Understanding the Rationale for the HVTN 702 Trial
What have scientists learned that helped inform the design of this pivotal AIDS vaccine study in South Africa?
By Mary Rushton
Seven years ago, a large efficacy trial in Thailand known as RV144 provided the first—and thus far only—clinical evidence of vaccine-induced protection against HIV. The two vaccine candidates tested in what is referred to as a prime-boost combination appeared to lower the risk of HIV infection by about 31%. This level of efficacy was not high enough for licensure of the vaccine regimen in Thailand, but it did provide a welcome turning point for a vaccine field that was characterized by two decades of disappointments.
Since then scientists have conducted numerous analyses and follow-up studies to try and determine which types of immune responses induced by the RV144 vaccine candidates may have led to the modest efficacy, a hunt for the so-called immune correlates of protection. Researchers have also tried modifying the vaccine candidates and the timing of the vaccinations in an attempt to strengthen and improve the durability of the immune responses and thereby improve the efficacy of this or similar regimens. This includes testing related vaccine candidates in countries or regions where the prevalence of HIV is highest, including sub-Saharan Africa, or in specific populations at highest risk for acquiring HIV, such as men-who-have-sex-with-men or high-risk heterosexual men and women.
These post-trial analyses have been enormously helpful in determining what immune responses contributed to the modest efficacy observed in RV144. The Pox-Protein Public Private Partnership or P5—which consists of representatives from the US National Institute of Allergy and Infectious Diseases (NIAID), the Bill & Melinda Gates Foundation (BMGF), the South African Medical Research Council, the HIV Vaccine Trials Network (HVTN), Sanofi Pasteur, GlaxoSmithKline, and the US Military HIV Research Program—was formed in 2010 to test variants of the RV144 regimen in future trials as well as learn more about vaccine-induced protection in that trial. Now the P5 is preparing for a large-scale AIDS vaccine efficacy trial in South Africa—the first to launch since the RV144 results were reported. This trial will test a modified prime-boost vaccine regimen and is expected to launch this November. The Phase IIb/III trial known as HVTN 702 will enroll 5,400 HIV-uninfected men and women ages 18-35 at risk for HIV infection at 15 clinical research sites. NIAID and BMGF are funding the US$130 million trial, which is being conducted by the HVTN.
A vaccine can induce many different types of immune responses, including antibodies (typically Y-shaped proteins that bind to viruses and prevent them from infecting cells), cellular immune responses (CD4+ and CD8+ T cells that orchestrate the killing of virus-infected cells), as well as the body’s built in or innate immune responses. The regimen tested in RV144 appeared to induce antibodies, but not the type that bind the virus and neutralize it. Rather the antibodies induced in some RV144 vaccine recipients appeared to latch onto HIV-infected cells and trap them until other components of the immune system could swoop in for the kill. This process is referred to as antibody-dependent cellular cytotoxicity (see VAX Jan. 2010 Primer on Understanding Antibody Functions: Beyond Neutralization).
From these initial findings, researchers went on to identify what they called “correlates of risk” associated with this vaccine regimen. Those studies revealed that one antibody response correlated with a reduced risk of HIV infection, while another correlated with an increased risk of infection (see VAX Sep. 2011 Spotlight article, More Surprises Stem from RV144).
But the most relevant data to support another large efficacy trial came from a P5-sponsored Phase I/II study known as HVTN 100 that is ongoing in South Africa. The trial, involving approximately 250 HIV-uninfected men and women, is evaluating the safety and immunogenicity of the same prime-boost vaccine regimen that will be tested in HVTN 702. The non-infectious viral vector prime and engineered HIV protein boost candidates are similar to those tested in RV144 but are based on clade C HIV, the strain that is predominant in South Africa. In RV144 the candidates were based on clade B/E, the most prevalent serotype in Thailand. An interim analysis showed that the vaccine regimen in HVTN 100 was eliciting similar immune responses to those induced in the RV144 trial. This helped convince trial sponsors to go forward with HVTN 702.
A modified regimen
In addition to the vaccine candidates being based on a different clade, there are some other significant differences between the HVTN 702 vaccine regimen and that tested in RV144. One is the dosing schedule. In RV144 six vaccinations were administered sequentially over six months. In HVTN 702, five vaccinations will take place: three by month six and two more at month 12. The hope is this will extend the early protective effect observed in the RV144 trial, which showed protection was as high as 60 percent in the first year.
A new adjuvant is also being tested in HVTN 702. Although researchers don’t know precisely how they work, adjuvants help to boost the immune responses induced by vaccines. RV144 used an alum adjuvant, which consists of insoluble aluminum salts, while the HVTN 702 trial will utilize MF9, a biodegradable oil that is used in influenza vaccines in Europe.
Researchers hope that results from the HVTN 702 trial, which are expected by 2020, will provide a clear answer about whether these vaccine candidates can protect against HIV infection.
Mary Rushton is a freelance writer based in Cambridge, Massachusetts.