Ever since Monday, when shares of Moderna shot up nearly 30% on early data from a trial of its COVID-19 vaccine, Wall Street analysts have been parsing the data to gauge the company’s chances of success. Late yesterday, one analyst sent out an analysis of Moderna’s data that investors—not to mention the White House—may not like.
It’s way too early to get excited about Moderna’s mRNA vaccine to prevent COVID-19, concluded Evercore ISI analyst Umer Raffat after analyzing the company’s data. He explained his reasoning in a 78-page slide deck he sent to clients.
The bottom line? The biggest strength in the data that Moderna released Monday pertained to “binding” antibodies, which are antibodies that attach to SARS-CoV-2, the virus that causes COVID-19, Raffat said. Problem is, what’s really important for an effective vaccine is its ability to generate “neutralizing” antibodies that actually prevent the virus from infecting healthy cells. And there Moderna’s data is lacking so far, Raffat concluded.
In measuring the antibody response to the vaccine, called mRNA-1273, Moderna compared blood samples taken from patients in the trial to “convalescent serum” collected from people who recovered from COVID-19. The company reported that 43 days after vaccination, the levels of binding antibodies in trial participants who received a priming dose of mRNA-1273 followed by a 100-microgram dose “significantly exceeded” that seen in convalescent serum.
But the levels of neutralizing antibodies were “at or above” convalescent serum. And Moderna may have stoked a bit too much enthusiasm about that during a conference call following the data release, Raffat said, because one of its executives mistakenly said the levels of neutralizing antibodies seen in trial patients “far exceed what you see with convalescent serum.”
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What’s more, using convalescent serum as a benchmark is problematic, particularly because Moderna generated that data internally, Raffat said. Studies have shown that people who have recovered from COVID-19 can generate a wide range of neutralizing-antibody responses, and it’s unclear from the data Moderna released how comparable the convalescent serum samples really were to those taken from the patients in the mRNA-1273 trial.
Experience with past coronaviruses suggests that neutralizing antibodies can wane over time. Moderna’s executives said the convalescent blood used as a benchmark was obtained “within a month or two after the disease.” Problem is, “if you capture it late, your benchmark is setting up an easier [comparison],” Raffat said in his report to investors.
The FDA hasn’t weighed in on what level of neutralizing antibody response it will need to see to deem a vaccine effective against COVID-19, Raffat pointed out. But it has provided one hint: The agency has issued guidance saying that when convalescent serum is used to treat critically ill COVID-19 patients, that blood should have high levels of neutralizing antibodies.
Another question that Moderna didn’t answer was whether or not mRNA-1273 generated a “T-cell response”—an indicator that the immune system is attacking COVID-19—Raffat said. But that data could be important. A past study of 175 recovered COVID patients showed that some with very low levels of neutralizing antibodies still managed to beat the disease, leading those researchers to conclude that a strong T-cell response may have been sufficient to tamp down the virus.
When an analyst asked during Monday’s conference call whether Moderna measured the activity of T cells after vaccination with mRNA-1273, the company’s chief medical officer, Tal Zaks, M.D., Ph.D., said he had no data on that to share. “You would expect that based on the fundamental scientific principles of how an mRNA vaccine works because it teaches the body’s own cells to make the protein from within the cell,” he said.
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Evercore ISI’s Raffat also noted other concerns about Moderna’s data release that investors have been voicing over the last couple of days. For one, there were only four patients analyzed to generate the data on neutralizing antibodies. Raffat asked: “But how do we know they didn’t cherry-pick” those people? He also wondered how old those people were, because past COVID studies suggest that people over age 40 generate more robust levels of neutralizing antibodies than younger patients do.
Another open question is how durable and long-lasting the neutralizing-antibody response is from Moderna’s vaccine, Raffat said. Neutralizing antibodies alone are unlikely to satisfy the agency’s reviewers, who could very well expect Moderna to show in the phase 3 trial that the vaccine protects patients for a significant amount of time after infection, he predicted. Then he reminded investors of a study of two Zika vaccines that were very similar in their ability to generate neutralizing antibodies—but that ended up offering wildly different levels of protection against that virus.
“Perhaps data like this rings loud in the FDA’s ears,” Raffat wrote.