Trial Results Presented at CROI
Results from two recently-conducted clinical trials of different prime-boost AIDS vaccine regimens were presented at the 15th Conference on Retroviruses and Opportunistic Infections (CROI) held February 3-6 in Boston. The first trial, conducted by the HIV Vaccine Trials Network (HVTN) at multiple sites in the US, tested two vaccine candidates developed at the Emory Vaccine Center and now licensed to the biotechnology company GeoVax. The prime-boost immunization regimen consisted of a DNA candidate and a modified vaccinia Ankara (MVA) vector-based candidate, both expressing HIV Gag, Pol, and Env proteins.
This trial, known as HVTN 065, evaluated the safety and immunogenicity of two doses of the candidates—10 volunteers received two injections of a low dose of the candidates (0.3 mg DNA followed by a 10,000,000 viral particle dose of the MVA vector-based candidate). Another 30 volunteers received two injections of the candidates at a high dose (3 mg DNA followed by a 100,000,000 viral particle dose of MVA). Immune responses were measured two weeks following each MVA boost using ELISPOT assays to measure secretion of interferon (IFN)-γ and interleukin (IL)-2 by both CD4+ and CD8+ T cells.
After the second MVA injection at the lower dose, 87% of participants were considered responders based on their CD4+ T-cell responses to any of the HIV immunogens included in the candidates. After the second MVA injection at the higher dose, 77% of participants mounted CD4+ T-cell responses to any of the included HIV immunogens. Overall the CD8+ T-cell responses were much lower. At the higher dose, 42% of participants were considered responders, compared to 33% in the low-dose group. Harriet Robinson, who recently announced she will be leaving Emory University to join GeoVax full time, presented the immunogenicity data at CROI, saying the vaccine candidates exhibited “excellent cytokine production profiles.”
The Gag-specific responses were boosted by the second administration of MVA and Robinson said this was promising since immune responses to HIV Gag correlate with successful control of HIV in infected individuals. Bruce Walker of Massachusetts General Hospital, who was in the audience, pointed out that based on his work, it is actually the breadth of Gag-specific responses that seems to be important in control of HIV infection. Robinson said data on the breadth of Gag-specific immune responses was not yet available from this trial.
Based on these results, the high-dose regimen will be tested in the second part of this trial, involving two groups of 30 volunteers. One group will receive a single injection of the DNA candidate and two MVA boosts, the other will receive three injections of the MVA-based vaccine candidate.
Immunogenicity data from a Phase I/II trial in Mbeya, Tanzania of the DNA and adenovirus serotype 5 (Ad5)-based candidates developed by the Vaccine Research Center (VRC), part of the US National Institute of Allergy and Infectious Diseases, were also presented at CROI. This trial was conducted by the United States Military HIV Research Program (USMHRP) and was one of a series of Phase I and II studies with the VRC’s candidates in preparation for the originally-planned Phase IIb test-of-concept trial known as PAVE 100.
The DNA plasmid vaccine candidate encodes Gag, Pol, and Nef from HIV clade B and Env from HIV clades A, B, and C. The Ad5-based candidate encodes the same immunogens except Nef. In this trial, 60 volunteers received three injections of the DNA vaccine candidate followed by a single booster immunization with the Ad5 candidate, or placebo. Immune responses in 40 of the volunteers were measured using IFN-γ ELISPOT assays. After the Ad5 boost, 80% of vaccinees had at least 55 spot-forming cells per million peripheral blood mononuclear cells (PBMCs). The majority of immune responses were directed toward Env, but researchers were not able to measure the magnitude of Gag-specific IFN-γ responses. This analysis will be completed later with frozen cells. The majority of participants in this trial had high levels of anti-Ad5 antibody, yet all individuals mounted some level of HIV-specific immune responses following receipt of the Ad5 candidate, indicating that pre-existing immunity to the vector from exposure to the naturally-circulating virus did not completely mitigate the effect of the Ad5 boost.
Last year, the US-based news magazine Time ranked male circumcision as the number one medical breakthrough of 2007 because of its potential to slow the spread of HIV. Results from three randomized, controlled clinical trials have shown that circumcision cuts the risk of HIV infection in men by roughly 60%. Subsequently, the World Health Organization (WHO) issued guidelines urging countries to consider adding male circumcision to their existing HIV/AIDS prevention strategies, but to date, only a handful of health ministries in sub-Saharan Africa—the region most severely affected by HIV/AIDS—have started developing national policies on circumcision. This has spurred some public health officials to question the delay.
In an editorial published in the January issue of the journal Future HIV Therapy, Daniel Halperin, senior research scientist at Harvard University, and colleagues emphasized the benefits of male circumcision and called upon countries, international leaders, and donor agencies to introduce safe circumcision practices in sub-Saharan Africa. Halperin says that so far approximately nine African governments have conducted consultations with the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the WHO. “I think in every case, after doing the consultation, they decided that they wanted to have a circumcision program or policy,” he says. But so far few policies have been established. “A lot of these countries are on their way, but only Kenya and Rwanda have actual policies as far as I know.”
Kenya’s Ministry of Health published its official policy on male circumcision in September 2007. The Kenyan policy stipulates that safe, voluntary male circumcision should be promoted in conjunction with other HIV prevention strategies, but provides no indication of when circumcision programs will be implemented.
At the 15th Conference on Retroviruses and Opportunistic Infections (CROI), held February 3-6 in Boston, Bertran Auvert, an investigator on the first trial of adult male circumcision in South Africa, provided an update on national circumcision policies in Africa. “Today, no country has started the rollout of male circumcision,” Auvert said in a conference session. He cautioned that even once policies are adopted, implementation will take time.
Previous surveys of men in sub-Saharan Africa found the procedure would be highly acceptable—between 65% and 81% of men said they would consider undergoing circumcision if it provided some protection against sexually-transmitted infections. Yet Auvert argues that this is not an indication that men will voluntarily opt to be circumcised. “We need to say: ‘Now, safe and free male circumcision is available. Will you go? And when?’” Studies are ongoing to address this question and results should be available within a year.
There are also many other challenges that have contributed to delays in instituting male circumcision programs, including cultural hurdles, a shortage of trained professionals, and financial constraints. While the US President’s Emergency Plan for AIDS Relief (PEPFAR) has agreed to fund circumcision programs, the governments and health ministries need to specifically request this support. “Once they ask for it, it’s like anything else, it takes a while for the money to come down,” says Halperin. “It’s going to vary in different places but I’m sure there will be a lag before things really get going.”
Study findings released at CROI indicate that while male circumcision provides significant protection against HIV transmission in men, it offers no direct benefit to the female partners of HIV-infected circumcised men (see Clues from CROI). Results of this study, conducted in Uganda, also suggest that women who engage in sexual activity with a recently circumcised HIV-infected partner before his wound has fully healed actually increase their risk of acquiring HIV.
Yet providing circumcision services to adult men in areas with high HIV prevalence could considerably reduce the number of new infections. Computer modeling studies conducted by the WHO to determine the potential impact of circumcision on the course of the HIV epidemic suggest that if all males in sub-Saharan Africa were circumcised, two million HIV infections could be averted over the next 10 years. An additional 3.7 million new infections could be prevented over the following decade.
Evidence for the potential impact of circumcision programs can already be seen on the population level, says Halperin. For example, in Cameroon, a country where male circumcision is common practice, the adult HIV prevalence rate is only 5%, whereas in Botswana and Swaziland, countries where the majority of men are uncircumcised, adult HIV prevalence rates are up to five times higher. “It’s not just about modeling. We can actually see the real-world impact,” says Halperin.
Vaccine Briefs written by Kristen Jill Kresge and Alix Morris, contributing writer.