An empirical approach to HIV vaccine development relies on observation and experimentation to quickly move vaccine candidates into human clinical trials. Although all vaccine trials ultimately help contribute to scientific progress, historically, many investigational vaccines that initially seemed promising in laboratory and animal studies yielded disappointing results when tested in humans. For example, in 2007, vaccinations were stopped in two large HIV vaccine clinical trials known as the STEP and Phambili studies after review of interim data by an independent data safety and monitoring board concluded that the vaccine candidate could not be shown to prevent HIV infection or affect the course of the disease in those who become infected with HIV.
The quest to develop a preventive HIV vaccine was reinvigorated in 2009 when results from the large RV144 trial showed for the first time that an investigational vaccine regimen could confer a modest degree of protection against HIV infection. Today, NIAID and its global partners are continuing to learn from and build upon findings from this and other HIV vaccine trials.
RV144: The First Signal of Vaccine Efficacy
The landmark RV144 study in Thailand was the first, and to date only, large clinical trial to demonstrate efficacy for an investigational HIV vaccine. At the end of the 3.5-year study period, investigators observed a 31 percent reduction in HIV infection among vaccine recipients compared to those who received a placebo. The trial, which involved more than 16,000 adult participants, was sponsored by the U.S. Military HIV Research Program in collaboration with NIAID and other partners.
RV144 evaluated the safety and effectiveness of a prime-boost combination of two vaccine components given in sequence: ALVAC-HIV, which uses a canarypox virus as a vector—or carrier—to deliver HIV genes, and AIDSVAX B/E, which contains a protein found on the HIV surface. The vaccine components, which individually had not protected recipients against HIV infection, were based on the HIV B and E subtypes common in Thailand. The prime-boost regimen appeared to provide the greatest protective effect during the first year after vaccination, providing a 60 percent reduction in infection risk, but the level of protection decreased over time.
Understanding the Modest Success of RV144
The RV144 trial spurred researchers to work to identify the factors in this vaccine that protected some recipients from HIV infection and to develop strategies to improve upon the modest results. NIAID joined with other organizations to form an international collaborative team known as the Pox-Protein Public-Private Partnership (P5) that is committed to building on the success of RV144.
Researchers have gained insight into the types of immune responses that may help predict an HIV vaccine’s efficacy, providing leads for new vaccine development strategies. Production of certain immunologic responses to the vaccine, including antiviral antibodies and specific CD4+ T cells directed towards HIV’s outer shell, or envelope, correlate with reduced HIV infection. RV144 vaccinees who produced high levels of immunoglobulin G (IgG) antibodies that bind part of the envelope called V1V2 were less likely to get infected with HIV. In contrast, vaccinated RV144 participants with relatively high levels of a different type of envelope-binding antibody belonging to the IgA family appeared to have less protection from the virus. When tested in 100 healthy adults in South Africa, the RV144 vaccine regimen elicited robust immune responses similar to those seen in Thailand.
Other HIV vaccine trials also have provided valuable information to help researchers improve vaccine efficacy. For example, in 2015, NIAID researchers and colleagues reported that antibodies stimulated by the vaccine used in the HVTN 505 clinical trial recognized HIV as well as microbes commonly found in the intestinal tract, providing a potential explanation for why the candidate vaccine was not protective against HIV infection. Immunizations in HVTN 505 were discontinued in 2013 when an interim review concluded that the vaccine regimen did not prevent HIV infection or reduce viral load in those who became infected with HIV.
Building on the RV144 Results
In parallel, scientists have been developing investigational vaccine regimens to improve the potency, breadth, and duration of protection seen in RV144. In 2015, NIAID and its P5 collaborators launched HVTN 100, an early-phase clinical trial in South Africa conducted by the NIAID-funded HIV Vaccine Trials Network that tested an experimental HIV vaccine regimen based upon the RV144 findings. The vaccines used in HVTN 100 were based on those platforms used in RV144, but were designed to elicit immune responses against HIV subtype C, which is the most common circulating strain of HIV in southern Africa. The HVTN 100 vaccine regimen included booster shots at the one-year mark to prolong the early protective effect observed in RV144, and the booster used a different adjuvant—a vaccine component that enhances a specific immune response—to generate a more robust immune response.
Once the HVTN 100 investigators determined that the experimental vaccine regimen was safe and generated comparable immune responses to those reported in RV144, NIAID and its partners decided to advance the vaccine regimen into a large clinical trial. This new study, which began in October 2016 and is called HVTN 702, is designed to determine whether the experimental vaccine regimen safely prevents HIV infection among South African adults. The HVTN study team is enrolling 5,400 HIV-uninfected, sexually active men and women aged 18 to 35 years at 15 sites across South Africa. Results are expected in late 2020.
The P5 aims to produce an HIV vaccine that could have a significant public health benefit in southern Africa and to deepen scientists' understanding of the immune responses associated with preventing HIV infection.
Exploring Multiple Vaccine Development Avenues
In addition to efforts to build on the RV144 findings, NIAID supports development and evaluation of other novel candidate vaccines. In late 2017, NIAID and partners launched a large proof-of-concept clinical trial in southern Africa, called Imbokodo, to assess whether an experimental vaccine regimen is safe and able to prevent HIV infection. The regimen includes four doses of a four-component “mosaic” adenovirus 26 vaccine (Ad26.Mos4.HIV) designed to induce immune responses against a wide variety of global HIV strains. The final two doses will be given together with doses of HIV clade C gp140 protein and an aluminum phosphate adjuvant.
In preclinical studies, regimens incorporating mosaic vaccines protected monkeys against infection with an HIV-like virus. Two early-stage human trials, called APPROACH and TRAVERSE, suggested that mosaic-based vaccine regimens are well-tolerated and can generate anti-HIV immune responses in healthy adults. The Imbokodo investigators aim to enroll 2,600 HIV-negative women, and results are expected in 2021. Imbokodo is sponsored by Janssen Vaccines & Prevention, B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, with co-funding from two primary partners, the Bill & Melinda Gates Foundation and NIAID.