Scientists have triggered protective levels of HIV-fighting antibodies in monkeys with unmodified immune systems for the first time, a new study in Nature reports — a milestone more than a decade in the making.
While only one primate produced antibody levels expected to guard against infection, and fewer than half showed any neutralising response, researchers said the result mattered less for its scale than for how it was achieved: through a process called germline targeting.
Most vaccines work by showing the immune system a piece of a virus and hoping that, among the countless responses it could make, a useful one turns up. Germline targeting reverses that: it starts from the antibody the vaccine wants the body to produce, finds the rare cells already capable of becoming it, and trains them there directly — closer to recruiting the person who can already do the job than advertising the vacancy and hoping the right applicant shows up.
“How could we flip the whole immune response on its head so the rare responses become the common responses? That was a critical challenge we faced,” said Shane Crotty, chief scientific officer at La Jolla Institute for Immunology, who co-led the research with Scripps Research’s William Schief, in a statement by the institute.
{{/usCountry}}“How could we flip the whole immune response on its head so the rare responses become the common responses? That was a critical challenge we faced,” said Shane Crotty, chief scientific officer at La Jolla Institute for Immunology, who co-led the research with Scripps Research’s William Schief, in a statement by the institute.
{{/usCountry}}In more technical terms, the vaccine works by intervening in B cell maturation. B cells make antibodies, but begin in an early “naive” stage before they are ready to. Once a rare class of naive B cell that already carries the genetic material needed to eventually produce a broadly neutralising antibody is identified — in this case, one capable of disabling many HIV strains, not just the one it first meets —it is through an engineered sequence of shots: a prime, boosters, and a final “polishing” stage, designed to walk it step by step into maturity.
“This series of vaccinations will guide, or ‘walk’, a B cell from its naive state to its broadly neutralising state,” said Patrick Madden, according to the LJI statement.
Nearly every HIV vaccine to reach large-scale human testing has failed outright, or worse. Only RV144, which reported results in 2009, has ever shown a protective effect, and even that was too weak to bring to market: 31% efficacy at three and a half years.
A Merck vaccine, tested in the STEP trial, was halted in 2007 after monitors found it was raising infection risk in some vaccinated men rather than lowering it. A redesigned version of the same regimen, tested in South Africa a decade later as HVTN 702, showed no protective effect.
Two further vaccines, built from mixed fragments of several HIV strains — Imbokodo and Mosaico — were both stopped for lack of effect, in 2021 and 2023.
None of those vaccines used germline targeting. The authors of the latest study see the new approach as hopeful given how HIV has been among the biggest challenges of modern medicine.
The scientists studied what made the HIV-fighting B cells special, then traced the process back to see how they matured as they were shown specific pieces of HIV’s structure. They found B cells matured toward broadly neutralising antibodies after an early look at a section of HIV’s outer “envelope” protein — a site that triggers an immune response, which researchers call an antigen.
HIV’s vast diversity — the mutations it quickly acquires let it evade a vaccine built against any single strain — means a useful antibody has to recognise what stays the same underneath that variation.
The idea, then, is that each booster in the sequence reintroduces more of that real-world variability, exposing the immune system to increasingly complex, native-like versions of HIV, so the antibody that eventually emerges has been tested against something closer to the diversity it would actually face
Overall, 44% of the animals developed neutralising antibodies in their blood — and it was only within that group that the strongest response reached protective levels.
“It was incredible to get those results, but of course we’d like to see a response in 100 percent of the animals,” Madden said.
The vaccinated animals were not exposed to HIV afterwards, so the study does not show that the antibodies actually prevent infection — only that, in the strongest-responding animal, antibody levels reached a threshold other research has linked to protection.
To be sure, it will be years before success is replicated in humans — if it replicated at all. Only the priming shot has been tested in people; the full three-stage regimen used on the monkeys hasn’t. Even a clean human result would only show the vaccine can produce the right antibodies in a person — not that those antibodies protect against HIV. That’s a separate, larger trial and germline targeting hasn’t come close to it yet.