A significant challenge in developing an HIV vaccine is the rapid mutation of the virus. Although a person initially gets infected with one or several strains of HIV, the virus quickly replicates and mutates, resulting in a "swarm" of virus strains within the body. However, scientists from Scripps Research, IAVI, the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, the La Jolla Institute for Immunology, and other institutions have conducted a series of preclinical trials indicating that they are potentially closer to an immunization regimen than ever before—one that could produce rare antibodies effective against a broad range of HIV strains.

These results, published on May 16, 2024, in the journals Science, Science Immunology, and Science Translational Medicine, are presented in four separate papers and are based on a Phase I clinical trial from 2022 conducted by the nonprofit scientific research organization IAVI. These findings represent a crucial step forward 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 iterating and building on these findings in future clinical trials," says co-senior author of all four studies, William Schief, Ph.D., who is also a professor at Scripps Research; Vice President of Antigen Design and Selection, 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 among the key players of the immune system in fighting HIV because they can block many variants of the virus. The problem is that bnAbs produced by the human body are rare. IAVI's trial, partly led by Schief, focused on inducing immune cells that could develop into true bnAbs—those that could protect native cells from more HIV strains. These precursor immune cells, known as B cells, were stimulated with the help of a priming immunogen—a tailored molecule to "prime" the immune system and elicit a response from the right precursor cells.

However, the primer also requires additional "booster" immunogens to stimulate the immune system to produce not just precursor cells, but the desired VRC01 class antibodies—a rare and specific class of antibodies known for neutralizing more than 90 percent of various HIV strains. Boosters are also needed to produce BG18—another important class of bnAbs that binds to sugars on the HIV spike protein. This is where the new studies come in: researchers have developed immunization regimens that can prime VRC01 or BG18 precursors and then further stimulate their development into bnAbs.

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

To confirm that they had successfully primed the correct precursors, the researchers collaborated with Andrew Ward, Ph.D., professor of integrative structural and computational biology at Scripps Research 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 suggests that it has a good chance of success in humans," says co-first author Jon Steichen, Ph.D., a researcher in the Department of Immunology and Microbiology at Scripps Research.

Steichen was also co-first author on the second study, where mice were modified to produce a low frequency of BG18 precursors. Scripps Research and IAVI scientists, along with a team of co-senior authors Facundo Batista, Ph.D., deputy director and chief scientific officer of the Ragon Institute of MGH, MIT, and Harvard, used priming methods similar to those used in the first paper. However, the key difference was that this time they also applied one of two booster immunogens using RNA technology. This resulted in the primed B cells recognizing more natural versions of HIV.

"This study showed that we can start steering B cells toward bnAb development," explains Steichen.

Supercharging the Immune System
For the third study, Schief and his team collaborated with IAVI scientists, priming a mouse model with the same immunogen used in IAVI's 2022 clinical trial. This resulted in mice producing VRC01-class precursor B cells similar to those found in humans. However, the researchers also designed a new booster immunogen to direct the antibody response toward more mature bnAbs—the next vital step in a sequential immunization series that could effectively combat HIV. The results: a "prime-boost" regimen that can direct VRC01-class B cells toward bnAb development.

"The findings show that we can steer antibody responses in the right direction using this heterologous booster, which applies a different version of the vaccine than previously given," says Christopher Cottrell, Ph.D., senior research associate at Scripps Research who was the first co-author of this study.

Understanding Immunology
In the fourth and final study, on which Cottrell was also co-first author, the team again collaborated with Batista's team at the Ragon Institute and used the same immunogens—but in another mouse model where his team could control the frequency of bnAb precursors modified to be similar to those found in humans. This allowed researchers to delve deeper into the immunology associated with HIV vaccination by examining germinal centers—specialized microstructures in the body that protect against reinfection by viruses. Germinal centers provide B cells with space to rapidly increase and mutate their antibody genes, ultimately helping the immune system fight viral strains.

Additionally, the researchers examined how germinal centers accumulate HIV mutations over time. They found that the prime-boost regimen increases the activity of precursor B cells in germinal centers of different lineages, which could ultimately lead to increased mature VRC01-class bnAbs.

What's Next
Overall, all four papers confirm that the step of priming the correct bnAb precursors is possible when it comes to developing an HIV vaccine. Three of those papers specifically demonstrate that it is also possible to direct antibody precursors toward developing bnAbs that can fight HIV.

"Taking these results into account, we gain more confidence that we are capable of priming precursors from more bnAb targets, and we are also beginning to learn the rules for advancing precursor maturation through heterologous boosting," added Schief.

Following these results, researchers are advancing Phase 1, experimental medical studies for the VRC01 and BG18 projects. Vaccines targeting the priming and boosting of VRC01-class antibodies are further being evaluated in two clinical trials led by IAVI, IAVI G002 and IAVI G003, and the vaccine for priming the BG18-class response is being evaluated in HVTN144. These studies use both adjuvanted protein immunizations (IAVI G001 and HVTN144) and mRNA delivery (IAVI G002 and G003).

The results of these studies will guide the critical next steps on the path to HIV vaccine discovery.

This work and the researchers involved are supported by funding from the National Institutes of Health (grant U24GM129547); the National Institute of Allergy and Infectious Diseases (grants UM1 Al100663, UM1 AI144462, R01 AI113867, and R24 AI162317); the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (grants NAC INV-007522/ OPP1084519, INV-021989, INV-034657, INV-009585, INV-046626, OPP1147787/INV-007385, OPP1196345/INV-008813, OPP1115782/INV-008556, and INV-002916); IAVI; and the Ragon Institute of MGH, MIT, and Harvard.

In addition to Schief and Steichen, authors of the study "Vaccine priming of rare HIV broadly neutralizing antibody precursors in nonhuman primates" are Gabriel Ozorowski, Sabyasachi Baboo, Christopher A. Cottrell, Jonathan L. Torres, Krystal M. Ma, Erik Georgeson, Michael Kubitz, Alison Burns, Shawn Barman, Torben Schiffner, Jolene K. Diedrich, Dennis R. Burton, John R. Yates III, James C. Paulson, and Andrew B. Ward from Scripps Research; Eugenia Salcedo, Jordan R. Willis, Alessia Liguori, Jeong Hyun Lee, Oleksandr Kalyuzhniy, Yumiko Adachi, Tina-Marie Mullen, and Devin Sok from IAVI; Ivy Phung, Patrick J. Madden, Henry J. Sutton, Tasha K. Altheide, and Shane Crotty from LJI; Oscar L. Rodriguez, Corey T. Watson, Swati Saha, Kaitlyn Shields, Steven E. Schultze, and Melissa L. Smith from the University of Louisville School of Medicine; Rohini Mopuri, Amanda Metz, and Steven E. Bosinger from Emory University; and Joel D. Allen and Max Crispin from the University of Southampton.

In addition to Schief and Steichen, authors of the study "mRNA-LNP HIV-1 trimer boosters elicit precursors to broad neutralizing antibodies" are Gabriel Ozorowski, Jonathan L. Torres, Sabyasachi Baboo, Erik Georgeson, Michael Kubitz, Abigail M. Jackson, Sara T. Richey, Reid M. Volk, Jolene K. Diedrich, John R. Yates III, James C. Paulson, and Andrew B. Ward from Scripps Research; Alessia Liguori, Oleksandr Kalyuzhniy, Yumiko Adachi, Jeong Hyun Lee, and Devin Sok from IAVI; Zhenfei Xie, Ying-Cing Lin, Sven Kratochvil, Rashmi Ray, Xuesong Wang, John E. Warner, Stephanie R. Weldon, Gordon A. Dale, Kathrin H. Kirsch, Usha Nair, Thavaleak Prum, and Facundo D. Batista from the Ragon Institute of MGH, MIT, and Harvard; and Samantha Falcone, Sunny Himansu, and Andrea Carfi from Moderna Inc.

In addition to Cottrell and Schief, authors of the study "Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice" are Xiaozhen Hu, Jonathan Hurtado, Sebastian Raemisch, Patrick Skog, Sabyasachi Baboo, Jolene K. Diedrich, Torben Schiffner, Daniel L.V. Bader, Daniel W. Kulp, Ryan Tingle, Erik Georgeson, Saman Eskandarzadeh, Nushin Alavi, Danny Lu, Troy Sincomb, Michael Kubitz, Tina-Marie Mullen, John R. Yates III, James C. Paulson, and Bryan Briney from Scripps Research; Jeong Hyun Lee, Claudia T. Flynn, Katherine R. McKenney, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Elise Landais, and Devin Sok from IAVI; Sai Luo and Frederick W. Alt from the Howard Hughes Medical Institute and Boston Children's Hospital; Xuejun Chen, Hongying Duan, Cheng Cheng, and John R. Mascola from the National Institute of Allergy and Infectious Diseases; and Sunny Himansu from Moderna Therapeutics.

In addition to Cottrell and Schief, authors of the study "mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models" are Xiaozhen Hu, Sergey Menis, Sebastian Rämisch, Saman Eskandarzadeh, Michael Kubitz, Ryan Tingle, and Nicole Phelps from Scripps Research; Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, and Bettina Groschel from IAVI; Xuesong Wang, Rashmi Ray, Maria Bottermann, Paula Maldonado Villavicencio, Yu Yan, Zhenfei Xie, John E. Warner, Jordan Renae Ellis-Pugh, Kathrin H. Kirsch, Stephanie R. Weldon, Usha Nair, and Facundo D. Batista from the Ragon Institute of MGH, MIT, and Harvard; and Sunny Himansu and Andrea Carfi from Moderna Inc.

About Scripps Research
Scripps Research is an independent, nonprofit biomedical institute that is one of the most influential in the world for its impact on innovation according to the Nature Index. We advance human health through profound discoveries that address urgent medical challenges worldwide. Our drug discovery and development unit, Calibr-Skaggs, collaborates with scientists across disciplines to bring new medicines to patients as quickly and efficiently as possible, while teams at the Scripps Research Translational Institute use genomics, digital medicine, and cutting-edge informatics to understand individual health and provide more effective healthcare. Scripps Research also trains the next generation of leading scientists at our Skaggs Graduate School, which is consistently among the top 10 programs in the U.S. for chemistry and biological sciences. Learn more at www.scripps.edu.

About IAVI
IAVI is a nonprofit scientific research organization dedicated to addressing urgent, unmet global health challenges, including HIV, tuberculosis, and emerging infectious diseases. Our mission is to translate scientific discoveries into affordable, globally accessible public health solutions. Read more at iavi.org.