July 02, 2024

Advancing toward a preventative HIV vaccine Across four preclinical studies, Scripps Research, IAVI, and additional collaborators make headway in stimulating the rare antibodies needed to fight HIV.

July 02, 2024

LA JOLLA, CA and NEW YORK, NY A major challenge in developing a vaccine for HIV is that the virus mutates fast very fast. Although a person initially becomes infected with one or a few HIV strains, the virus replicates and mutates quickly, resulting in a swarm of viral strains existing in a single body. But scientists at Scripps Research; IAVI; the Ragon Institute of Mass General, MIT, and Harvard; La Jolla Institute for Immunology; and additional institutions have conducted a series of preclinical trials indicating that they're potentially closer to an immunization regimen than ever before one that could produce rare antibodies that would be effective against a wide range of HIV strains.

Published in Science, Science Immunology, and Science Translation Medicine on May 16, 2024, the findings are outlined in four individual papers and build on a 2022 phase I clinical trial conducted by the nonprofit scientific research organization IAVI. The findings represent a key step forward in an immunization strategy that could protect against the virus.

All in all, these studies show that we have a good chance at creating an effective HIV vaccine we just need to keep iterating and build on these findings in future clinical trials, says co-senior author of all four studies, William Schief, PhD, who is also a Scripps Research professor; vice president for antigen design and selection, Infectious Disease Research, at Moderna, Inc.; and executive director of vaccine design at IAVIs Neutralizing Antibody Center.

The HIV vaccine strategy involves stimulating the body to produce mature broadly neutralizing antibodies (bnAbs). bnAbs are among the immune system's key players in fighting HIV, since they can block many variants of the virus. The problem is that bnAbs produced by the human body are rare. The IAVI trial, spearheaded in part by Schief, focused on inducing the immune cells that could eventually evolve into the right bnAbs ones that could protect host cells from multiple HIV strains. These precursor immune cells, known as B cells, were stimulated with the help of a priming immunogen a customized molecule to prime the immune system and elicit responses from the correct precursor cells.

But the primer also requires additional booster immunogens to coax the immune system into producing not just precursor cells, but coveted VRC01-class bnAbs a rare and specific class of antibodies known to neutralize more than 90 percent of diverse HIV strains. Boosters are also needed for the production of BG18 another important bnAb class that binds to sugars on the HIV spike protein. That's where the new studies come in: Researchers developed immunization regimens that could prime either VRC01 or BG18 precursors, and subsequently boost those precursors further down the path toward becoming bnAbs.

The results contained in these papers are deeply exciting and further support the germline-targeting strategy to HIV vaccine development that IAVI and our partners are pursuing, says Mark Feinberg, MD, PhD, president and CEO of IAVI. We look forward to continuing our collaboration with Scripps Research and partners to advance further research building on these promising findings.

This groundbreaking science is enabled by collaboration between scientific institutions and funding partners. Without the ongoing, critical support of the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), the Collaboration for AIDS Vaccine Discovery (CAVD), the Bill & Melinda Gates Foundation, and Moderna (the manufacturer of the mRNA used in these studies), this research would not have been possible.

Priming rare antibodies

In the first study, which focused on BG18, Scripps Research scientists collaborated with co-senior authors Shane Crotty, PhD, chief scientific officer at La Jolla Institute for Immunology, and Devin Sok, PhD, former vice president of discovery and innovation at IAVI. Using a priming immunogen, they consistently primed exceptionally rare BG18 precursors in a wild-type animal model.

To confirm they were able to prime the correct precursors, the researchers then teamed up with Andrew Ward, PhD, Scripps Research integrative structural and computational biology professor and co-senior author of the study. Using cryo-EM structural analysis, they validated that the antibodies were indeed part of the BG18 class.

The fact that priming worked well in macaques suggests that it has a good chance of succeeding in humans, says co-first author, Jon Steichen, PhD, an institute investigator in the Department of Immunology and Microbiology at Scripps Research.

Steichen was also co-first author on a second study, in which mice were modified to produce a low frequency of BG18 precursors. Scripps Research and IAVI scientists, along with the team of co-senior author Facundo Batista, PhD, associate director and scientific director of the Ragon Institute of MGH, MIT, and Harvard, used priming methods similar to the ones used in the first paper. However, a key difference was that this time, they also administered one of two boost immunogens using RNA technology. This resulted in boosting the primed B cells to adapt to recognize more native-like versions of HIV.

This study showed that we can start to walk the B cells along toward bnAb development, Steichen explains.

Supercharging the immune system into action

For the third study, Schief and his team worked with IAVI scientists, wherein they primed a mouse model with the same immunogen used in the 2022 IAVI clinical trial. This resulted in mice that produced VRC01-class precursor B cells similar to those found in people. But the researchers a

LINK:	https://www.scripps.edu/news-and-events/press-room/2024/20240702-schie...
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