In the past seven months, more than 100 COVID-19 vaccines, therapies, and drugs have been pushed into development. But for any of these treatments to make it to humans, they usually have to face another animal first: a monkey. And here, scientists in the United States say they are facing a bottleneck. There just aren’t enough monkeys to go around.
“Nationally, there is basically a big shortage,” says Koen Van Rompay, an infectious-disease scientist at the California National Primate Research Center. Primate research in the U.S. is expensive and often controversial, making it challenging even in normal circumstances. The pandemic has made acquiring monkeys even harder. “We can’t find any rhesus any longer. They’ve completely disappeared,” says Mark Lewis, the CEO of Bioqual, a contract research organization that specializes in animal testing. Scientists in academia and industry alike are all competing for a limited pool of monkeys.
The reasons for the shortage are threefold. First, COVID-19 has created extraordinary demand for monkeys. Second, this coincided with a massive drop in supply from China, which provided 60 percent of the nearly 35,000 monkeys imported to the U.S. last year and which shut off exports after COVID-19 hit. And third, these pandemic-related events are exacerbating preexisting monkey shortfalls. A 2018 National Institutes of Health report had found that NIH-funded national primate centers would be unable to meet future demand and specifically discussed a “strategic monkey reserve” to provide “surge capability for unpredictable disease outbreaks.” A disease outbreak is upon us; the strategic monkey reserve was never created.
Furthermore, monkeys infected with COVID-19 have to be kept in Animal Biosafety Level 3 labs, which have specific design and ventilation requirements to prevent the spread of pathogens. The U.S. has a limited number of ABSL-3 labs.
The result, Van Rompay says, is that he gets emails and calls weekly from companies looking to test COVID-19 treatments at the California research center, one of the seven NIH-funded primate centers that work with both academic and industry researchers. “I have to tell them, ‘I’m sorry, we are not allowed to start your research,’” he says. With so much demand for monkeys, the NIH is now centrally deciding which studies can use the national primate centers under a public-private initiative called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), creating a new bureaucratic bottleneck. Meanwhile, non-COVID-19 research is also getting pushed aside.
Monkeys account for just 0.5 percent of the animals used in U.S. biomedical research, but they typically represent the last step before human clinical trials. They are closely related to humans, after all—so closely related that scientists refer to the research animals as, technically, “nonhuman primates.” For example, monkey and human immune systems are so similar that vaccine studies can use the same tests to measure antibodies in both. “Literally the same test,” says Skip Bohm, the associate director of the Tulane National Primate Research Center. The similarity means that monkeys are also a good model for testing the agents that help boost the effectiveness of a vaccine, says JoAnne Flynn, a vaccine researcher at the University of Pittsburgh.
As COVID-19 vaccine development has moved forward at an unprecedented pace, though, some pharmaceutical companies have started human trials before monkey studies have concluded. And with monkeys so hard to come by, others are wondering if certain studies can be skipped altogether. Linda Marbán, the CEO of the biotech company Capricor Therapeutics, says her company originally tried to test its vaccine candidates at the California primate center. It couldn’t get in. She’s now exploring how to go straight into human-safety trials.
Scientists who work with primates, however, say that the animal research still offers certain advantages. Monkeys can be challenged—that is, deliberately infected with COVID-19 after being given an experimental vaccine. Researchers can then follow the animals’ exact progression of disease or lack thereof, tracking how quickly antibody levels shoot up or whether a vaccine reduces how long the monkey sheds the virus. These details are harder to get in human trials because people are naturally exposed to COVID-19 and aren’t being monitored every day. (Although some researchers have proposed human challenge trials for COVID-19, the idea is controversial and none has begun.)
Primate research can also be used to study safety in vulnerable populations, says Sallie Permar, a vaccine scientist at Duke University who is planning a study with Van Rompay to look at how infant monkeys respond to several of the leading COVID-19 vaccine candidates. While young children rarely get seriously ill from COVID-19, they can spread it, so vaccinating kids is likely important for reopening schools. But current vaccine trials are mostly restricted to healthy participants ages 18 and up. Without testing the shots in children, it will remain unclear whether COVID-19 vaccines are actually safe and effective for them. “Those trials are difficult to plan and are often not pursued by vaccine companies,” Permar says. She hopes that showing the vaccines are safe and effective in infant monkeys will encourage pharmaceutical companies to test vaccines in children.
Primates are not always the best animal model for every aspect of the disease. Most monkeys, including rhesus macaques and cynomolgus macaques, which are the two most widely used species, get only mildly sick from COVID-19. To study severe illness, scientists are turning to animals such as hamsters. COVID-19-infected hamsters develop lethargy, rapid breathing, and weight loss of up to 11 percent. Plus, says Vineet Menachery, a virologist at the University of Texas Medical Branch, “in terms of a model, hamsters breed well. They’re small enough; they’re easy enough to handle.”
Nonhuman primates are the opposite in this regard. They do not breed well, they’re relatively big animals, and they’re expensive to care for. That’s why nonhuman-primate studies are the last step, not the first, in the development process before human trials. Van Rompay says that he advises companies trying to do research at the primate center to gather data in rodents as an interim step. “Doing experiments in rodents is a lot cheaper,” he says. “The most promising ones can then be tested in nonhuman primates.”
Breeding more monkeys in the U.S. will take years, along with sustained funding. The country has a limited number of breeding facilities, including the NIH-funded primate centers. Monkeys set aside for breeding can’t be used for research either.
Decades ago, the vision for a network of federally funded primate-research centers grew out of an NIH scientist’s visit to a Soviet monkey lab in 1956. But the centers have struggled to get more funding in recent years, and one that was affiliated with Harvard closed for financial reasons in 2015. (It had also been subject to protests and an investigation following several monkey deaths.) Several years ago, Van Rompay says, the California center began breeding more monkeys to meet research demand, but the funding for maintaining the colonies didn’t go up accordingly. So it had to downsize the colony again. And while researchers have talked about a strategic monkey reserve for pandemics, one has never been funded. “There needs to be a real national investment to build the infrastructure, not only for this pandemic, but also for the future with the next pandemic,” says Jay Rappaport, the director of the Tulane National Primate Center.
Meanwhile, China has invested in large monkey-breeding facilities and is a major supplier for the rest of the world. In China, breeding monkeys is cheaper and the animal-rights movement is also quieter. The biopharmaceutical industry in the U.S., in particular, relies heavily on macaques bred in China. The ongoing trade war between the U.S. and China had already made importing monkeys more expensive. Then, when the pandemic hit earlier this year, China stopped exporting them entirely. “I’m not seeing any nonhuman primates moving out of China,” says Matthew R. Bailey, the president of the National Association for Biomedical Research, which advocates for animal research. Industry experts speculate that China, whose scientists are also racing to find COVID-19 treatments, is interested in keeping the animals for its own studies. No one knows when China might start exporting monkeys again.
This reliance on primates from China, Bailey says, is a strategic problem. As primate research becomes harder to do in the U.S., that work may simply get shifted abroad. “Is the American public okay with that? Do we want treatments and cures to be developed here? Or are we okay with them being developed in other countries?” Bailey asks. While many have called for international collaboration in the fight against COVID-19, the pandemic has increased the salience of borders and inflamed “vaccine nationalism,” fears that any country that develops a vaccine first will hoard it for its own citizens.
The current monkey shortage is also forcing scientists to think creatively about how to reduce the number of animals needed for research. For example, says Jeffrey Roberts, the associate director of primate services at the California National Primate Research Center, the different NIH-funded centers are trying to use one group of animals as controls in experiments across different labs. In a typical randomized controlled trial, the control animals are the ones not given the treatment, so they serve as a baseline for comparison. Having the control group and the treated groups in different labs is unusual; to make sure that small changes from lab to lab don’t affect the results, scientists have to be extremely careful to harmonize their protocols. “It’s really impressive,” Roberts says. “I’ve been involved in nonhuman-primate research for 37 years, and I’ve never, ever seen this degree of coordination between different research institutes.”
The shortage is also unlikely to let up soon. Lewis, whose company, Bioqual, has done primate research for several COVID-19 studies, including on Moderna’s vaccine, says that Bioqual was initially able to reuse some animals from non-disease studies. That supply has been used up now; monkeys infected with COVID-19 are euthanized to prevent spread to other monkeys or even potentially humans. The cost of a macaque has since doubled to almost $10,000, according to Lewis. Big companies, he says, which purchase thousands of animals, are also locking out smaller research outfits. And as scientists now try to resume non-COVID-19 research in primates, they’re also contending with delays and much more expensive monkeys. “This may just be the beginning. And I think that we’re all preparing for there to be significant delays,” says R. Keith Reeves, a virologist at Harvard working on HIV.
With so much hope riding on a COVID-19 vaccine, the pandemic has made the stakes of animal research very clear to Americans. Bohm, from Tulane, wonders if, on balance, the pandemic will change how the public views animal research. “I think the answer to the question is yes. In my dealing with neighbors and family and friends, they have a much better understanding of how important animals are to research,” he says. “Whenever a disease affects a family member, people tend to be more supportive of animal research. And in this case, entire communities and families have been affected.” The path back to normal will require a vaccine, and a vaccine will need to be tested first in monkeys.