In the long battle to create an effective HIV vaccine, scientists have made a major leap forward. A new study shows that a series of vaccines can coax the immune system to produce powerful antibodies capable of blocking a wide range of HIV strains — including those that are typically the hardest to stop.
Published in Immunity on May 7, 2025, the research comes from a collaboration led by scientists at Scripps Research and Sweden’s Karolinska Institute. Their results mark a strong demonstration that broadly neutralizing antibodies (bNAbs) — long considered a key goal for HIV vaccination — can be successfully induced in nonhuman primates. It also points to a new target on the HIV spike protein that future antibodies may be able to successfully bind to block the virus.
“What sets this work apart is that we didn’t just see initial signs of a promising response; we actually isolated functional broadly neutralizing antibodies and pinpointed exactly where they bind on the surface of the virus,” says senior author Richard Wyatt, professor in the Department of Immunology and Microbiology at Scripps Research. “This tells us not only that the approach works, but also specifically why it works.”
Because HIV rapidly mutates and there are literally millions of different strains circulating in humans around the world, scientists have focused their research efforts on creating vaccines that can stimulate the body to produce bNAbs that simultaneously recognize many strains at once. While some people spontaneously produce bNAbs after exposure to HIV, it has been a challenge to create a vaccine that reliably induces bNAbs in nonhuman primates or humans.
A two-step strategy
In the new work, Wyatt and his team first designed a mimic for the HIV spike protein — a key section of HIV’s machinery that antibodies target to block infection. Unlike earlier designs, the new “spike mimics” don’t fall apart after injection and closely resemble the HIV spike protein’s structure.
Then, the group turned to a two-step vaccination strategy. First, they primed the immune system with a version of the spike mimic that lacked key sugar molecules, which normally coat the protein and make it harder to recognize. This helped expose a critical, conserved region of the spike: the CD4 binding site, where the spike protein attaches to human immune cells.
After two sequential doses of the priming vaccine, five boosters were administered, each about twelve weeks apart. This booster series of spike proteins from different HIV strains — now with their sugar coat intact — retrained the immune system to recognize the same region even when it was partially hidden.
The deliberate sequence of vaccines, the researchers say, was key to success. “We weren’t just vaccinating at random,” says Javier Guenaga, a senior staff scientist at Scripps Research and co-first author of the new paper. “This was a rational, structure-guided approach to elicit the right kinds of antibodies.”
Encouraging results
The approach paid off. Several of the vaccinated animal models produced antibodies that could neutralize “tier 2” HIV strains, which are among the hardest to block. From one animal model, researchers isolated a family of antibodies, named LJF-0034, that neutralized nearly 70% of a global panel of 84 HIV strains.
“It is incredibly exciting to see a vaccine generate this kind of breadth in nonhuman primates,” says senior staff scientist Shridhar Bale, a co-first author of the work. “And it’s not just a one-off. We saw responses targeting this site in multiple animals.”
The group then showed that antibodies like LJF-0034 bound to a previously undescribed site on the virus, bridging two sections of the spike protein. Future research can help guide the development of additional vaccines targeting this new, promising site. Wyatt says his team would like to optimize the vaccine so that it can reliably elicit LJF-0034-like responses in a greater fraction of recipients.
Ultimately, an effective HIV vaccine regimen will likely include a combination of vaccines that yield different bNAbs, all acting together.
“This is far from a final vaccine,” says Wyatt. “But having a new, highly effective target is incredibly exciting and will help shape our efforts moving forward.”
One vaccine candidate used in this study is already being tested in a phase 1 clinical trial, with early results expected soon. In that trial, human participants are receiving the same spike protein (lacking sugar molecules) used as the priming vaccine in this study.
In addition to Wyatt, Bale, and Guenaga, authors of the study, “Vaccination of nonhuman primates elicits a broadly neutralizing antibody lineage targeting a quaternary epitope on the HIV-1 Env trimer,” include Richard Wilson, Jocelyn Cluff, Esmeralda D. Doyle, Gabriel Ozorowski, Xiaohe Lin, Leigh M. Sewall, Wen-Hsin Lee, Shiyu Zhang, Ian A. Wilson, and Andrew B. Ward of Scripps Research; Fabian-Alexander Schleich, Monika Àdori, Xaquin Castro Dopico, Mark Chernyshev, Alma Teresia Cotgreave, Marco Mandolesi, Martin Corcoran, and Gunilla B. Karlsson Hedestam of the Karolinska Institutet; Sijy O’Dell and Nicole A. Doria-Rose of the National Institute of Allergy and Infectious Diseases; Brandon S. Healy, Deuk Lim, Vanessa R. Lewis, Diane Carnathan, and Guido Silvestri of Emory University; and Elana Ben-Akiva and Darrell J. Irvine of the Massachusetts Institute of Technology.
This work was supported by funding from HIVRAD (P01 AI104722, P01 AI157299, P01 AI124337), Scripps CHAVD (UM1 AI144462), the James B. Pendleton Trust, the Swedish Research Council (2017-00968) and the Emory National Primate Research Center (ORIP/ODP51OD011132, U42PDP11023).
