One of the most promising attempts to reinvigorate the stalled quest for an HIV vaccine has hit a snag that might seem minor but has major consequences: delaying the larger trials needed to show whether the concept works.
In small safety and immune tests of the innovative vaccine strategy, which relies on a series of messenger RNA (mRNA) shots, an unusually high percentage of recipients developed rashes, welts, or other skin irritations, the journal Science reports.
“We are taking this very seriously,” says Carl Dieffenbach, who heads the Division of Aids at the US National Institute of Allergy and Infectious Diseases, which funded a recent phase 1 trial of the vaccine.
‘Researchers want to understand the cause of the skin problems and how to minimise them before expanding tests of the vaccines, which are made by Moderna, and we would be moving more quickly if this finding had not been observed,” said Mark Feinberg, who heads IAVI, a non-profit organisation that is the vaccine’s major sponsor.
The complex vaccine strategy involves injections of different mRNAs, encoding various pieces of HIV’s surface protein or the entire molecule, over the course of several months. The goal is to gradually guide the immune system’s B cells to produce so-called broadly neutralising antibodies, or bnAbs, capable of stopping many different variants of the Aids virus.
People living with HIV on rare occasions eventually produce bnAbs, but no vaccine has ever done so – which has become the “holy grail” for the field, says Linda-Gail Bekker, who runs the Desmond Tutu HIV Centre at the University of Cape Town.
Different versions of this HIV vaccine have already gone through three phase 1 trials, but they totalled fewer than 200 participants. The recipients responded with impressive antibodies that were moving toward bnAbs, fuelling hopes for the vaccines.
But skin problems, including urticaria (hives), pruritus (itching), and dermatographism (welts after scratching), occurred at a noticeably high level in all of the studies, affecting 11 out 60 people in one of them.
These HIV vaccines deliver a relatively high dose of mRNA, which Moderna scientists and others think could explain the skin issues.
The company’s original Covid-19 mRNA vaccine used the same dose and has also been linked to skin problems, although at much lower frequencies, of 1% to 3%. (The Pfizer-BioNTech collaboration’s Covid-19 vaccine, also based on mRNA but given at a 70% lower dose, triggers skin problems, too, but one Swiss study suggests they occur 20 times less frequently than with the Moderna product.)
Potentially more worrisome, however, would be if the problem is tied to a cumulative effect from multiple mRNA shots or the genetic background of the recipients, or if the HIV sequence itself were responsible for the welts and hives.
Most of these skin problems resolved quickly and weren’t severe enough to stop any trial, but researchers do not want to minimise them.
“At a time when vaccine hesitancy is high, it is critically important not to dismiss urticaria as an unimportant side effect,” says Kimberly Blumenthal, an allergist at Massachusetts General Hospital who has also found a link between Moderna’s Covid-19 vaccine and higher rates of urticaria.
Feinberg agrees the side effect issue needs studying, but is also concerned that people who are vaccine opponents might misrepresent the scope of the problem.
“This finding has not been seen to the same frequency with other mRNA vaccines against other pathogens,” he says.
Had the problem in the HIV trials not surfaced, the researchers would have moved closer to conducting – or even launched – a study that involved a few hundred people and had a placebo control. If the results were positive, a phase 3 efficacy trial would determine whether it was safe, worked, and should come to market.
“We’ve hit this rather miserable bump in the road,” Bekker says.
Multiple research groups are pursuing similar strategies to create bnAbs.
Moderna’s effort grew out of a project led by biophysicist William Schief, who developed it at Scripps Research and then brought the strategy to the company, where he is now a vice-president.
It exploits the fact that B cells begin as naïve, or germline, cells and then, during an infection, undergo a series of mutations that, in effect, hone the ability of the antibodies they produce to bind to specific parts of viruses and “neutralise” their ability to infect cells.
The “germline targeting” vaccine strategy relies on several shots to take B cells through this maturation process, eventually leading them to produce bnAbs against viruses.
“We call it priming, shepherding and polishing,” says Dennis Burton, an immunologist at Scripps who works with Schief. Initially the group did not use mRNA. Its vaccine contained a small piece of HIV’s viral surface protein attached to a nanoparticle that presented it to the immune system in a novel way, and early results were promising.
In a 2022 Science paper, Schief and colleagues reported that 97% of the 36 people who received the vaccine developed the B cell antibody gene mutations needed to progress toward becoming broadly neutralizing.
Schief switched to mRNA because it provides far more flexibility, allowing the researchers to readily fine-tune the HIV component of the vaccine.
Because of the enormous diversity of HIVs in circulation, he contends that an effective vaccine will probably have to trigger production of up to five different bnAbs.
That would mean priming, shepherding, and polishing multiple B cell lineages.
Without the easy-to-modify mRNA, Schief says, “good luck – that is a daunting, daunting task”.
NIAID now plans to repeat the phase 1 trials of some of these Moderna/IAVI HIV vaccines with a lower dose.
Bekker is still hopeful the approach will pan out. “We’ve got to chapter one of an exciting novel.”
After decades of failed attempts to develop an HIV vaccine, the goal remains pressing, she says. “Last year, the world had 1.3m infections of HIV. I think it remains an urgent requirement to find a good solution.”
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