Skipping to testing of humans without rigorous testing on animals can result in a vaccine that does the opposite of what it was meant to do, says Julie Steenhuysen
Drug-makers are working as quickly as possible to develop a vaccine to combat the rapidly spreading coronavirus, which has infected more than 100,000 people worldwide.
But scientists and medical experts are concerned that rushing a vaccine might worsen the infection in some patients.
Studies have suggested that coronavirus vaccines carry the risk of vaccine enhancement: instead of protecting against infection, the vaccine can 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 development of a coronavirus vaccine.
Normally, researchers would take months to test for vaccine enhancement in animals. Given the urgency to stem the spread of coronavirus, some drugmakers are going straight to small-scale human tests, without waiting for the completion of 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,” said Dr Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine.
He 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 than unvaccinated animals when 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.”
For now, the experts have concluded that accelerated testing is a risk worth taking.
At a specially convened World Health Organisation (WHO) meeting in mid-February, to co-ordinate a global response to the new coronavirus, scientists representing government-funded research organisations and drugmakers agreed that the threat was so great that vaccine developers should move quickly to human trials, before animal testing was completed.
“You want to have a vaccine as quickly as possible,” said Dr Marie-Paule Kieny, former assistant director-general at the WHO, who co-chaired the meeting.
The conclusion of that meeting, which was not open to media, has not been officially publicised 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.
Oversight of drugmakers and medical research is in the hands of national regulators. The most powerful of those, the US Food and Drug Administration (FDA), has signalled 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,” said FDA spokeswoman Stephanie Caccomo. 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 that it is likely to help the immune system respond to the virus.
Some 20 coronavirus vaccine candidates are being developed by research institutes and drugmakers, including America’s Johnson & Johnson and France’s Sanofi SA.
Biotechnology company Moderna, which is working with the US-funded National Institutes of Health (NIH), is the closest to human testing, announcing plans to start a trial this month, with 45 people in Seattle.
Testing for the specific risk of vaccine enhancement in animals will proceed simultaneously with human trials, the NIH said, to establish whether it is safe to expose larger numbers of people to the vaccine. Moderna did not respond to requests for comment.
The trial is expected to take 14 months, said a spokeswoman for the NIH.
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 said.
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.
US immunotherapy company Inovio Pharmaceuticals, which is developing a coronavirus vaccine in collaboration with a Chinese company, also expects to start human clinical trials in 30 US 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 one studies,” said Inovio chief executive, Joseph Kim.
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.
Tragic lessons from other vaccines and from prior work on coronaviruses have raised some warning flags for developers.
The best-known example occurred in a US trial, in the 1960s, of a vaccine created by the NIH and licensed to Pfizer 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 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.
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 like humans to the virus.
Work on these, and other animal models, is just getting underway in several laboratories around the world.
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.”