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Two vaccine candidates using mRNA technology elicit a potent immune response against HIV, according to an early-stage clinical trial1.
The trial is only the third to test mRNA vaccines against HIV. “These are the first studies, so they’re very, very important,” says infectious-disease physician Sharon Lewin, who heads the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia.
Around 41 million people globally live with HIV, for which there is currently no vaccine.
To design vaccines against a virus, researchers often study how the body clears the pathogen from its system, says Lewin. But HIV attacks the immune system, and the body rarely manages to clear it out. As a result, candidates for vaccines against the virus must undergo lots of testing through trial and error.
That makes HIV vaccines a good place to use mRNA technology. The first mRNA vaccine was approved in 2020, for COVID-19. Compared with other modes of delivery, mRNA vaccines can be modified at low cost quickly — in months, not years — which enables researchers to test out different strategies. The vaccines work by delivering instructions to cells, in the form of mRNA, to produce specific proteins typically found on the surface of viruses. This induces an immune response, which helps the body to recognize and clear out a virus, should it be exposed to the real thing.
HIV uses an ‘envelope’ protein on its outer membrane to bind to and infect cells. In the latest study, published in Science Translational Medicine, a team including William Schief at Scripps Research in La Jolla, California, who works on protein design, conducted a small trial, comparing two vaccine approaches. In one, the standard method for HIV vaccine candidates, the cell is directed to produce envelope proteins that float freely. In the other, the mRNA vaccine instructs the cell to make envelope proteins that are attached to the cell membrane — similar to how they are found in the live virus. The authors describe animal tests of this method in a companion paper2.
The trial involved 108 healthy adults aged between 18 and 55 across ten study sites in the United States. It tested two membrane-bound vaccine candidates and one unbound candidate.
Participants each received three doses of a single vaccine, at a low or high dose, several weeks apart; which vaccine they received was selected randomly. The vaccines were provided by pharmaceutical company Moderna in Cambridge, Massachusetts, where Schief is vice-president for protein design.
Some 80% of the participants who received either of the vaccines that made membrane-bound proteins went on to produce antibodies that could block that protein from entering cells. By contrast, only 4% of the participants who received the unbound-protein vaccine produced corresponding antibodies.
“The difference is pretty striking,” says Lewin. She expects the findings to inform the development of future vaccine candidates.
All three vaccines were well tolerated by most participants, in both high and low doses. However, seven people — 6.5% of the study group — developed hives, large, itchy rashes. Five of them had symptoms that lasted for more than six weeks, some even for years. The reaction was seen across all three vaccine candidates, at both doses.
Two previous trials by the same team, described in May3, tested a strategy in which participants receive initial injections of one mRNA vaccine candidate and booster doses of others, with the goal of inducing a broad immune response that could defend against a range of HIV variants. The approach made good progress. The trials were conducted in the United States, Rwanda and South Africa.
In one of those trials, 18% of participants developed hives or other skin reactions. In their May paper, Schief and his colleagues determined that something about the combination of HIV and mRNA — not each individually — probably caused the side effect, but they couldn’t pinpoint what exactly. Lewin says researchers need to work out what is causing these side effects to help prevent them, but they aren’t a reason to stop experimental development of HIV mRNA vaccines. “The need for an HIV vaccine is high,” she says.
Schief and his colleagues plan to conduct trials using lower doses of mRNA to see whether this results in fewer cases of hives. They intend to focus on membrane-bound versions of the protein.
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