Johnson & Johnson said Monday night that it would stop its trial to investigate an illness, which it did not specify, in a study participant. Meanwhile, AstraZeneca Plc’s US trial of the vaccine it is developing with the University of Oxford has been halted by regulators for more than a month after neurological symptoms appeared in two volunteers.
With AstraZeneca at a pit stop, Moderna Inc. vaccines and the Pfizer Inc.-BioNTech SE partnership have taken the lead in the race to be the first to fire. Meanwhile, the two trials on hiatus are reviving questions about adenoviral vectors, which have been used in laboratory, animal and human experiments for years. In some cases, the experiments have been successful, but not always.
And this year, with Covid-19 vaccines entering the politics of the moment with force, transparency and trust are key to fighting a virus that has affected more than 39 million people around the world and has paralyzed economies. Validating concerns about the side effects of experimental vaccines in trials using adenovirus could heighten skepticism in the general public and raise questions for other drug manufacturers.
“While it could be a coincidence,” said Sam Fazeli, an analyst at Bloomberg Intelligence, in a research note, “there is still the possibility that adenoviral vector vaccines are at increased risk of rare side effects, such as autoimmune attacks like transverse myelitis. – than those of Pfizer-BioNTech, Moderna or Novavax “.
Pauses to investigate side effects are not unusual in vaccine trials, which require a high safety bar because they are taken by healthy people. Oxford has said that there is not enough evidence to connect the diseases of the participants to their vaccine. Its human trials in the UK, South Africa and Brazil resumed weeks ago.
Adenoviral vectors are well-studied, versatile, and well-tolerated, making them good candidates for Covid vaccines, AstraZeneca said in an email. Reactions to the Astra / Oxford vaccine in early studies were comparable to those seen in previous trials of other vaccines using adenovirus, the company said. The Oxford researchers declined to comment.
In some cases, adenovirus experiments have been successful. Earlier this year, for example, a J&J vaccine based partially on an adenovirus was approved to fight Ebola, which has killed thousands in Africa.
In other experiments, however, there were disappointing results. In 2008, a vaccine that uses an adenovirus developed by Merck & Co. to prevent HIV was linked to an increase in infections among those who received it in a trial. Merck abandoned shooting and several similar programs fell by the wayside.
If researchers in current trials determine that the cause of the episodes is related to vaccines, they would look for potential links to the adenovirus approach, as well as to the spike protein that the vaccine is designed to prepare to prime the immune system for a actual infection. according to Michael Kinch, a vaccine specialist at Washington University in St. Louis.
At this point, he said, there is not enough information to know. “Is this just a fluke?” Kinch said. “First of all, there is bad luck. If it turns out that there is a correlation and a causality, then the conversation changes very quickly.”
J&J said he is still learning about the participant’s illness in his trial. The adenovirus in its experimental Covid injection has been used worldwide in more than 110,000 people, according to Paul Stoffels, the company’s chief scientific officer.
“We are building very quickly on a very large carrier safety database,” Stoffels said in an interview before the trial was stopped.
Gene switching
Discovered in human adenoid glands in 1953, adenoviruses have a number of characteristics that lend themselves to drug delivery. While some infect human cells easily, in most cases they only cause mild symptoms. Strains that appear in different animals, such as cows and chimpanzees, can be adapted for different purposes, such as veterinary vaccines.
And best of all, scientists have found that it is relatively easy to mix and match genes within them, offering a variety of characteristics and properties.
“The genes that control the proliferation capacity of the virus are removed,” said Ron Crystal, a researcher at Weill Cornell Medicine in New York who pioneered the use of adenoviruses as vectors, “and the genes are introduced.”
Viruses naturally add their genomes to those of cells, inducing them to produce viral proteins. In the 1990s, researchers added genes to an adenovirus to produce an enzyme that was missing in a genetic disorder.
The idea was for the infected cells to produce the enzyme, curing the disease. Instead, the first patient who was treated in this way died of a severe immune reaction.
“We didn’t realize how immunogenic these viruses were,” Crystal said.
The tragic death was a setback for gene therapy, which was only revived in recent years when several therapies that could save lives were approved, and even more are making their way through trials.
Meanwhile, drug and vaccine developers continued to create vaccines around much smaller doses of adenovirus. When used in smaller amounts, the immune reaction to adenovirus “is not a problem,” according to Crystal. If anything, vaccine designers see the body’s immune reaction as a potential advantage, he said.
“They basically act as adjuvants and that amplifies the immune response” to the vaccine, Crystal said.
Pre-existing human immunity to chimpanzee adenoviruses, such as that used in the Oxford vaccine, is less of a concern, said Lindsey Baden, an infectious disease specialist at Harvard-affiliated Brigham and Women’s Hospital, in a podcast sponsored by the New England Journal of Medicine.
Still, with these new technologies, “safety is hard to know,” said Baden, who has worked in the field of HIV vaccines for decades. “If you’ve studied it in 1,000 people, you don’t know a 1 in 10,000 risk; if you’ve studied it in 10,000 people, you don’t know a 1 in 100,000, and so on.”
If adenoviruses are associated with the side effects that have appeared in Covid vaccines, it can delay the development of numerous projects, as happened with HIV and gene therapy. There are more than a dozen Adenovirus-based Covid vaccines in development, according to the World Health Organization.
If researchers in current trials determine that the cause of the episodes is related to vaccines, they would look for potential links to the adenovirus approach, as well as to the spike protein that the vaccine is designed to prepare to prime the immune system for a actual infection. , according to Kinch of the University of Washington.
At this point, he said, there is not enough information to know. “Is this just a fluke?” Kinch said. “First of all, there is bad luck. If it turns out that there is a correlation and a causality, then the conversation changes very quickly.”
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