In DepthCOVID-19

# A call to test new vaccines head to head, in monkeys

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Science  09 Oct 2020:
Vol. 370, Issue 6513, pp. 154-155
DOI: 10.1126/science.370.6513.154

Science's COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation

Primate researchers in the United States have banded together in a push for an ambitious monkey study that would do head-to-head comparisons of the leading COVID-19 vaccine candidates. Although 10 candidates are already undergoing large-scale tests in people, proponents of the monkey plan say those clinical trials may not deliver the comprehensive data needed to choose the safest and most effective vaccines. The comparison trial in monkeys, in contrast, could shed light in a matter of weeks on how the candidates stack up on measures including potential side effects, the strength of immune responses they trigger, and how well they protect against infection and disease.

“We should take a cold, hard look at all of the data and ask ourselves, ‘What appears to work best?’” says Nancy Haigwood, who directs the Oregon National Primate Research Center and is a key advocate for the comparative monkey study.

The proposed monkey vaccine comparison faces hurdles: It would add to the pressure on the dwindling U.S. supply of research monkeys, potentially delaying research on other diseases, and it does not yet have funding. Haigwood says she expected the U.S. government would gladly support the effort, which would cost an estimated $10 million, compared with the$10 billion the Trump administration's Operation Warp Speed has already devoted to a COVID-19 vaccine push. But facing a lack of interest by current Warp Speed officials, Haigwood and colleagues at the six other national primate research centers are now turning to the National Institutes of Health (NIH) for support.

Most developers of the vaccine candidates in efficacy trials have already published how well each works in monkeys against a “challenge” with SARS-CoV-2—a deliberate exposure to the pandemic coronavirus that causes COVID-19. But the details of how the experiments were conducted and the ways the results were analyzed differ so profoundly that immunologist John Moore of Weill Cornell Medicine says he can't make sense of how the candidates compare. “It's comparing apples to oranges and bananas,” says Moore, who has co-authored a review, on preprint.org, that compares the various monkey studies.

A study comparing COVID-19 vaccines would use monkeys at the Oregon National Primate Research Center.

PHOTO: WILLIAM SUTTON/ONPRC/OHSU

The human vaccine trials, for their part, are likely to yield only preliminary signals of efficacy over the next few months, not clear-cut evidence that one or more is safe and protects people. “We're going to get data dribbling in from clinical trials,” says Haigwood, a veteran AIDS vaccine researcher.

The data from the many human trials, some in multiple countries, will also be tough to compare. Jay Rappaport, who heads the Tulane National Primate Research Center, notes the trial populations differ and are infected by different variants of SARS-CoV-2. In addition, the human trials—as with the monkey experiments—often use different assays to measure immune responses. “There's so much variation in the primate studies, but there's even more variation in the human studies,” Rappaport says.

In contrast to the human trials that must wait for enough participants to become naturally infected to gauge a vaccine's worth, Haigwood says, monkey challenge studies could deliver definitive results quickly. She says the monkey comparison could start as soon as this month and would require only about 6 weeks to vaccinate animals, challenge them, and assess their immune responses and levels of protection.

Yet now that human vaccine efficacy trials are underway, says Moncef Slaoui, Warp Speed's chief scientific adviser, monkey studies won't add much. “Frankly, I did this for 30 years,” adds Slaoui, who headed vaccine development at GlaxoSmithKline, “and the primate study is relevant to give you information before the clinical trial. But when you have a phase III trial in tens of thousands of subjects, the relevance of that information is 10 times, 100 times more significant.”

The backers of the monkey comparison see the situation differently. “I understand that some people say it's too little, too late, but it's not,” insists Haigwood, who helped the seven national primate research centers form a consortium to conduct the study. “This is not a competition with Warp Speed. The goal here is to have data that are additive.”

The comparison study would likely require a few hundred rhesus macaques, at a time when the long-standing U.S. shortage of monkeys for biomedical research has been exacerbated by China's decision in January to stop exporting all wild animals in the wake of COVID-19. The foreign monkeys went to private labs that do contract research for companies and academic groups, but because those firms have been short on animals, more researchers have turned to the national primate centers for help. Haigwood says the U.S. consortium has many experiments now in the wings that they're willing to delay to conduct the comparative COVID-19 vaccine work. “We have set aside our precious monkeys for this use, because we think it's in the national interest.”

The proposed comparative study would use a standardized stock of challenge virus that NIH's National Institute of Allergy and Infectious Diseases (NIAID) recently made, and it would follow consistent protocols to challenge the monkeys and evaluate immune responses to the vaccine candidates. As a first step, Tulane has applied to NIH for a \$1.7 million grant to establish a coordinating center to develop standard techniques and data collection for the study. If NIH backs the full study, Haigwood and colleagues expect to test roughly 10 vaccines. Each vaccine challenge study would require eight to 10 rhesus macaques; shared placebo groups would limit the animals needed.

A comparative monkey experiment was part of Warp Speed's early plans developed by Peter Marks of the Food and Drug Administration (FDA). Marks, who left Warp Speed in part because it conflicted with his job as head of the FDA division that oversees vaccines, had wanted to select 14 candidates for phase I and II human studies—early trials that focus on safety and immune responses, not efficacy—and, in parallel, conduct the apples-to-apples monkey studies. After Warp Speed assessed both the monkey and human data, Marks hoped it would pick the best four or five for human efficacy trials. “It may be that at the end of the day, they'll get to a vaccine with 90%, 95% efficacy here, but that [proposed comparative monkey study] was just a way to try to get there,” Marks says. “I can't say that I was right or wrong.”

NIAID head Anthony Fauci says “it would be worthwhile” to conduct a rigorous comparative study, noting that animal results from vaccine studies for AIDS and other infectious diseases have also been difficult to compare, complicating attempts to translate their results to humans. “It's been one of the banes of our existence.”

If NIH won't fund the work, Haigwood says, she'll turn to philanthropic institutions. She also needs to persuade vaccine companies to supply their candidates. “I'll do whatever it takes,” Haigwood says, including “twisting the arms” of companies. “We can get a hell of a lot of information before the end of December. Wouldn't you like to have that?”

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