Ailments in Covid-19 trials raise questions about vaccine method

Two Covid-19 vaccines stalled by potential side effects have one key feature in common: Both are based on adenoviruses, cold germs that researchers have used in experimental therapies for decades with varying results.

Johnson & Johnson said late Monday it would pause its trial to investigate an illness, which it didn’t specify, in a study participant. Meanwhile, AstraZeneca Plc’s US trial of the vaccine it’s developing with the University of Oxford has been halted by regulators for more than a month after neurological symptoms arose in two volunteers.

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With AstraZeneca in a pit stop, vaccines from Moderna Inc. and the Pfizer Inc.-BioNTech SE partnership have taken the lead in the race to be first out with a shot. Meanwhile, the two paused trials are reviving questions about adenoviral vectors, which have been used in laboratory, animal and human experiments for years. In some cases, the experiments have succeeded, but not always.

And this year, with Covid-19 vaccines entering strongly into the politics of the hour, transparency and trust are key to fighting a virus that’s hit more than 39 million people globally and hamstrung economies. If concerns about side effects in experimental vaccines in trials using adenoviruses are validated, it could boost skepticism in the general public and raise questions for other drugmakers.

“While it could be a coincidence,” said Sam Fazeli, a Bloomberg Intelligence analyst, in a research note, “there’s still the possibility that adenoviral vector vaccines run a higher 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 aren’t unusual in vaccine trials, which require a high safety bar because they’re taken by healthy people. Oxford has said there’s insufficient evidence to connect the participants’ illnesses to their vaccine. Its human tests in the U.K., South Africa and Brazil resumed weeks ago.

Adenoviral vectors are well studied, versatile, and shown to be 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 adenoviruses, the company said. Oxford researchers declined to comment.

In some cases, experiments using adenoviruses have succeeded. Earlier this year, for instance, a J&J vaccine based partially on an adenovirus was approved to fight Ebola, which has killed thousands in Africa.

In other experiments, though, there were disappointing results. In 2008, a vaccine using an adenovirus developed by Merck & Co. to prevent HIV was tied to increased infections among some who received it in a trial. Merck abandoned the shot, and several similar programs fell by the wayside.

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If investigators in the current trials determine the cause of the episodes is related to the vaccines, they would look for potential links to the adenovirus approach as well as to the spike protein the vaccine is designed to make to prepare the immune system for a real infection, according to Michael Kinch, a vaccine specialist at Washington University in St. Louis.

At this point, he said, there’s not enough information to know. “Is this just random chance?” Kinch said. “First and foremost, there’s bad luck. If it turns out there’s a correlation and a causation, then the conversation very quickly turns.”

J&J said it’s still learning about the illness of the participant in its trial. The adenovirus in its experimental Covid shot 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 safety database of the carrier,” Stoffels said in an interview before the trial was paused.

Switching Genes

Discovered in human adenoid glands in 1953, adenoviruses have a number of features that lend themselves to drug delivery. While some infect human cells easily, they cause only mild symptoms in most cases. Strains that appear in different animals, such as cows and chimps, can be adapted to different purposes, such as veterinary vaccines.

And best of all, scientists have found it relatively easy to mix and match genes within them, offering a variety of features and properties.

“You take out the genes that control the ability of the virus to proliferate,” said Ron Crystal, a researcher at Weill Cornell Medicine in New York who pioneered the use of adenoviruses as vectors, “and put in your genes.”

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Viruses naturally add their genomes to those of cells, inducing them to make viral proteins. In the 1990s, researchers added genes to an adenovirus to make an enzyme that was missing in a genetic disorder.

The idea was that infected cells would make the enzyme, curing the disease. Instead, the first patient to be treated this way died from 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 only revived in the past few years as a number of potentially life-saving therapies were approved, and even more are making their way through testing.

In the meantime, drug and vaccine developers continued to build vaccines around much smaller doses of adenoviruses. When used in smaller amounts, the immune reaction to adenovirus is “not an issue,” according to Crystal. If anything, vaccine designers see the body’s immune reaction as a potential advantage, he said.

“They’re essentially acting as an adjuvant, and that amplifies the immune response” to the vaccine, Crystal said.

Pre-existing human immunity to chimpanzee adenoviruses like the one 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.

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Still, with such new technologies, “safety is difficult to know,” said Baden, who’s worked in the HIV vaccine field 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 may set back development of numerous projects, as it did with HIV and gene therapy. There are more than a dozen Covid vaccines in development based on adenoviruses, according to the World Health Organization.

Should investigators in the current trials determine the cause of the episodes is related to the vaccines, they would look for potential links to the adenovirus approach as well as to the spike protein the vaccine is designed to make to prepare the immune system for a real infection, according to Washington University’s Kinch.

At this point, he said, there’s not enough information to know. “Is this just random chance?” Kinch said. “First and foremost, there’s bad luck. If it turns out there’s a correlation and a causation, then the conversation very quickly turns.”