One of the major challenges in developing an HIV vaccine is that the virus mutates rapidly — very rapidly. Although a person is initially infected with one or several strains of HIV, the virus replicates and mutates rapidly, giving rise to a “swarm” of viral strains coexisting in a single body. But scientists at Scripps Research; IAVI; the Ragon Institute of Mass General, MIT, and Harvard; the La Jolla Institute for Immunology; and other institutions have conducted a series of preclinical trials that indicate they are potentially closer than ever to an immunization regimen — one that could produce rare antibodies that would be effective against a broad range of HIV strains.
Published in Science, Science Immunologyand Scientific translation of medicine The findings are described in four separate papers on May 16, 2024, and are based on a 2022 Phase I clinical trial conducted by the nonprofit scientific research organization IAVI. The findings represent a key advance in an immunization strategy that could protect against the virus.
“Overall, these studies show that we have a good chance of creating an effective HIV vaccine; we just need to continue to iterate 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 of antigen design and selection, Infectious Disease Research, at Moderna, Inc.; and executive director of vaccine design at the IAVI Neutralizing Antibody Center.
The HIV vaccine strategy involves stimulating the body to produce mature broadly neutralizing antibodies (bnAbs). bnAbs are one of the key elements of the immune system in the fight against HIV, as they can block many variants of the virus. The problem is that bnAbs produced by the human body are rare. The IAVI trial, led in part by Schief, focused on inducing immune cells that could evolve into the right bnAbs—that is, those that could protect host cells from multiple strains of HIV. These precursor immune cells, known as B cells, were stimulated with the help of a priming immunogen, a molecule customized to “prime” the immune system and elicit responses from the right precursor cells.
But priming also requires additional “booster” immunogens to induce the immune system to produce not only precursor cells but also coveted VRC01-class bnAbs, a rare, specific class of antibodies known to neutralize more than 90 percent of various HIV strains. Boosters are also necessary for the production of BG18, another important class of bnAb that binds to sugars on the HIV spike protein. That’s where the new studies come in: The researchers developed immunization regimens that could prime either VRC01 or BG18 precursors and subsequently push those precursors even further along the path to becoming bnAbs.
“The results reported in these papers are very exciting and further support the germline-targeted HIV vaccine development strategy that IAVI and our partners are pursuing,” said Dr. Mark Feinberg, IAVI President and CEO. “We look forward to continuing to collaborate with Scripps Research and its partners to further advance research based on these promising findings.”
This groundbreaking science is made possible by collaboration between scientific institutions and funding partners. Without the ongoing and 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.
Preparation of rare antibodies
In the first study, which focused on BG18, Scripps Research scientists collaborated with co-senior authors Shane Crotty, PhD, scientific director of the La Jolla Institute for Immunology, and Devin Sok, PhD, former vice president of discovery and innovation at IAVI. Using a priming immunogen, they consistently prepared exceptionally rare BG18 precursors in a wild-type animal model.
To confirm that they were able to prepare the right precursors, the researchers teamed up with Andrew Ward, PhD, professor of integrative structural and computational biology at Scripps Research and co-senior author on the paper. Using cryo-EM structural analysis, they validated that the antibodies were indeed part of the BG18 class.
“The fact that the preparation worked well in macaques suggests it has a good chance of being successful in humans,” says co-senior author Jon Steichen, PhD, an institute investigator in the Department of Immunology and Microbiology at Scripps Research.
Steichen was also co-senior author on a second study, in which mice were engineered to produce a low frequency of BG18 precursors. The scientists at Scripps Research and IAVI, along with the team of co-senior author Facundo Batista, PhD, associate director and scientific director of the Ragon Institute at MGH, MIT, and Harvard, used similar priming methods to those used in the first paper. One key difference, however, was that this time, they also delivered one of two booster immunogens using RNA technology. This resulted in a boost of B cells primed to adapt to and recognize more native-like versions of HIV.
“This study showed that we can begin to guide B cells toward bnAb development,” Steichen explains.
How to boost the immune system
For the third study, Schief and his team worked with scientists at IAVI, in which they primed a mouse model with the same immunogen used in IAVI’s 2022 clinical trial. This resulted in mice that produced VRC01-class precursor B cells similar to those found in people. But the researchers also designed a new booster immunogen to drive the antibody response toward bnAb maturation — the vital next step in a sequential immunization series that could effectively combat HIV. The results: a “prime-boost” regimen that can drive VRC01-class B cells toward bnAb development.
“The findings demonstrate that we can get antibody responses going in the right direction using this heterologous booster, which delivers a different version of the vaccine than was previously given,” says Christopher Cottrell, PhD, a senior staff scientist at Scripps Research who was the first co-author on this study.
Understanding immunology
In the fourth and final study, on which Cottrell was also co-senior author, the team again worked with Batista’s team at the Ragon Institute and used the same immunogens but in a different mouse model where his team could control the frequency of bnAb precursors that were modified to be similar to those found in humans. This allowed the researchers to delve deeper into the immunology associated with HIV vaccination by examining germinal centers, specialized microstructures in the body that protect against viral reinfection. Germinal centers provide B cells with a space to rapidly ramp up and mutate their antibody genes, ultimately helping the immune system fight off viral strains.
Furthermore, the researchers examined how germinal centers accumulate HIV mutations over time. They found that a prime-boost regimen increased precursor B cell activity in germinal centers across different lineages, which could eventually lead to an increase in mature VRC01-class bnAbs.
Whats Next
Overall, all four papers confirm that it is possible to perform the priming step to activate the appropriate bnAb precursors when it comes to developing an HIV vaccine. Three of those papers specifically demonstrate that it is also possible to guide antibody precursors to become bnAbs that can fight HIV.
“Taken together, the findings give us more confidence that we can prepare precursors from multiple bnAb targets, and also show that we are beginning to learn the rules for how to advance precursor maturation through heterologous enhancement,” Schief added.
Following these results, investigators are advancing Phase 1 investigational medicine trials for the VRC01 and BG18 projects. Vaccines aimed at priming and boosting VRC01-class antibodies are being further evaluated in two IAVI-led clinical trials, IAVI G002 and IAVI G003, and a vaccine to prime BG18-class responses is being evaluated in HVTN144. These studies utilize both adjuvanted protein immunizations (IAVI G001 and HVTN144) and mRNA delivery (IAVI G002 and G003).
The results of these studies will guide the next critical steps on the path to HIV vaccine discovery.