Key Insights
- Vaccinating against HIV has been a decades-long effort, stymied by the virus’s high mutation rate and mask of human glycans.
- In recent years, germline targeting—a vaccinate-and-boost approach that coaches the immune system toward producing antibodies that bind in a highly specific way—has picked up steam.
- Researchers from several teams have cleared a new milestone in primates, raising antibodies that can neutralize multiple strains of HIV.
Since the height of the AIDS crisis, when researchers first began to test possible vaccines against HIV, medical advances have revolutionized living with the virus. But while drugs to treat HIV and prevent infection have come a long way, a vaccine that uses a patient’s own immune system has remained out of reach.
In recent months, a flurry of papers have described promising results from primate studies of vaccines that gradually train the immune system to recognize HIV’s sugar-coated envelope protein. Scientists can, for the first time, raise antibodies that could block HIV from infecting cells.
Components from two of the papers are already in early clinical testing in humans. But with US funding for HIV research, which supported most of these projects, evaporating, the future of these projects is uncertain.
“We believe we are on the most promising path ever pursued for the development of an effective vaccine against HIV.”
Training B cells to produce the right antibodies
For an effective vaccine, researchers need the immune system’s B cells to produce antibodies that recognize HIV’s envelope glycoprotein and block it from getting into cells. From time to time, researchers have isolated broadly virus-neutralizing antibodies from people living with HIV. But these antibodies are rare; because the envelope protein is quick to mutate, highly diverse, and camouflaged by human glycans, it takes an unusually flexible antibody to reach under the glycan shield and recognize specific, widely conserved epitopes.
Persuading an uninfected body to make similar antibodies is difficult because their fine-tuning depends on repeated encounters between B cells—which are constantly reshuffling and fine-tuning their antibody-producing genes—and the virus, which also mutates frequently. “It’s just a race between these two,” says Lorie Marchitto, a postdoc at the University of Pennsylvania and co–first author on one of the recent vaccine studies. “One evolves, the other evolves, until you have the perfect antibody.”
To try to guide the immune system to produce broadly neutralizing antibodies (bnAbs), immunologists have worked to design priming immunogens that activate naive B cells that show potential to make the right kind of antibody, and a series of boosters that keep the B cells engaged. The process leads the B cells through the evolution-like process of affinity maturation.
The end goal is groups of antibodies shaped just right to target a conserved part of the HIV envelope.
Three HIV vaccine candidates announced
Researchers have worked the B cell training strategy for years, and a few groups have shown that the priming step can work in humans to expand the B cells that make bnAb precursors. But until now, no one had managed to induce an immune response that put bnAbs against HIV into circulation.
Now, all at once, three groups of researchers have cracked the problem. Barney Graham, a vaccinologist at the Morehouse School of Medicine who spent most of his career at the National Institute of Allergy and Infectious Diseases and who was not involved in these studies, says, “This is a major biological step and a major immunological step.”
The three research teams use different approaches to engineer the perfect training series for B cells. They are going after different target regions on the envelope glycoprotein, employing diverse immunogen series, and testing different delivery modalities, including messenger RNA (mRNA), soluble protein complexes, and structured nanoparticles.
In a paper published this April, researchers at Scripps Research and the Karolinska Institute showed that macaques immunized against a region of the envelope protein called the apex produced antibodies that could neutralize a variety of HIV strains (Nature, DOI: 10.1038/s41586-026-10429-3). Corresponding author Gunilla Karlsson Hedestam said in a press release, “The study shows that it is possible, through vaccination, to steer the immune system towards this specific part of the HIV surface protein.”
Then, at the end of June, scientists led by Beatrice H. Hahn and George M. Shaw at the University of Pennsylvania described a vaccine series driven by a new priming antigen that can rapidly raise bnAbs against the apex in macaques (Nature, DOI: 10.1038/s41586-026-10838-4).
According to Marchitto and her co–first author Ryan S. Roark, the work depended on closely following the way B cell lineages and their antibodies develop over time in a primate infection and on precise structural understanding of how intermediate antibodies interacted with epitopes. By studying the structures of intermediate antibodies in complex with immunogens, Marchitto says, the researchers could identify specific amino acid changes they needed to encourage. “And when we did that in a vaccine trial, that gave breadth [of neutralizing activity].”
“From that point on, we were kind of blind. . . . But we made pretty good guesses, and it did work.”
In a third paper, also published at the end of June, a consortium of researchers led by William Schief, a professor at Scripps Research who is also vice president of protein design at Moderna, describes vaccinating macaques with a series of eight protein immunogens against a different region of the envelope glycoprotein (Nature, DOI: 10.1038/s41586-026-10837-5). As in the other studies, macaques immunized with this series produced circulating antibodies that can neutralize a range of HIV isolates; Schief estimates that the immune response in the best-responding animal would offer about 90% protection to roughly half of circulating HIV strains if it were replicated in humans.
That study was initially planned to test a regimen of just a primer and a single booster, Schief tells C&EN, because engineering an effective first booster is even harder than designing a good priming immunogen. But when they analyzed B cell populations from animals that received their three candidate boostesr, the researchers found such promising antibody precursors that they applied for more funding to keep working with the same animals, in hopes of eliciting the coveted bnAb-producing cells they had been working toward. “From that point on, we were kind of blind,” Schief says. “We designed a series of candidate boost immunogens that were successively closer and closer to native envelope, but we didn’t know how the B cells would evolve after each boost. So there was a possibility that the bnAb-precursor B cells might not mature into bnAbs or might even die out entirely. But we made pretty good guesses, including by using nanoparticles as the last vaccination, and it did work.”
Darrell Irvine, a Scripps immunologist and bioengineer who works with Schief, says “there several steps remaining to get us to a bona fide vaccine.” Researchers will probably need to coax out bnAbs to bind three or four sites on the envelope protein, instead of just one, he says. The resulting vaccine would also need to raise a durable immune response, and it would be more practical if it required fewer injections.
And, critically, it would have to work in humans.
Difficult conditions for clinical development
The priming immunogen from the Scripps consortium is already being tested in humans in two trials. A phase 1 study of the protein immunogen, based in the US, recently concluded and is being analyzed, and in January, the global vaccine nonprofit International AIDS Vaccine Initiative (IAVI) announced that researchers in South Africa had begun dosing uninfected volunteers in a phase 1 study of an mRNA version.
But conditions for further development will be challenging. The US National Institutes of Health terminated its support for HIV vaccine programs, effective June 30. That brought an end to two massive research consortia that had run for decades, including the team headquartered at Scripps. According to Irvine, “The Nature paper came out literally on the last day of the consortium, which is bittersweet.”
Meanwhile, a trial in South Africa of the apex-targeting vaccine developed at Scripps and the Karolinska Institute was almost canceled when the US Agency for International Development (USAID) cut its funding. The trial is still running but had to be scaled back dramatically in light of smaller dollar amounts from South Africa’s research council and the Gates Foundation. The latter has invested in HIV vaccine development for years, and “is continuing to do so at the present time,” says Schief, adding that researchers also have applied for other NIH funding.
“It’s inevitable that the work will continue. It’s just a matter of who gets to lead the work and how fast it progresses,” Graham says.
Federal funders are also moving to make animal research—such as proof-of-concept studies in primates—more difficult. And antivaccine sentiment at the US Food and Drug Administration, especially with respect to mRNA technology, has delayed approvals for other vaccines from Moderna.
“With this year’s global funding cuts to HIV prevention, care, and treatment, bringing new prevention tools forward is more important than ever,” the CEO of IAVI, Mark Feinberg, said in a statement released in January, at the beginning of the mRNA vaccine trial. “We believe we are on the most promising path ever pursued for the development of an effective vaccine against HIV.”
