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For the first time, one of the many COVID-19 vaccines in development has protected an animal, rhesus macaques, from infection by the new coronavirus, scientists report. The vaccine, an old-fashioned formulation consisting of a chemically inactivated version of the virus, produced no obvious side effects in the monkeys, and human trials began on 16 April.
Researchers from Sinovac Biotech, a privately held Beijing-based company, gave two different doses of their COVID-19 vaccine to a total of eight rhesus macaque monkeys. Three weeks later, the group introduced SARS-CoV-2, the virus that causes COVID-19, into the monkeys’ lungs through tubes down their tracheas, and none developed a full-blown infection.
The monkeys given the highest dose of vaccine had the best response: Seven days after the animals received the virus, researchers could not detect it in the pharynx or lungs of any of them. Some of the lower dosed animals had a “viral blip” but also appeared to have controlled the infection, the Sinovac team reports in a paper published on 19 April on the preprint server bioRxiv. In contrast, four control animals developed high levels of viral RNA in several body parts and severe pneumonia. The results “give us a lot of confidence” that the vaccine will work in humans, says Meng Weining, Sinovac’s senior director for overseas regulatory affairs.
“I like it,” says Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai who has co-authored a status report about the many different COVID-19 vaccines in development. “This is old school but it might work. What I like most is that many vaccine producers, also in lower–middle-income countries, could make such a vaccine.”
But Douglas Reed of the University of Pittsburgh, who is developing and testing COVID-19 vaccines in monkey studies, says the number of animals was too small to yield statistically significant results. His team also has a manuscript in preparation that raises concerns about the way the Sinovac team grew the stock of novel coronavirus used to challenge the animals: It may have caused changes that make it less reflective of the ones that infect humans.
Another concern is that monkeys do not develop the most severe symptoms that SARS-CoV-2 causes in humans. The Sinovac researchers acknowledge in the paper that “It’s still too early to define the best animal model for studying SARS-CoV-2,” but noted that unvaccinated rhesus macaques given the virus “mimic COVID-19-like symptoms.”
The study also addressed worries that partial protection could be dangerous. Earlier animal experiments with vaccines against the related coronaviruses that cause severe acute respiratory syndrome and Middle East respiratory syndrome had found that low antibody levels could lead to aberrant immune responses when an animal was given the pathogens, enhancing the infection and causing pathology in their lungs. But the Sinovac team did not find any evidence of lung damage in vaccinated animals who produced relatively low levels of antibodies, which “lessens the concern about vaccine enhancement,” Reed says. “More work needs to be done though.”
SARS-CoV-2 seems to accumulate mutations slowly; even so, variants might pose a challenge for a vaccine. In test tube experiments, the Sinovac researchers mixed antibodies taken from monkeys, rats, and mice given their vaccine with strains of the virus isolated from COVID-19 patients in China, Italy, Switzerland, Spain, and the United Kingdom. The antibodies potently “neutralized” all the strains, which are “widely scattered on the phylogenic tree,” the researchers noted.
“This provides strong evidence that the virus is not mutating in a way that would make it resistant to a #COVID19 vaccine,” tweeted immunologist Mark Slifka of Oregon Health & Science University. “Good to know.”
Sinovac is an experienced vaccinemaker—it has marketed inactivated viral vaccines for hand, foot, and mouth disease; hepatitis A and B; and H5N1 influenza or bird flu. But Meng says it could produce, at most, about 100 million doses of the vaccine and might need to partner with other makers if the company’s COVID-19 vaccine proves safe and effective in human trials.
The company recently started phase I clinical trials in Jiangsu province, north of Shanghai, which aim to gauge safety and immune responses in 144 volunteers. An equal number of participants will receive the high and low doses or a placebo. Although placebos are not typically used in phase I studies—which do not assess efficacy—Meng says this can help better evaluate whether the vaccine causes any dangerous side effects. The company hopes to start phase II studies by mid-May that have the same design but enroll more than 1000 people, with results due by the end of June.
If all goes well, Meng says, Sinovac will seek to launch traditional phase III efficacy trials that compare the vaccine with a placebo in thousands of people. The company has also discussed joining international vaccine trials being organized by the World Health Organization (WHO). Given the low level of transmission now occurring in China, the company is considering still more efficacy trials in other countries being hit harder by the virus. “We can’t put all our eggs in one basket,” Meng says.
To quickly obtain more efficacy data after the phase I and II trials and potentially help people, Meng says Sinovac may ask regulatory agencies in China and other countries for emergency authorization to give the vaccine to those at high risk of becoming infected, such as customs agents and police officers who do not typically wear the protective gear used by health care workers. The Democratic Republic of the Congo in 2018 began to widely use an experimental Ebola vaccine under that status and the evidence suggests it powerfully helped curb that epidemic. (That Ebola vaccine first received regulatory approval in November 2019.)
According to WHO, six other vaccines had entered human trials as of 23 April, and 77 others were in development. The vast majority of these vaccines use the modern tools of genetic engineering—only four rely on the old-fashioned inactivation technology—but Meng says what ultimately matters is whether a vaccine is safe and effective, not how it’s made. “We are not comparing ourselves to anyone,” Meng says. “In this pandemic situation, the most important thing is to make a vaccine, no matter what kind of vaccine it is, that’s safe and effective as soon as possible.”