As they race to test an experimental coronavirus vaccine, researchers aren’t waiting to see how well it prevents infection in animals before trying it in people, breaking from the usual protocol.
“I don’t think proving this in an animal model is on the critical path to getting this to a clinical trial,” said Tal Zaks, chief medical officer at Moderna, a Cambridge, Mass.-based biotech that has produced a Covid-19 vaccine candidate at record speed. He told STAT that scientists at the National Institutes of Health are “working on non-clinical research in parallel.” Meanwhile, the clinical trial started recruiting healthy participants in the first week of March.
That isn’t how vaccine testing normally happens. Regulators require that a manufacturer show a product is safe before it goes into people, and while it isn’t enshrined in law, researchers almost always check that a new concoction is effective in lab animals before putting human volunteers at potential risk.
“This is very unusual,” explained Akiko Iwasaki, a Yale University microbiologist who studies the immune response to viruses. “It reflects the urgency to develop vaccines to counter the Covid-19 pandemic.”
To some, the sweep of outbreak is emergency enough to justify simultaneously working on steps that would normally be done sequentially. To others, jumbling the order of the recipe seems morally questionable, because there could potentially be unknown hazards and it’s unclear how effective this particular formulation is.
“The traditional vaccine timeline is 15 to 20 years. That would not be acceptable here,” said Mark Feinberg, president and CEO of the International AIDS Vaccine Initiative, whose work as chief public health and science officer at Merck Vaccines was instrumental in the development of the immunization against Ebola. “When you hear predictions about it taking at best a year or a year and a half to have a vaccine available … there’s no way to come close to those timelines unless we take new approaches.”
He knows that it’s important to see how well a new vaccine can stop infection in animals, but to him, given the current emergency, it makes sense to start human safety testing before those studies are finished. “I personally think that’s not only appropriate; I think that’s the only option we have,” Feinberg went on.
Yet ethicists aren’t so sure that the eventual benefits of rushing this unproven vaccine into clinical trials will outweigh the risks. “Outbreaks and national emergencies often create pressure to suspend rights, standards and/or normal rules of ethical conduct. Often our decision to do so seems unwise in retrospect,” wrote Jonathan Kimmelman, director of McGill University’s biomedical ethics unit, in an email to STAT.
The question is complicated by the newness of the science at play. The technology that has allowed Moderna to craft an experimental vaccine so fast has not yielded a single immunization that’s made it to market so far. It’s a trendy idea: Instead of injecting people with a weakened pathogen or proteins from the surface of a pathogen, so that our bodies will learn to fight off such infections in the future, scientists are betting on a kind of genetic hack, a lab-made concoction that gets the body to produce its own virus-like bits which it will then train itself to combat.
At the center of it all is a molecule called messenger RNA, or mRNA. Inside of us, its normal function is to transmit the instructions contained within our DNA to the cellular protein-making factories that carry them out. In Moderna’s recipe, the mRNA is synthetic, programmed with the goal of getting our inner machinery to produce certain coronavirus-like proteins — the very proteins that the pathogen uses to gain entry into our cells. Once those homemade dummy virus particles are there, the thinking goes, our bodies will learn to recognize and clobber the real thing.
The method’s greatest advantage is its speed. The virus behind the outbreak that began in Wuhan, China, was identified on January 7. Less than a week later—on January 13—researchers at Moderna and NIH had a proposed sequence for an mRNA vaccine against it, and, as the company wrote in government documents, “we mobilized toward clinical manufacture.” By February 24, the team was shipping vials from a plant in Norwood, Mass., to the National Institute of Allergy and Infectious Diseases, in Bethesda, Md., for a planned clinical trial to test its safety.
Though sponsored by the NIAID, the first-in-human experiment is taking place in Seattle, at the Kaiser Permanente Washington Health Research Institute. Researchers began recruiting healthy volunteers in early March. Their plan is to enroll 45 people between 18 and 55, who will get two shots of Moderna’s investigational vaccine, about a month apart. For their trouble, participants will get $100 for each in-person study visit, for a total of $1,100.
That doesn’t mean the scientists have sped past animal testing entirely. Virologists at NIAID tried the new vaccine on run-of-the-mill lab mice, the institute told STAT by email, on the same day that the trial began enrolling participants. Barney Graham, director of NIAID’s vaccine research center, later added that those mice showed the same sort of immune response generated by a similar mRNA vaccine against MERS, another coronavirus. “That level of immune response was sufficient to protect mice from MERS CoV infection,” Graham wrote.
The trouble is, your average lab mouse doesn’t seem susceptible to the new virus. While the bug behind Covid-19 has no trouble co-opting molecules on human cells to get inside and start multiplying, it isn’t so good at latching onto the mouse equivalent. Although Graham can say the response produced in everyday mice looks similar to one that helped mice combat the virus in their bodies when infected with MERS, he can’t yet say the same thing for the new coronavirus, because the mice susceptible to this pathogen aren’t ready yet.
These pathogen-susceptible rodents were specially engineered in the wake of another coronavirus outbreak: SARS, in the early 2000s. To make them easier to infect, scientists adorned their cells with the human molecule that allows certain coronaviruses to slip inside. But when coronavirus research slowed between outbreaks, scientists couldn’t justify the expense of keeping many of them; so while these mice seem to be susceptible to the new virus, too, there aren’t currently enough for experiments to start.
“Those mice in the U.S. are being bred so that the colony can be enlarged,” explained Graham, adding, that they “will be available for experiments within the next few weeks.”
The researchers have not said outright that they’ll start dosing humans before they have results showing how well the vaccine works in virus-susceptible animals, but when asked whether they would, Graham replied, “Safety and product integrity are the primary criteria for starting a Phase 1 trial and mRNA has now been used in several clinical trials and shown to be safe and well tolerated.”
https://www.scientificamerican.com/article/researchers-rush-to-test...
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