In a small trial across ten U.S. research sites, a novel HIV vaccine candidate has shown a result that has eluded scientists for four decades: it reliably produced potent, virus-blocking antibodies in most participants.
The work, published last week in Science Translational Medicine, tested three experimental vaccines built with the same mRNA technology used in COVID-19 shots but with a crucial twist. Instead of encoding HIV’s outer protein in its free-floating form, two of the vaccines instructed cells to make a “membrane-anchored” version, mimicking how the protein appears on the actual virus.
That one subtle change made a striking difference. After three doses, 80% of volunteers who received a membrane-bound version produced “tier 2” neutralizing antibodies. This is a benchmark that suggests good protection against the virus. Meanwhile, in the group that received the traditional soluble form, only 4% did.
“The difference is pretty striking,” Sharon Lewin, head of the Peter Doherty Institute for Infection and Immunity, who was not involved in the research, told Nature. “These are the first studies, so they’re very, very important.”
Why is an HIV vaccine so hard to make
Since its discovery in 1983, HIV has proven uniquely slippery. The virus wears a dense coat of sugars, shielding key targets from antibodies, and mutates so rapidly that even an immune system that manages to block one strain is often powerless against the next.
For decades, most vaccine candidates have targeted the “envelope trimer”—a three-pronged protein that HIV uses to latch onto immune cells. In reality, much of the trimer’s base is hidden against the viral membrane. Soluble protein vaccines, however, expose that base. This, in turn, prompts the body to make antibodies that bind there. But these antibodies can’t stop the actual infection.
The new approach, developed by William Schief and colleagues at Scripps Research and Moderna, anchors the protein to cell membranes. That way, the immune system learns to recognize more vulnerable, real-world parts of the virus and can effectively eliminate the virus
Over 100 HIV vaccine trials have been undertaken over the years. But this one seemed particularly promising.
Animal tests hinted that such vaccines might work better. The new trial, involving humans, confirmed it.
What the Trial Found
The study enrolled 108 healthy adults aged 18 to 55. Participants were randomly assigned to one of three vaccines: the soluble trimer, a membrane-bound trimer, or a membrane-bound version with a mutation to block CD4 receptor binding. Each group received either a low (100 μg) or high (250 μg) dose, three times over six months.
Tests on volunteers’ blood showed that the membrane-bound vaccines spurred a stronger immune reaction than the traditional approach. They also seemed to “train” the immune system to focus less on parts of the virus that don’t help much in stopping infection, and more on its weak spots—regions known as V1/V3 and C3/V5—that are more likely to block HIV.
These vaccines also built up a stockpile of memory B cells, which act like long-term sentries, and activated specialized T cells, which help coordinate the body’s entire immune defense. The entire body’s immune system mobilized for the task.
But there were limits. The antibodies produced were “autologous.” They recognized the particular virus strain the vaccine had, but not the many other HIV strains circulating worldwide. The ultimate goal is to elicit broadly neutralizing antibodies (bnAbs), which can target conserved sites across diverse strains.
The side effects were significant, but not truly threatening.
Seven participants — about 6.5 percent — developed hives, or urticaria, after vaccination. In five cases, the condition became chronic, lasting more than six weeks; in some, symptoms persisted for years. The reaction occurred across all three vaccine types, at both doses, and has not been seen in mRNA vaccines against other viruses.
“It is a scientific mystery at the moment,” Schief told New Scientist.
Researchers suspect that something about the combination of HIV proteins and the mRNA delivery platform triggers the effect, but they have yet to pinpoint the cause. Future trials will test lower doses in hopes of reducing the risk.
Can we actually make an HIV vaccine?
Despite all the unknown variables, the study is a milestone. Only two other mRNA HIV vaccine trials have ever reached human testing, and none until now have shown such a high rate of neutralizing antibody production. It’s truly promising.
Experts say the technology’s speed and flexibility brought by mRNA (which allows new designs built in just months) can accelerate the long, trial-and-error process of training the immune system to fight HIV. In the future, scientists could program a single mRNA shot to release a full sequence of priming and boosting proteins in timed waves, replacing months or even years of repeated clinic visits.
But it’s far from a solved problem. First, studies with a greater sample size need to demonstrate safety and effectiveness. Then, researchers need to find a way to make the vaccine effective against multiple strains.
But it’s a worthy task.
Even the best current HIV prevention tools, such as the twice-yearly injectable drug lenacapavir, require ongoing use and access to healthcare. A durable, widely protective vaccine would be transformative, especially in low-resource settings.
