine that contains a fusion protein comprising HIV subtype B p17, p24, Rev, and Nef antigens.
IAVI, the trial’s sponsor and the developer of the Ad35 candidate, will conduct additional arms of the B002 trial in Entebbe and Masaka, Uganda, and in Lusaka, Zambia, with plans to enroll approximately 140 HIV-uninfected volunteers between the ages of 18 and 40. The trial is being conducted in partnership with GlaxoSmithKline (GSK; the pharmaceutical company that developed and manufactured the adjuvanted protein vaccine candidate), KAVI, and other partners in Africa.
Volunteers in B002 will receive either placebo, two injections of the adjuvanted protein as a prime followed by an Ad35-GRIN boost, one injection of Ad35-GRIN as a prime followed by two injections of the adjuvanted protein as a boost, or three vaccinations with both Ad35-GRIN and the adjuvanted protein vaccine.
Researchers will measure immune responses in blood samples from volunteers, as well as in genital and oral mucosal fluids collected from volunteers who agree to provide such samples. The mucosal work will be done at the clinical research center in Nairobi, says Patricia Fast, chief medical officer at IAVI.
Previous Phase I trials have shown that separately, both the Ad35 and protein candidates have acceptable safety profiles and induce immune responses against HIV. The B002 trial is the first time these two vaccine candidates will be tested in combination. “There is a lot of interest in combining vectors and proteins following on the success of RV144,” says Fast, referring to the trial conducted in Thailand that showed that a different viral vector-based/protein prime-boost regimen provided a modest 31% protection against HIV infection.
Individuals with pre-existing immunity to Ad35 will be excluded from enrolling in B002. In the Phase IIb STEP trial of Merck’s MRKAd5 vaccine candidate, vaccinated uncircumcised male volunteers with pre-existing antibody immunity to naturally circulating Ad5 appeared to have an increased risk of HIV acquisition (see A Change of Tune, IAVI Report, Sep.-Oct. 2010).
One advantage of using Ad35 is that fewer people have preexisting immunity to Ad35 than to Ad5, says James Mullins, a professor of microbiology and medicine at the University of Washington, who is not involved in B002. Mullins led a recent study that analyzed MRKAd5 vaccinated individuals from the STEP trial who became HIV infected (see Study Finds Evidence of Sieve Effect in Phase IIb STEP Trial Vaccinees, below). “I think the idea of using Ad35 is a good one,” Mullins says. “Because of its rarity, the populations that already have immune responses against Ad35 are much smaller, therefore the vaccine is more likely to be usable in a larger fraction of the population. I think it’s a more viable approach than an Ad5” —Andreas von Bubnoff
The Enterprise Introduces Information Clearinghouse for Researchers
The Global HIV Vaccine Enterprise introduced an electronic information clearinghouse called HIVe that is both a forum for researchers to air their opinions and views on vaccine-related issues, as well as a link to jobs, grants, and scholarships.
HIVe, which can be accessed at www.hivvaccineenterprise.org, was developed for all researchers, but its focus was proposed and shaped by the Enterprise’s Young and Early Career Investigator’s Committee, and as such is particularly suited to serving the needs of young scientists. HIVe took root in the Enterprise’s 2010 Scientific Strategic Plan, which called for new strategies to recruit and retain the best young investigators in HIV vaccine research. —Regina McEnery
PrEP Trial in Women Halted Due to Doubts That it Could Show Efficacy
In a disappointing twist for the study of pre-exposure prophylaxis (PrEP), the sponsor of a Phase III trial testing the effectiveness of daily, oral Truvada—a combination of the antiretrovirals (ARVs) tenofovir (TDF) and emtricitabine (FTC)—in preventing HIV transmission in 1,951 high-risk women in Africa was stopped this month after an Independent Data Monitoring Committee (IDMC) said it was highly unlikely that the trial would be able to show that this strategy was effective.
The trial, known as FEM-PrEP, was designed to continue until 72 new HIV infections were accrued. But on February 18, the IDMC reported that the 56 new HIV infections that occurred among volunteers since the start of the trial were equally distributed among women who received Truvada and those who received placebo. “Consequently, the decision was made to do an orderly closure of the study because there really was no good reason to continue a randomized trial and to have the participants remain in the study,” said Tim Mastro, senior director of research at Family Health International (FHI), the non-profit AIDS research organization based in North Carolina that was conducting the trial at four clinical research centers in three countries (South Africa, Kenya, and Tanzania). The study was funded by the United States Agency for International Development and the Bill & Melinda Gates Foundation.
The news took people by surprise, given the positive results from two other large-scale PrEP trials completed recently, including the iPrEx trial that found daily, oral Truvada was 44% effective in protecting against HIV infection in men and transgendered women who have sex with men (see A PrEP Rally, this issue). In a briefing with more than 125 HIV prevention advocates, funders, and researchers from a dozen countries, FEM-PrEP’s principal investigator Lut Van Damme said staff and volunteers were disappointed that the study, launched in 2009, was stopped, and she said investigators at the clinical research centers were meeting with study participants to make sure they understood the reasons for the decision. “We are confident, despite the disappointing and surprising outcome, that the FEM-PrEP trial makes a contribution toward the understanding of antiretrovirals for prevention in women,” she said during the briefing, which was arranged by AVAC, an HIV prevention advocacy organization based in New York City.
Female volunteers still receiving Truvada or placebo have been asked to come in for three final visits over the next three months. Women who seroconverted during the course of the trial will be followed for one year post-diagnosis, said Van Damme.
In light of the FEM-PrEP results, the US Centers for Disease Control and Prevention (CDC) issued a statement cautioning women against “using PrEP for HIV prevention at this time.” The CDC released interim guidance earlier this year on the use of PrEP among men who have sex with men (MSM) and expects more detailed guidelines to be issued soon.
Mastro said poor adherence to the daily regimen is one possible explanation for the FEM-PrEP findings. The self-reported adherence to the regimen was 95% when women were asked at their monthly visit whether they had adhered to the regimen during the previous week. But in previous PrEP studies, there has been a big difference between self-reported and actual adherence. Investigators have not yet determined the drug concentrations in blood samples from women in FEM-PrEP.
Preliminary data from FEM-PrEP also showed higher pregnancy rates among women in the Truvada arm as compared to placebo, which means that women in the Truvada group spent more time off PrEP because it had to be stopped during pregnancy because of safety concerns. The overall pregnancy rate among all female participants was 9% during the trial, despite that at the time of enrollment all women were given hormonal contraceptives, with 66% of participants choosing the injectable form and 30% opting for pills. The oral contraceptive users had the highest rates of pregnancy in the trial, suggesting sub-optimal adherence. Mastro noted that the study is still ongoing, and that additional pregnancies have occurred since the IDMC issued its recommendation in February.
Mastro said it is also possible that Truvada simply didn’t work, even in women who took the pill every day. He said using TDF in gel form results in much higher levels of drug in vaginal and cervical tissues than oral TDF, which could have contributed to some of the success in the CAPRISA 004 study, which showed that a 1% TDF gel, when applied vaginally, was 39% effective in preventing HIV transmission in heterosexual women at high risk of infection (see Microbicides Finally Gel, Securing Spotlight at the International AIDS Conference, IAVI Report, July-Aug. 2010). “We also know that oral Truvada [results in] different distributions of TDF in rectal and vaginal tissue,” he said. A recent study sponsored by Gilead and conducted by Kristine Patterson, a clinical assistant professor at the University of North Carolina School of Medicine, showed that following a single dose of Truvada, the highest concentrations of TDF were in rectal tissue and the highest concentrations of FTC were in cervicovaginal fluid and cervical tissue.
Robert Grant, principal investigator of the iPrEx trial, noted in a statement that it is yet to be determined whether the different results of the iPrEx and FEM-PrEP trials are attributable to differences in the biological activity of the drug in men and women, its effectiveness at reducing infection risk based on different routes of HIV exposure, or other factors such as pill use.
There are still two other ongoing PrEP trials in women. The VOICE trial is testing oral TDF, oral Truvada, and a 1% TDF gel in 5,000 women at clinical research centers in sub-Saharan Africa. The Partners PrEP trial is evaluating oral TDF and Truvada in the uninfected partners of serodiscordant couples in Kenya and Uganda. Another trial is also evaluating the efficacy of PrEP in injection drug users. —Regina McEnery
Study Finds Evidence of Sieve Effect in Phase IIb STEP Trial Vaccinees
Merck’s MRKAd5 vaccine candidate, which was tested in the Phase IIb STEP trial, failed to protect volunteers from acquiring HIV infection, and even showed a trend toward an increased risk of HIV infection in vaccinees that were uncircumcised and had preexisting immunity to adenovirus serotype 5 (Ad5), the vector used in the vaccine. But a research team led by James Mullins, a professor of microbiology and medicine at the University of Washington, recently reported that the vaccine had a “sieve effect,” which means that it may have kept virus strains most similar to the vaccine from establishing infection (Nat. Med. 17, 366, 2011).
In the study, which Mullins says is the first to observe a possible sieve effect of a vaccine, the researchers sequenced transmitted founder viruses, which were the viruses that established infection, in 40 vaccine and 27 placebo recipients from the STEP trial, most of whom were men who have sex with men. The samples came from blood plasma taken between two weeks and a few months after infection (after the second or third vaccination).
Because the MRKAd5 vaccine was designed to induce CD8+ T-cell responses directed against the HIV components in the vaccine, the researchers used a computer algorithm to predict the epitope targets of the CD8+ T-cell response to the transmitted founder virus in vaccine and placebo recipients. They found that the predicted CD8+ T-cell epitope target sequences in the vaccine recipients differed more from the HIV sequences used in the vaccine than the predicted epitope target sequence in the placebo recipients, but only in Gag, Pol, and Nef, the proteins contained in the MRKAd5 vaccine, and not in other HIV proteins.
Much of this sieve effect seemed to be in Gag. The most pronounced difference was at position 84 in the Gag protein—one third of the placebo recipients, but about 80% of the vaccine recipients had an amino acid at that position that differed from MRKAd5.
Overall, this sieve effect suggests that the immune system did have an impact on the incoming virus by exerting selective pressure that resulted in transmitted founder viruses that were different from vaccine components, especially from the Gag protein in the vaccine. However, Mullins cautions that this is an analysis of predicted, not actual CD8+ T-cell responses in the HIV-infected STEP trial participants because too few T cells were available for them to perform a comprehensive analysis, and responses were typically very low. In addition, it does not show whether epitopes like the one that contains Gag 84 are protective or not because the MRKAd5 vaccine didn’t show any protection in the STEP trial.
However, if MRKAd5 did elicit CD8+ T-cell immune responses to epitopes in the Gag protein contained in the vaccine, this may translate into lower viral load, Mullins says, because in previous studies immune responses to Gag were associated with better immune control of HIV replication, and therefore with lower viral load. The sieve effect elicited by MRKAd5 would also be expected to make it more difficult for HIV variants that are very similar to the vaccine components to establish infection, or to at least delay the establishment of clinically productive infection. “Whether that translated into blocking infection in a few individuals we can’t say,” Mullins says, because any positive effects of the vaccine were likely overwhelmed by negative effects that led to a higher rate of infection in uncircumcised men with preexisting Ad5 immunity.
Better clues might come from studying the sieve effect in other trials, such as the HVTN 505 trial, in which a vaccine regimen that contains Ad5 as a vector was given to circumcised men without preexisting Ad5 immunity. “[This] will be an opportunity to see if the sieving effect is reproduced and whether the sieving effect is translated into a protective effect for virus acquisition,” says Mullins. He and his colleagues are also collaborating with the US Military HIV Research Program to do a similar analysis in volunteers from the RV144 trial in Thailand, the first to show modest protection against HIV infection.
James Whitney, an instructor in medicine at the Beth Israel Deaconess Medical Center and Harvard Medical School, who was not involved in the study, says this observation of a sieve effect with MRKAd5 gives reason for optimism. “This study does show that even in the setting of STEP, where to a large degree things didn’t work out as hoped, we still see very clear evidence of vaccine-induced selection on the virus, [so] there is still a relatively hopeful outcome in terms of [a] vaccine effect,” says Whitney, who also studies the sieve effect, but in vaccinated rhesus macaques.
Just how MRKAd5 caused the observed sieve effect is unclear, Mullins says. “We don’t know if the vaccine blocked certain variants or led to the evolution of escape mutants very rapidly,” he says. To find out, Mullins and colleagues will sequence thousands of HIV sequences in infected STEP trial participants at several time points early after infection. —Andreas von Bubnoff
IAVI Founder and CEO to Resign this June to Head GAVI Alliance
In June, Seth Berkley will relinquish his role as president and chief executive officer of IAVI after spending 15 years at the helm of the organization he founded in 1996. Berkley will become chief executive officer of the GAVI Alliance, a Geneva-based global health partnership launched in 2000 to increase access to immunizations.
This decision, which Berkley calls “the most difficult of my life,” comes at a time when the AIDS vaccine field is making notable progress. The field has been buoyed over the past few years by the results of the RV144 trial in Thailand, which provided the first evidence of vaccine efficacy in humans, and a spate of discoveries of new HIV-specific broadly neutralizing antibodies. “It is the most exciting time we’ve ever had in the AIDS vaccine field,” Berkley says. Still, he felt it was the right time to make this change. “I’ve been doing this job for 17 years and it’s a good time for my family to have an experience overseas. I care passionately about IAVI and I know IAVI and the field will succeed.”
When IAVI was created, the landscape of AIDS vaccine research was much different. “The reason IAVI was started was because there was very little interest in AIDS vaccines from either public or private sectors. We had a fundamental belief that science could solve the problem,” Berkley says. In 1993, less than US$160 million was being spent globally on AIDS vaccine research and development. “I think IAVI sprouted because of Seth and his passion and knowledge that we would solve the epidemic with a vaccine,” says Peggy Johnston, who retired in December from her post as director of the vaccine research program at the Division of AIDS at the US National Institute of Allergy and Infectious Diseases.
For the past 17 years, Berkley has campaigned tirelessly to keep AIDS vaccine research on the agenda. “He’s such an energetic force,” says Johnston. In 2009, the global investment in AIDS vaccine research and development reached $868 million. And IAVI, which now has more than 200 employees and an annual budget of approximately $87 million, has helped to advance the research and development process through its own network of laboratories, consortia, and collaborations. Johnston, who served as IAVI’s first scientific director, met Berkley in Italy in 1994 at a meeting convened by the Rockefeller Foundation, where Berkley worked at the time. Ever since then, Johnston says Berkley was a pivotal force in helping to make the case for an AIDS vaccine. She also credits IAVI with playing a role in trying to achieve that goal. “It’s hard to imagine IAVI without Seth,” she says.
Berkley’s roots in AIDS extend back to the late 1980s. Working as an epidemiologist at the Ministry of Health in Uganda, he helped characterize the extent of the epidemic in that country and set up its National AIDS Control programs. Ever since, he’s believed in engaging with developing country scientists in the research and development of AIDS vaccine candidates. “IAVI followed a different model which was to begin to work in partnership with developing country scientists early,” says Berkley, who views this as one of the organization’s greatest accomplishments. “I must say I’m extraordinarily proud of the quality of the work done in the developing world.”
Margaret McCluskey, a senior adviser at the US Agency for International Development, who called Berkley a “visionary and courageous” leader, also sees this as one of Berkley’s strengths. “Seth had the insight to really partner with in-country scientists and stakeholders,” she says.
McCluskey also credits Berkley and IAVI with trying to fill the gaps left by the work of government research agencies and the pharmaceutical industry. “He realizes the benefits of vaccines in global public health,” says McCluskey, adding that his work at GAVI will “only make it easier to roll out new vaccines, including an eventual HIV vaccine.”
At GAVI, Berkley’s focus will be on delivering existing vaccines, including recently licensed vaccines such as those against human papillomavirus, to individuals in developing countries. To date, the GAVI Alliance has funded immunizations for more than 288 million children, saving an estimated five million lives, according to the World Health Organization. “The challenge is to get that story out and get funds for it,” says Berkley. “The other two aspects are to try to drive down the price of vaccines and also to get governments to put more of a priority on immunization.” At least initially, this will probably involve Berkley racking up some serious travel miles after he relocates to Geneva in August with his wife, their two children, ages four and six, and their dog Ella. —Kristen Jill Kresge