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Breakthroughs in HIV Vaccine Research Offer New Hope
One of the most formidable challenges in developing a vaccine for HIV is the virus’s rapid mutation rate. After initial infection, HIV replicates and mutates so quickly that a diverse “swarm” of viral strains emerges within a single body. However, a series of preclinical trials conducted by scientists at Scripps Research, IAVI, the Ragon Institute of Mass General, MIT, and Harvard, La Jolla Institute for Immunology, and other institutions suggest that a viable immunization regimen may be closer than ever. These studies indicate progress toward producing rare antibodies capable of neutralizing a broad range of HIV strains.
Published on May 16, 2024, in the journals Science, Science Immunology, and Science Translational Medicine, these findings build on a 2022 phase I clinical trial led by IAVI. The research represents a significant step forward in developing an immunization strategy to protect against HIV.
“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 William Schief, PhD, co-senior author of all four studies, Scripps Research professor, vice president for antigen design and selection at Moderna, and executive director of vaccine design at IAVI’s Neutralizing Antibody Center.
Stimulating Broadly Neutralizing Antibodies
The innovative HIV vaccine strategy focuses on stimulating the body to produce mature broadly neutralizing antibodies (bnAbs), which can block many variants of the virus. However, bnAbs are rarely produced by the human body. The 2022 IAVI trial, partially led by Schief, aimed to induce immune cells that could evolve into bnAbs, protecting host cells from multiple HIV strains. These precursor immune cells, known as B cells, were stimulated using a priming immunogen—a customized molecule designed to elicit responses from the correct precursor cells.
In addition to the primer, “booster” immunogens are required to encourage the immune system to produce not only precursor cells but also VRC01-class bnAbs. These antibodies can neutralize over 90% of diverse HIV strains. Boosters are also necessary for producing BG18, another critical bnAb class that binds to sugars on the HIV spike protein. The new studies focused on developing immunization regimens to prime either VRC01 or BG18 precursors and boost them further 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.”
The Power of Collaboration
This groundbreaking research has been made possible through collaboration between scientific institutions and funding partners. Support from 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) has been crucial.
Priming Rare Antibodies
In the first study, Scripps Research scientists, in collaboration with Shane Crotty, PhD, and Devin Sok, PhD, used a priming immunogen to consistently prime exceptionally rare BG18 precursors in a wild-type animal model. The team confirmed the priming of the correct precursors using cryo-EM structural analysis.
“The fact that priming worked well in macaques suggests that it has a good chance of succeeding in humans,” says Jon Steichen, PhD, co-first author of the study and institute investigator at Scripps Research.
A second study involved modified mice producing a low frequency of BG18 precursors. The team used priming methods similar to those in the first study but also administered booster immunogens using RNA technology. This boosted the primed B cells 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
In the third study, Schief and his team worked with IAVI scientists to prime a mouse model with the same immunogen used in the 2022 IAVI clinical trial. They designed a new booster immunogen to drive the antibody response toward matured bnAbs, resulting in a “prime-boost” regimen that can drive VRC01-class B cells toward bnAb development.
“The findings demonstrate that we are able to make the antibody responses go in the right direction using this heterologous booster,” says Christopher Cottrell, PhD, senior staff scientist at Scripps Research and first co-author of the study.
Understanding the Immunology
In the fourth study, the team, in collaboration with the Ragon Institute, used immunogens in a different mouse model to examine the immunology associated with HIV vaccination. They explored how germinal centers—specialized microstructures in the body—play a role in rapidly increasing and mutating antibody genes to help the immune system fight off viral strains.
The researchers found that a prime-boost regimen increased precursor B-cell activity in germinal centers across different lineages, potentially leading to an increase in matured VRC01-class bnAbs.
Next Steps
Collectively, these four papers confirm that the priming step to activate the right bnAb precursors is feasible in developing an HIV vaccine. The studies also demonstrate the possibility of guiding antibody precursors toward becoming bnAbs capable of fighting HIV.
“Taken together, the findings give us more confidence that we’re able to prime precursors from multiple bnAb targets, and they also show that we’re starting to learn the rules for how to advance precursor maturation through heterologous boosting,” Schief adds.
Following these promising results, researchers are advancing phase 1 experimental medicine trials for the VRC01 and BG18 projects. Vaccines aimed at priming and boosting VRC01-class antibodies are being evaluated in two clinical trials run by IAVI, IAVI G002 and IAVI G003, while a vaccine to prime BG18-class responses is being evaluated in HVTN144. These studies employ both adjuvanted protein immunizations (IAVI G001 and HVTN144) and mRNA delivery (IAVI G002 and G003).
The outcomes of these studies will guide the critical next steps on the path to discovering an effective HIV vaccine.
