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 Behind the scenes, scientists and medical experts are concerned that
rushing a vaccine could end up worsening the infection in some
patients rather than preventing it.
Studies have suggested that coronavirus vaccines carry the risk of
what is known as vaccine enhancement, where instead of protecting
against infection, the vaccine can actually make the disease worse
when a vaccinated person is infected with the virus. The mechanism
that causes that risk is not fully understood and is one of the
stumbling blocks that has prevented the successful development of a
coronavirus vaccine.
Normally, researchers would take months to test for the possibility
of vaccine enhancement in animals. Given the urgency to stem the
spread of the new coronavirus, some drugmakers are moving straight
into small-scale human tests, without waiting for the completion of
such animal tests.
"I understand the importance of accelerating timelines for vaccines
in general, but from everything I know, this is not the vaccine to
be doing it with," Dr Peter Hotez, dean of the National School of
Tropical Medicine at Baylor College of Medicine, told Reuters.
Hotez worked on development of a vaccine for SARS (Severe Acute
Respiratory Syndrome), the coronavirus behind a major 2003 outbreak,
and found that some vaccinated animals developed more severe disease
compared with unvaccinated animals when they were exposed to the
virus.
"There is a risk of immune enhancement," said Hotez. "The way you
reduce that risk is first you show it does not occur in laboratory
animals."
Hotez testified last week before the U.S. House Committee on
Science, Space and Technology about the need for sustained funding
for vaccine research. There remains no vaccine for any of the new
coronaviruses that have caused outbreaks in the past 20 years.
At least for now, the world's experts have concluded that
accelerated testing is a risk worth taking.
At a specially convened World Health Organization (WHO) meeting in
mid-February, designed to co-ordinate a global response to the new
coronavirus, scientists representing government-funded research
organizations and drugmakers around the world agreed that the threat
was so great that vaccine developers should move quickly into human
trials, before animal testing is completed, four people who attended
the meeting told Reuters.
"You want to have a vaccine as quickly as possible," Dr Marie-Paule
Kieny, former assistant director-general at the WHO, who co-chaired
the meeting, told Reuters. "You have to balance this with the risk
that you impose on a very small number of people, and do all you can
do to mitigate this risk as much as possible."
The conclusion of that meeting, which was not open to media, has not
been officially publicized by the WHO. It does not reflect any
official position adopted by the WHO, a United Nations body whose
job it is to help shape global health policy.
Regulatory oversight of drugmakers and medical research is in the
hands of national regulators. The most powerful of those, the U.S.
Food and Drug Administration (FDA), has signaled that it is in
agreement with the consensus and will not stand in the way of
accelerated testing schedules.
"When responding to an urgent public health situation such as novel
coronavirus, we intend to exercise regulatory flexibility and
consider all data relevant to a certain vaccine platform," FDA
spokeswoman Stephanie Caccomo said in a statement. The agency had no
comment specifically on animal testing for vaccine enhancement.
Coronavirus vaccine developers are still required to conduct routine
animal testing to make sure the vaccine itself is not toxic and is
likely to help the immune system respond to the virus.
SEATTLE RISK
Some 20 coronavirus vaccine candidates are being developed by
research institutes and drugmakers including America's Johnson &
Johnson and France's Sanofi SA. The U.S. government has earmarked
more than $3 billion for coronavirus treatments and vaccines.
Biotechnology company Moderna Inc, which is working with the
U.S.-funded National Institutes of Health (NIH), is the closest to
human testing, announcing plans to start a trial with 45 people in
Seattle this month.
Testing for the specific risk of vaccine enhancement in animals will
proceed simultaneously with human trials, the NIH told Reuters,
which it said should establish whether it is safe to expose larger
numbers of people to the vaccine. Moderna did not respond to
requests for comment.
The plan is consistent with the WHO consensus and FDA requirements,
said Dr Emily Erbelding, director of the Division of Microbiology
and Infectious Diseases of the National Institute of Allergy and
Infectious Diseases (NIAID), part of the NIH. The trial is expected
to take 14 months, a spokeswoman for the NIH said.
Dr Gregory Poland, a virologist and vaccine researcher with the Mayo
Clinic in Rochester, Minnesota, expressed doubts about that
approach. "This is important, but it has to be done in a way that
reassures scientists and the public that these (vaccines) are not
only efficacious, but safe," he told Reuters.
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Hotez said he was surprised human trials were going ahead. "If there is immune
enhancement in laboratory animals vaccinated with the Moderna vaccine, that's a
showstopper," he said.
U.S. immunotherapy company Inovio Pharmaceuticals Inc, which is developing a
coronavirus vaccine in collaboration with a Chinese company, also expects to
start human clinical trials in 30 U.S. volunteers in April rather than wait for
animal studies on vaccine enhancement.
"The community as a whole weighed that and said we don't want to delay the
clinical process. We've been encouraged to go as rapidly as possible into Phase
1 studies," Inovio Chief Executive Joseph Kim told Reuters.
The company plans to start human safety trials shortly thereafter in China and
South Korea - two countries that have been hit hard by the virus. Kim said he
expects to have an answer to the question of vaccine enhancement at some point
this year.
The Moderna/NIH trial is enrolling patients at the Kaiser Permanente Washington
Health Research Institute in Seattle. The choice of location, made several weeks
ago, could prove to be problematic.
To reduce the risk to volunteers, scientists at the WHO meeting recommended that
drugmakers restrict early clinical trials to small groups of healthy people and
conduct them in places where the virus is not spreading, according to Kieny, who
now works at French research institute Inserm. That lowers the chances that
people who get the vaccine could encounter the virus and trigger a more severe
reaction.
Since the location was chosen, the Seattle metro area has emerged as the
epicenter of infections in the United States. Washington state has reported 162
coronavirus infections and 22 deaths, out of a total of 755 infections and 26
deaths in the country as of Tuesday, according to a tally by Johns Hopkins
University.
Research, including that conducted by Hotez, has shown that coronaviruses in
particular have the potential to produce this kind of response. But testing for
the risk of vaccine enhancement is time-consuming because it requires scientists
to breed mice that are genetically altered to respond to the virus like humans.
Work on these and other animal models is just getting under way in several
laboratories around the world.
Moderna, Inovio and several other vaccine developers are not waiting for that
process to be completed and are planning to launch human trials in record time
for a virus that was only discovered in December.
Nevertheless, Moderna and the NIH plan to go ahead.
"We think there is no reason to have to change the site. If you change it, there
might be community transmission in another site over the next couple of weeks,"
Erbelding said. "Any risk of that to participants is very small. It would be
manageable as the trial progresses. People are being observed very, very
carefully."
EARLY WARNING SIGNS
Tragic lessons from other vaccines and prior work on coronaviruses have raised
some warning flags for developers.
The best-known example occurred in a U.S. trial in the 1960s of a vaccine
created by the NIH and licensed to Pfizer Inc to fight respiratory syncytial
virus (RSV), which causes pneumonia in infants. The vast majority of babies who
received the vaccine developed more severe disease, and two toddlers died. A
more recent example occurred in the Philippines, where some 800,000 children
were vaccinated with Sanofi’s dengue vaccine, Dengvaxia. Only afterward did the
company learn that it could increase the risk of more severe disease in a small
percentage of individuals.
Both Moderna and Inovio say their vaccines are likely to have a lower risk of
vaccine enhancement because they are made using newer technology that focuses on
specific genes on the outer 'spike' portion of the virus. Coronavirus vaccines
that caused vaccine enhancement were typically made using an inactivated version
of the entire virus. Neither company has produced a licensed vaccine to date.
J&J said it is developing animal models to test for vaccine enhancement and
hopes to have a vaccine candidate ready for human trials in October. A Sanofi
spokeswoman said the company will examine this risk before testing the vaccine
in clinical trials.
"People know how traumatic the RSV experience was," said Dr Johan Van Hoof,
global head of Janssen Vaccines, J&J's vaccine unit. "When you see signals in
animals like this, we should not ignore them."
(Reporting by Julie Steenhuysen in Chicago; Additional reporting by Michael
Erman in New York; Editing by Michele Gershberg and Bill Rigby)
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