An Empirical Approach to HIV Vaccine Development

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 acquire 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 developed investigational vaccine regimens to try to improve the potency, breadth, and duration of protection seen in RV144. In 2015, NIAID and its P5 collaborators launched an early-phase clinical trial in South Africa that tested an experimental HIV vaccine regimen based upon the RV144 findings. The trial, called HVTN 100, was conducted by the NIAID-funded HIV Vaccine Trials Network. The vaccines used in HVTN 100 were based on the RV144 regimen but were modified to elicit immune responses against HIV subtype C, which is the most common strain of HIV circulating in southern Africa. The HVTN 100 vaccine regimen included booster shots at the one-year mark to try to prolong the early protective effect observed in RV144. To try to generate a more robust immune response, the boosters in HVTN 100 contained a different adjuvant than the one used in RV144.

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 study, which began in October 2016 and is called HVTN 702, was designed to determine whether the experimental vaccine regimen was safe and prevented HIV acquisition among 5,400 South African adults.

In January 2020, an independent data and safety monitoring board (DSMB) found during an interim review that the HVTN 702 vaccine regimen did not prevent HIV. Importantly, the DSMB did not express any concern regarding participant safety. Study investigators will continue following these study participants over time.

Exploring Multiple Vaccine Development Avenues

NIAID and its partners continue to invest in multiple approaches to an HIV vaccine. These efforts include two late-stage, multinational trials of investigational vaccines based on "mosaic" immunogens—vaccine components comprising elements from multiple HIV subtypes—that aim to induce immune responses against the wide variety of global HIV strains. The vaccine concept being tested in these trials is different than the one investigated in HVTN 702.

In late 2017, Janssen Vaccines & Prevention, B.V., partnered with NIAID and others to launch a large, proof-of-concept clinical trial to assess whether an experimental vaccine regimen is safe and able to prevent HIV in women in southern Africa. The trial is called Imbokodo or HVTN 705/HPX2008. "Imbokodo," the Zulu word for rock, is part of a well-known proverb in South Africa that refers to the strength of women and their importance in the community. 

In 2019, NIAID and partners also began a complementary Phase 3 HIV vaccine trial to assess an investigational vaccine regimen for safety and efficacy among men who have sex with men and transgender people. The trial, called HPX3002/HVTN 706 or Mosaico, is taking place at multiple clinical research sites in North America, South America and Europe.

Different HIV subtypes, or clades, predominate in various geographic regions around the world. Clade C HIV is common in southern Africa, where Imbokodo is being conducted, while clade B is predominant in the regions of Europe and the Americas where Mosaico is enrolling participants. Conducting studies in different regions aims to understand if mosaic vaccines can indeed protect globally.

In preclinical studies, regimens with mosaic-based vaccines protected monkeys against infection with an HIV-like virus. Findings from a series of early-stage human clinical trials suggested that these vaccines are well-tolerated and can generate anti-HIV immune responses in healthy adult volunteers. Based on results from an early-stage clinical trial called APPROACH, reported in July 2017, as well as findings from a second early-stage trial called TRAVERSE, researchers selected a lead candidate regimen for further evaluation in Imbokodo. The phase 2a ASCENT trial added an additional mosaic protein to the Imbokodo regimen, which improved immune responses to clade B HIV. This expanded regimen is being tested in the Mosaico trial.

Imbokodo and Mosaico are sponsored by Janssen Vaccines & Prevention, B.V., part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Imbokodo has co-funding from two primary partners, the Bill & Melinda Gates Foundation and NIAID. Mosaico has funding support from NIAID.

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