HVTN 702 Efficacy Trial Ready to Launch in South Africa
Seven years ago, a large-scale HIV vaccine trial in Thailand known as RV144 surprised scientists and funders alike when it provided the first and thus far only example of vaccine-induced protection against HIV. Now, a long-awaited follow-up study that is trying to improve upon RV144’s modest 31.2 percent efficacy result is preparing to launch in November. This new Phase IIb/III efficacy trial, led by the HIV Vaccine Trials Network (HVTN), is known as HVTN 702 and will enroll 5,400 HIV-uninfected men and women at risk for HIV in South Africa, which remains the country with the greatest HIV/AIDS burden in the world.
“We’re obviously looking to this trial with a great deal of interest,” says Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases (NIAID), which is funding the US$130 million study along with the Bill & Melinda Gates Foundation. “You know HIV is not an easy vaccine to make for the simple reason that the body does not naturally make a good immune response. So the fact that we did get that first positive signal with RV144, even though it was modest, the idea of being able to improve upon that and sustain it is exciting. Hopefully we will get enough data over a reasonable period of time to determine whether we have something or not.”
There are some notable differences between the HVTN 702 vaccine regimen and that tested in RV144 that investigators hope will improve the efficacy of the prime-boost candidates and also increase the durability of the immune responses they induce. Like RV144, HVTN 702 will test a canarypox vector-based candidate prime, ALVAC-HIV (vCP2438), made by Sanofi Pasteur. This time, however, the ALVAC candidate contains clade C HIV genetic inserts to match the predominantly circulating clade in South Africa. The boost in HVTN 702 is a genetically engineered HIV gp120 protein also derived from subtype C (manufactured by GlaxoSmithKline) that is co-formulated with the adjuvant M59, whereas in RV144 alum was used as the adjuvant.
The dosing schedule for HVTN 702 also differs. In HVTN 702, the vaccine candidates will be administered sequentially in a series of five injections over 12 months. The dosing schedule for RV144 consisted of four injections over six months. A fifth dose at 12 months was added to HVTN 702 in hopes of extending the early protective effect observed in the RV144 trial, which was as high as 60 percent after the first year, but waned over time.
Glenda Gray, president and chief executive officer of the South African Medical Research Council and the principal investigator of HVTN 702, said there is a huge sense of relief that this trial is finally coming to fruition and also excitement about its potential. “We have new products—a new protein and a new adjuvant—so although the approach is the same, pox-protein prime boost, there are distinct differences,” says Gray. “Scientifically, we hope that we can improve on RV144 and that our choice of proteins and adjuvant address this. Logistically, there are new sites, new investigators, places that have never done trials before, so it will be a big learning experience for all of us.”
HVTN 702 was a long time in coming. It is the first large-scale efficacy trial of any HIV vaccine candidate to begin since the RV144 results came in. Larry Corey, principal investigator of the HVTN, says he is happy to see the efficacy trial finally move forward after five and a half years. “People have worked very hard to get us this far,” he says.
The trial is part of the Pox-Protein Public Private Partnership or P5, which formed in 2010 to test variants of the RV144 regimen in future trials as well as to learn more about the immune responses induced in the RV144 trial. The P5 consists of representatives from NIAID; the Gates Foundation; the South African Medical Research Council; the HVTN; the drug companies, Sanofi-Pasteur and GlaxoSmithKline; and the Military HIV Research Program (MHRP), a key collaborator in the RV144 trial.
Multiple factors are responsible for delaying 702’s start, some logistical and others scientific. On the logistics, VaxGen, which manufactured the gp120 protein used in the RV144 trial, no longer exists, so a new commercial partner had to be found to manufacture the modified protein candidate for 702. Preliminary studies of this candidate also had to be conducted.
On the scientific side, researchers worked diligently in the seven years since the RV144 results were first reported to try to understand what immunological mechanism might be responsible for the modest 31.2 percent efficacy afforded by the RV144 vaccine regimen. This included analyzing the RV144 samples as well as conducting a myriad of follow-up studies in animals and humans.
In 2011, scientists identified two so-called “correlates of risk” associated with the experimental vaccine regimen: immunoglobulin (Ig)G antibodies that bound to the V1/V2 loops of HIV Env were correlated with a 43 percent reduction in HIV infection rate, and plasma IgA antibodies that bound to HIV Env were correlated with a 54 percent increase in HIV infection rate among vaccinated volunteers (see A Bangkok Surprise, IAVI Report, Sep.-Oct. 2011). The following year, researchers found two genetic signatures in a specific region of HIV’s surface protein that closely correlated with vaccine efficacy (see A Slew of Science in Seattle, IAVI Report, Mar.-Apr. 2012).
Researchers also conducted a small safety and immunogenicity trial in South Africa known as HVTN 100 that served as a litmus test for whether another efficacy trial was warranted. As a secondary objective, the South African trial of 252 HIV-uninfected men and women needed to meet certain immunogenicity parameters in order for the vaccine candidate to “graduate” to HVTN 702.
Last May, an interim analysis found that the vaccine regimen tested in HVTN 100 induced a comparable if not better immune response profile (using the same assays run in the same labs) than what was observed in vaccine recipients in RV144. “The HVTN 100 study clearly showed that V2 responses seen in RV144 are even more robustly elicited in South Africans with the new ALVAC and gp120 vaccine products developed for the region,” says Nelson Michael, director of MHRP. He added that the HVTN 702 trial in South Africa is the next logical step.
Corey shares some of this optimism. “The results from HVTN 100 are quite gratifying, with some areas of immunogenicity better than what we saw in RV144. That’s good.” However, Corey notes that it remains to be seen how well the candidate protects against clade C viruses in South Africa. “Why the clade C virus is so rampant, why the prevalence rates are so high has never been fully explained,” says Corey. “Whether that will be played out in this vaccine trial we don’t know yet, but we are excited to do the experiment.”
Mitchell Warren, executive director of AVAC, the HIV prevention advocacy group based in New York City, agreed that the field needs to settle the question about whether this vaccine regimen can provide high enough efficacy to be licensed, but says the AIDS vaccine field should keep its options open. “You don’t leave a positive result on the table,” says Warren. “That said, a 50 percent efficacious vaccine that requires five doses over a year is not the ultimate vaccine that we want, and there is no disagreement that even as 702 goes forward we have to accelerate other vaccine candidates.”
Moving forward, HVTN investigators will also need to contend with the impending roll-out of pre-exposure prophylaxis (PrEP)—the administration of antiretroviral drugs to prevent transmission of HIV. HVTN 702 was designed so investigators will be able to discern a preventive effect from the vaccine regimen even if some participants are taking PrEP. Study participants will be referred to available local programs where they can obtain the oral PrEP drug Truvada. The government is finalizing PrEP guidelines for commercial sex workers and hopes to expand the program to other vulnerable groups as well. —Mary Rushton
Mary Rushton is a freelance writer based in Cambridge, MA.