Still no animal models, three months into global crisis
BEIJING, WASHINGTON D.C.––A hint of the desperation of practitioners of traditional animal-based biomedical research to contribute something of relevance to the global fight against COVID-19 was posted late on March 18, 2019 by the online periodical Live Science.
“When exposed to the novel coronavirus SARS-CoV-2 [COVID-19] twice in a row, two monkeys did not contract an infection a second time, according to a preliminary study,” reported Live Science staff writer Nicoletta Lanese.
Conducted by the Institute of Laboratory Animal Sciences at the Chinese Academy of Medical Sciences in Beijing, posted on March 14, 2020 to the preprint database medRxiv, “The small study has not been peer reviewed,” Lanese cautioned. “Additionally, the study included only four rhesus macaques, two of whom were exposed to the virus twice.”
“One monkey don’t stop no show”––& two monkeys don’t, either
Flimsy though the study was, Lanese struggled to give it the appearance of significance.
“China, Japan and South Korea have reported cases of people testing positive for COVID-19, recovering, being released from care, and then later testing positive a second time,” Lanese wrote. “Evidence suggests that the virus can persist in the body for several weeks after recovery, so it may be that these patients still tested positive but were not reinfected, Live Science previously reported.”
In other words, the two rhesus macaques confirmed something that was already known from human clinical data.
But as Big Maybelle sang back in 1955, “One monkey don’t stop no show,” and two monkeys don’t, either.
Lab inventories don’t include bats & pangolins
Seldom have animal-based biomedical researchers had more difficulty making a case for themselves to a frightened public than amid the ongoing worldwide COVID-19 panic.
COVID-19 is zoonotic in origin, meaning that it crossed into humans from animals, probably cave-dwelling bats in a remote part of China, possibly with pangolins as an intermediary host at the Huanan Seafood Wholesale Market in Wuhan.
If those were familiar species, intensive research use of bats and pangolins might have been underway months ago to identify antigens to COVID-19 that might be synthesized to develop a vaccine to protect humans.
But no one knows as yet exactly which bat species or subspecies might carry COVID-19 antigens. No laboratory has large stocks of bats or pangolins to be used in experiments.
More potential human models than bat & pangolin populations
And even if any laboratories did have hundreds or even thousands of live bats or pangolins of the right subspecies to be COVID-19 carriers, the numbers of humans exposed to COVID-19 who have apparently developed effective antigens may now exceed the total population of bats carrying it––and almost certainly exceeds the global population of all eight pangolin species.
Therefore the fastest path to COVID-19 vaccine development would appear to be through investigating the antibodies produced by the more than 72,000 people who have had confirmed infections, but have recovered without relapse.
Some of that work, however, would be “reinventing the wheel.” COVID-19, originally named SARS-CoV-2, is closely enough related to the SARS-CoV-1 coronavirus, which killed nearly 800 people in 2002-2003, that much of the research done to try to develop a SARS vaccine in 2003-2005 has already been recycled by the estimated 35 academic institutions and pharmaceutical companies that are reportedly racing to be first on the market with an effective, reliable COVID-19 vaccination.
“At least four are already testing in animals, and another two are preparing to begin human trials,” reported Nick Sas for the Australian Broadcasting Corporation on March 17, 2020.
Among the front runners, the Peter Doherty Institute for Infection and Immunity, of Melbourne, Australia, in early March 2020 became the first laboratory outside of China to reproduce COVID-19 outside of a living host.
The Doherty Institute then “found people’s immune systems responded to coronavirus in the same way that they try to fight the flu,” Sas of the Australian Broadcasting Corporation summarized.
“Scientists have taken the blood samples of one of Australia’s first patients diagnosed with coronavirus and identified the antibodies recruited by the body to fight the illness,” Sas continued.
Other front-runners include the Academy of Military Medical Sciences in Beijing, China; the Boston-based biotech firm Moderna; and the Kaiser Permanente Washington Health Research Institute in Seattle, which has now begun human trials. The latter project is funded by the National Institute of Allergy and Infectious Diseases, a branch of the National Institutes of Health.
Leap-frogging over animal tests
Much of this work has leap-frogged over the extensive animal testing that typically precedes any tests of a new vaccine on human subjects, even well-paid volunteers.
That does not mean that animal testing will not be involved in the many stages of vaccine development that are still ahead.
The six stages of vaccine development identified by the U.S. Centers for Disease Control & Prevention are the exploratory phase, already well underway; pre-clinical testing, either just begun or soon to begin at most of the laboratories working to develop a COVID-19 vaccine; clinical development; regulatory review and approval; and finally, manufacturing and quality control.
Thousands of animals will almost certainly be used in the latter stages of producing a COVID-19 vaccine. But finding or genetically modifying animals who respond to COVID-19 in the same manner as humans is a challenge, with no off-the-shelf experimental subjects ready for use, and with the possibility that no such experimental subjects will ever exist.
“We get diseases from other animals, and then we use more animals to figure out how to stop the diseases”
Should researchers fail to discover or develop animal models for COVID-19 within a relatively brief time frame, a much less traditional non-animal approach to perfecting a COVID-19 vaccine will have to be used instead.
If that happens, the whole regulatory review and approval regimen will have to be revised, and familiar manufacturing and quality control procedures will have to be updated to take into account that so far as is currently known, non-human animals just do not contract COVID-19 in a form producing human-like symptoms.
“Among the many lessons of the coronavirus pandemic is how close humans are to the rest of the animal kingdom. We get diseases from other animals, and then we use more animals to figure out how to stop the diseases,” observed New York Times science writer James Gorman on March 14, 2020.
University of Iowa microbiologist Stanley Perlman in 2003 developed a genetically modified mouse, called hACE2, who is susceptible to SARS-CoV-1 infection––sometimes.
Mice on ice
“The advantage of this strain,” Gorman explained, “is that it has a human receptor on its cells called an ACE2 receptor, thus its name. That allows it to be infected with SARS and the COVID-19, which both target that receptor as they try to invade cells.”
“Most of the mice don’t care at all that they’re infected,” Perlman told Gorman.
Wrote Gorman, “The hACE2 strain of mice susceptible to SARS got sick, but developed a brain disease,” according to Perlman, “in addition to other symptoms. A new study from China, not yet peer-reviewed, suggests that these mice do get infected with the new pandemic virus,” COVID-19, “and develop mild pneumonia. The paper made no mention of the virus affecting the brain.
“This strain of mice will be used in some of the first laboratory experiments,” Gorman continued. “But first it is necessary to breed them. Like many other genetically engineered mice varieties, scientists don’t keep live colonies on hand. Instead, frozen sperm and embryos are kept ready.
Cat in charge
“The hACE2 mice were put on ice when the SARS outbreak stopped,” more than 15 years ago, Gorman reported. “Chien-Te Tseng at the University of Texas Medical Branch, who independently developed an hACE2 mouse, is now building up a colony from frozen embryos in his lab. Mice have a three-week gestation period, or pregnancy, and take eight weeks to reach sexual maturity.
“Perlman is not rejuvenating the strain himself,” Gorman added. “He sent 16 vials of frozen sperm to the Jackson Laboratory in Maine, one of the biggest breeders of laboratory animals, so they can ramp up their production. They hope to have mice ready for distribution, at cost, by May, according to Cat Lutz, director of the [Jackson Laboratory] mouse repository,” who is also known as the Cat in charge of watching the mice.
Concluded Gorman, “Lutz said that researchers at the Jackson Laboratory will also be investigating other ways to make mice more susceptible to the new coronavirus.”
Observed Psychology Today online columnist Marc Bekoff, “Existing animal models haven’t worked very well.”
PETA alleges lab animal massacre
Meanwhile, alleged People for the Ethical Treatment of Animals staff writer Danny Prater on March 16, 2020, “Across the country, school closures caused by the COVID-19 outbreak have led to a mass killing of countless animals who were slated to be used in crude and worthless experiments in university laboratories. Many experiments that harm animals are now being ‘ramped down, curtailed, or delayed,’” Prater charged without identifying the source of his quote, “causing an increasing number of major universities to order a purge of animals who are not considered ‘critical’ to their archaic experiments.
“Johns Hopkins University, Stanford University, the University of California at Berkeley, the University of Washington, and the University of Michigan are among the institutions calling on faculty to work on ‘reducing population numbers’ of animals in laboratories,” Prater charged.
Labs say “No way”
Science writer David Grimm immediately investigated.
“The U.S. National Institutes of Health announced this week it is “deeply concerned about the impact of [COVID-19] on the ability of … institutions to support the well-being of animals and personnel during this public health emergency,” Grimm reported on March 18, 2020.
“Indeed, many universities are currently grappling with the best way to care for the millions of mice, monkeys, and other research animals they care for across the country, in addition to protecting the health of their own employees.”
“Right now, it’s like a 4-week snow emergency,” said Eric Hutchinson, associate director of research animal resources at Johns Hopkins University in Baltimore. “We haven’t lost anybody yet. Everyone’s mind immediately leaps to a massive depopulation [of employees], but I don’t think we would ever get there. In the worst-case scenario, we would go into food-and-water mode with the animals. Everything else would take a back seat. Most of our animals could go without their cages being cleaned for 14 days without violating any welfare guidelines. We’re also doing a lot of cross-training, so that no one person disappearing leaves us vulnerable.”
Could handle losing half of staff
Yale University’s Animal Resources Center director Peter Smith told Grimm that “Losing a quarter of our staff would have minimal to no impact on the daily care of our animals. It could delay some cleaning and sanitation, as well as elective veterinary procedures, such as teeth cleaning, vasectomies, and routine blood work. If we lost half of our staff, we could still do basic animal care,” Smith said, “but we would have to limit our preventative care, and we would likely encourage researchers to curtail any rodent breeding. If we lost three-quarters of our staff,” Smith finished, “we would only be able to perform emergency care.”
Asked Grimm specifically, “PETA claimed that universities were being ordered to purge animals who are not considered critical to experiments. Is anything like this happening at your institutions?”
Responded Hutchinson, “I will say categorically that no mice or any other animals have been euthanized in an effort to conserve resources.”
Agreed Smith, “No. We have not [euthanized animals to reduce inventory], nor can I envision a scenario in the context of this pandemic in which we would mandate euthanasia of research animals. But we trust that labs will scale back the breeding of experimental mice accordingly if their research needs are diminished.”
The exception to scaling back breeding experimental mice would be if and when anyone develops a mouse model specifically responsive to COVID-19 in the form experienced by humans.