Innovative HIV vaccine approaches offer the potential for broad protection against viral strains


A major challenge in developing a vaccine for HIV is that the virus mutates rapidly — very rapidly. Although a person initially becomes infected with one or a few HIV strains, the virus replicates and mutates rapidly, resulting in a “swarm” of viral strains co-existing in the same body. But scientists at Scripps Research; IAVI; the Ragan 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 a vaccine regimen — a regimen that could produce rare antibodies that would be effective against a wide range of HIV strains.

published in Science, Science ImmunologyAnd science translation medicine On May 16, 2024, the findings are outlined in four separate papers and are based on a 2022 Phase I clinical trial conducted by the nonprofit scientific research organization IAVI. The findings mark a significant step forward in a vaccination strategy that could protect against the virus.

“Overall, these studies suggest that we have a good chance of creating an effective HIV vaccine — we just need to continue to replicate these findings and build on them in future clinical trials,” says co-senior author of all four studies, William Schiff, PhD, who is also a professor at Scripps Research; vice president of antigen design and selection in infectious disease research at Moderna Inc.; and executive director of vaccine design at IAVI’s Neutralizing Antibody Center.

The HIV vaccine strategy involves stimulating the body to produce mature broadly neutralizing antibodies (bnAbs). bNAbs are one of the immune system's key players in fighting HIV, as they can block many strains of the virus. The problem is that bNAbs produced by the human body are rare. The IAVI trial, led in part by Schiff, focused on inducing immune cells that could eventually develop into the right bNAbs – those 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 a response from the right precursor cells.

But the primers also require additional “booster” immunogens to prompt the immune system to produce not just precursor cells, but also the 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 to produce BG18—another important bnAb class that binds to sugars on the HIV spike protein. That's where the new studies come in: Researchers have developed vaccination regimens that can prime either the VRC01 or BG18 precursors, and subsequently steer those precursors toward becoming bnAbs.

The results contained in these papers are extremely exciting and support the germline-targeting strategy for HIV vaccine development that IAVI and our partners are pursuing. We look forward to continuing our collaboration with Scripps Research and partners to advance further research on these promising findings.”


Mark Feinberg, MD, PhD, President and CEO of IAVI

This groundbreaking science is made possible by collaboration between scientific institutions and funding partners. Without the continued, 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, scientists at Scripps Research collaborated with co-senior authors Shane Crotty, PhD, chief scientific officer at the La Jolla Institute for Immunology, and Devin Sok, PhD, former vice president, discovery and innovation at IAVI. Using a priming immunogen, they consistently primed exceptionally rare BG18 precursors in a wild-type animal model.

To confirm that they were able to prime the correct precursor, the researchers then teamed up with Andrew Ward, Ph.D., Scripps Research Professor of Integrative Structural and Computational Biology and co-senior author of the study. Using cryo-EM structural analysis, they confirmed that the antibodies were indeed part of the BG18 class.

“The fact that priming worked well in macaques indicates that it has a good chance of being successful in humans as well,” says co-first author John Steichen, PhD, an Institute Investigator in the Department of Immunology and Microbiology at Scripps Research.

Steichen was also co-first author of the second study, in which mice were modified to generate a reduced frequency of BG18 precursors. The Scripps Research and IAVI scientists, along with a team led by co-senior author Facundo Batista, PhD, associate director and scientific director of the Ragan Institute of MGH, MIT, and Harvard, used priming methods similar to those 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 the primed B cells being adapted to recognize more original-like versions of HIV.

“This study showed that we can steer B cells toward bNAb development,” explains Steichen.

Activating the immune system

For the third study, Schiff and his team worked with IAVI scientists to prime 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 also designed a new booster immunogen to move the antibody response toward becoming mature bnAbs—the next critical step in a sequential vaccination series that can effectively fight HIV. The result: a “prime-boost” regimen that can lead VRC01-class B cells toward bnAb development.

“The findings demonstrate that we are able to nudge antibody responses in the right direction by using this heterologous booster, which administers a different version of the vaccine than the one previously given,” says Christopher Cottrell, PhD, a senior staff scientist at Scripps Research who was the first co-author of the study.

Understanding immunology

In the fourth and final study, on which Cottrell was also co-first author, the team worked again with Batista's team at the Ragan Institute and used the same immunogens—but in a different mouse model where their team could control the frequency of bNAb precursors that were modified to be similar to those found in humans. This allowed the researchers to dive 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 a place for B cells to rapidly increase and mutate their antibody genes, which ultimately help the immune system fight off viral strains.

In addition, the researchers examined how germinal centers accumulate HIV mutations over time. They found that the prime-boost regimen increased precursor B-cell activity in the germinal center across different lineages, which could ultimately lead to an increase in mature VRC01-class bnAbs.

what will happen next

Overall, all four papers confirm that a priming step to turn on the right bnAb precursor is possible in terms of developing an HIV vaccine. Three of those papers specifically demonstrate that it is also possible to direct antibody precursors towards becoming bnAbs that can fight HIV.

“Overall, the findings give us greater confidence that we are able to prime precursors from multiple bnAb targets, and they also demonstrate that we are beginning to learn the rules for advancing precursor maturation via heterologous boosting,” Schiff said.

Following these results, researchers are advancing Phase 1, experimental drug trials for both the VRC01 and BG18 projects. Vaccines intended to prime and boost VRC01-class antibodies are being further evaluated in two clinical trials run by IAVI, IAVI G002 and IAVI G003, and a vaccine to prime BG18-class responses is being evaluated in HVTN144. These studies use both adjuvanted protein immunization (IAVI G001 and HVTN144) and mRNA delivery (IAVI G002 and G003).

The results of these studies will guide the next important steps in the search for an HIV vaccine.

Source:

The Scripps Research Institute

Journal Reference:

Wang, X., and others(2024). mRNA-LNP prime boost develops precursors to broadly neutralizing antibodies such as VRC01 in preclinical humanized mouse models. Science Immunologydoi.org/10.1126/sciimmunol.adn0622.

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