A new HIV vaccine developed by La Jolla Institute for Immunology (LJI), Scripps Research Institute scientists, and IAVI has the potential to protect humans from HIV infection and the development of AIDS. For the first time, this HIV vaccine produces large amounts of “broadly neutralizing” antibodies that fight the virus in primates.
“We feel this is a huge success,” says LJI Professor and Chief Scientific Officer Shane Crotty, Ph.D., who led the study with Scripps Research Professor William Sheeff, Ph.D. “We built a successful vaccine from scratch, which required a deep understanding of the immune system.”
This groundbreaking research natureis the result of a 14-year collaboration between the La Jolla Institute for Immunology and Scripps Research as part of the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD). “This is one of the Apollo lunar exploration projects, with exceptional goals and requiring the team to make countless discoveries and inventions along the way,” Crotty said.
Outwit HIV
The new vaccine works by intervening in a process called B cell maturation. B cells make antibodies. Like many immune cells, B cells have an initial “naive” stage before they are ready to make antibodies. B cells begin to mature when they receive a signal that a pathogen, such as a virus, is about to attack. B cells recognize parts of the pathogen’s molecular structure and begin producing antibodies that can bind to that structure and stop the infection.
It can take some time for B cells to find the right “landmark” on a pathogen. But B cells keep trying. As B cells mature, they fine-tune their antibody production, refining the antibody structure to bind to pathogens at the right vulnerable points.
Scientists describe B cell development as a training process or boot camp. In most cases, the body is left with a highly honed army of B cells.
HIV is difficult to defeat because it does not give B cells a chance to produce effective antibodies. The first problem is that HIV hides from the immune system. Viruses are wrapped in a mantle of constantly changing sugar molecules called glycans. This allows HIV to pass through glycan-coated human cells undetected.
The second big problem is that HIV mutates very quickly. “The diversity of global HIV mutations is extraordinary; the variation even within a single individual living with HIV is dramatic,” says LJI instructor Dr. Patrick Madden, who served as co-lead author of the study with John Steichen, Ph.D., a research associate at the Scripps Research Institute.
The third problem is that HIV changes its shape when it infects human cells. Even if B cells catch a glimpse of the structure of the virus, the structure changes.
Taken together, these problems provide little opportunity for B cells to hone their antibody responses to HIV. Even if B cells are able to produce neutralizing antibodies, the virus can mutate or change shape, rendering those antibodies useless.
LJI and the Scripps research team have spent years searching for “broadly neutralizing” antibodies that can actually bind to HIV and recognize key viral structures even if the rest of the virus has mutated. These antibodies are very rare but may be detected in blood samples from a small number of people living with HIV.
An effective HIV vaccine must prompt the immune system to produce these same broadly neutralizing antibodies. “How do we flip the entire immune response so that a rare response becomes a common response? That was a critical challenge we faced,” Crotty says.
testing new vaccines
It’s time to return to B-cell boot camp. Scientists have studied what makes the B cells that fight HIV so special. They then reversed this process and looked at exactly how B cells mature. By looking back at the maturation process, the researchers were able to track how B cells changed when looking at specific parts of the HIV structure.
After early observations of some of HIV’s outer “envelope” proteins, the researchers discovered that B cells mature to produce broadly neutralizing antibodies. Scientists call these viral parts “antigens” because they trigger an immune response.
An effective HIV vaccine will likely need to include models for these antigens. Antigens would function like mugshots of America’s most wanted people. If B cells can recognize these antigens early and often, they will become very good at recognizing and even neutralizing HIV.
We were trying to mimic the progression of these neutralizing antibodies. ”
Dr. Patrick Madden, LJI Instructor
In a feat of molecular engineering, the Seeff Institute has developed a vaccine molecule that resembles the real HIV antigen. The scientists then worked with the Emory National Primate Research Center to test this potential HIV vaccine in nonhuman primates called rhesus macaques.
The researchers first administered a “priming” vaccine aimed at activating each animal’s naïve B cells. The animals then received a series of “shepherding” booster shots to help the B cells grow along the right path.
“This series of vaccinations takes B cells from a naive state to a broadly neutralized state, or ‘walks’ them,” Professor Madden said.
This new type of vaccine approach is called “germline targeting” because it targets “germline” or naive B cells before they begin the training process.
The researchers found that about 44 percent of the animals produced broadly neutralizing antibodies against HIV in their blood. These antibodies were surprisingly abundant.
“We were able to take a very rare antibody response and turn it into a common response by the end of the vaccination process,” Crotty added. Other recently published studies reported new strategies to accelerate relevant vaccine antibody responses.
Although the research team did not test whether these antibodies could protect against infection, it is important to note that these antibodies are present in the blood and may encounter and block HIV.
Bringing an HIV vaccine to humans
The Crotty Lab will investigate how booster regimens can be modified to make HIV vaccines even more effective. “It was incredible to see these results, but of course we want to see a response in 100% of the animals,” Madden says.
Importantly, the antibodies found in the animal subjects were exactly the same type of broadly neutralizing antibodies seen in rare humans who have created their own neutralizing antibodies. It is clear that with proper training, our immune system is capable of producing these powerful antibodies.
“Thanks to immunogenetics, we believe this vaccine approach has an even higher chance of success in humans,” Crotty says.
The priming immunogen used in this study was evaluated in humans in the HVTN 144 trial and is currently being tested in the Phase 1 trial IAVI G004. IAVI, Scripps Research, the HIV Vaccine Trials Network, and partners are currently planning to further evaluate the complete immunization regimen in future human clinical studies.
sauce:
La Jolla Immunology Institute
Reference magazines:
Steichen, J.M.; Others. (2026) Vaccination induces antibodies that broadly neutralize HIV in primates. Nature. DOI: 10.1038/s41586-026-10837-5. https://www.nature.com/articles/s41586-026-10837-5
