Ailments in Covid-19 Trials Raise
Questions About Vaccine Method
Questions About Vaccine Method
By John Lauerman, James Paton, and Stephanie Baker
October 17, 2020, 8:30 AM EDT
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.
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 U.S. 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.
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 U.S. 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.
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.
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.
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.”
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.
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.
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.
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.
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.
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.
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.”
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.
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.
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.
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.
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.”
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.”
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.
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.
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.
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.
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.
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.
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.
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.
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.”
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.
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.
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.”
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.”
— With assistance by Robert Langreth, Suzi Ring, and Riley
Griffin
Griffin
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