A significant hurdle in developing an HIV vaccine is the virus’s rapid mutation rate. Although initial infection involves only a few strains, HIV replicates quickly, resulting in a multitude of viral strains within one body. However, scientists from Scripps Research, IAVI, the Ragon Institute of MGH, MIT, and Harvard, La Jolla Institute for Immunology, and other institutions have conducted preclinical trials that suggest they are closer than ever to creating a vaccine regimen that can produce rare antibodies effective against a broad range of HIV strains.
Published in Science, Science Immunology, and Science Translational Medicine on May 16, 2024, the findings build on a 2022 phase I clinical trial by IAVI. These results represent a key step forward in an immunization strategy that could protect against HIV.
“These studies indicate a promising path toward an effective HIV vaccine,” says William Schief, PhD, co-senior author of all four studies, Scripps Research professor, and vice president for antigen design at Moderna. “We need to continue building on these findings in future trials.”
The HIV vaccine strategy focuses on stimulating the body to produce broadly neutralizing antibodies (bnAbs). While bnAbs are crucial in fighting HIV due to their ability to block many virus variants, they are rare in the human body. The IAVI trial aimed to induce the immune cells that could evolve into bnAbs to protect against multiple HIV strains. These precursor immune cells, known as B cells, were stimulated with a priming immunogen—a customized molecule to trigger the immune system and elicit responses from the correct precursor cells.
However, the primer needs additional booster immunogens to guide the immune system in producing not only precursor cells but also VRC01-class bnAbs, a rare class of antibodies that neutralize over 90% of diverse HIV strains. Boosters are also necessary for producing BG18, another bnAb class that binds to sugars on the HIV spike protein. Researchers developed immunization regimens to prime VRC01 or BG18 precursors and boost those precursors towards becoming bnAbs.
“The results support the germline-targeting strategy for HIV vaccine development that IAVI and partners are pursuing,” says Mark Feinberg, MD, PhD, IAVI president and CEO. “We look forward to further research based on these findings.”
This groundbreaking research is enabled by collaboration and funding from institutions like the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), the Collaboration for AIDS Vaccine Discovery (CAVD), the Bill & Melinda Gates Foundation, and Moderna.
In the first study focusing on BG18, scientists at Scripps Research, La Jolla Institute for Immunology, and IAVI used a priming immunogen to prime BG18 precursors in a wild-type animal model. Using cryo-EM structural analysis, they confirmed that the antibodies were part of the BG18 class. “The success in priming BG18 precursors in macaques suggests a good chance of success in humans,” says co-first author Jon Steichen, PhD.
In the second study, involving mice modified to produce BG18 precursors, the team used priming methods and administered boost immunogens using RNA technology. This resulted in boosting primed B cells to recognize more native-like HIV versions. “This study showed progress toward bnAb development,” Steichen explains.
For the third study, Schief and IAVI scientists used a mouse model primed with the same immunogen from the 2022 IAVI clinical trial. They designed a new booster immunogen to drive the antibody response toward matured bnAbs. “The prime-boost regimen showed promising results,” says Christopher Cottrell, PhD, senior staff scientist at Scripps Research.
In the fourth study, using a different mouse model, researchers took a deeper dive into the immunology of HIV vaccination. They found that a prime-boost regimen increased precursor B-cell activity in germinal centers, potentially leading to an increase in matured VRC01-class bnAbs.
Overall, the papers confirm the possibility of priming bnAb precursors for an HIV vaccine. Following these results, researchers are advancing phase 1 trials for VRC01 and BG18 projects. These studies will guide the next steps toward discovering an HIV vaccine.
