These Coronavirus Trials Don’t Answer the One Question We Need to Know

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We may not find out whether the vaccines prevent moderate or severe cases of Covid-19.

Peter Doshi and

Dr. Doshi is an associate professor at the University of Maryland School of Pharmacy. Dr. Topol is a professor of molecular medicine at Scripps Research.

If you were to approve a coronavirus vaccine, would you approve one that you only knew protected people only from the most mild form of Covid-19, or one that would prevent its serious complications?

The answer is obvious. You would want to protect against the worst cases.

But that’s not how the companies testing three of the leading coronavirus vaccine candidates, Moderna, Pfizer and AstraZeneca, whose U.S. trial is on hold, are approaching the problem.

According to the protocols for their studies, which they released late last week, a vaccine could meet the companies’ benchmark for success if it lowered the risk of mild Covid-19, but was never shown to reduce moderate or severe forms of the disease, or the risk of hospitalization, admissions to the intensive care unit or death.

To say a vaccine works should mean that most people no longer run the risk of getting seriously sick. That’s not what these trials will determine.

The Moderna and AstraZeneca studies will involve about 30,000 participants each; Pfizer’s will have 44,000. Half the participants will receive two doses of vaccines separated by three or four weeks, and the other half will receive saltwater placebo shots. The final determination of efficacy will occur after 150 to 160 participants develop Covid-19. But that is only if the trials are allowed to run long enough. Pfizer will look at the accumulating data four times, Moderna twice and AstraZeneca once to determine if efficacy has been established, potentially leading to an early end to the trials.

Questions surrounding the Covid-19 vaccine and its rollout.
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Knowing how a clinical trial defines its primary endpoint — the measure used to determine a vaccine’s efficacy — is critical to understanding the knowledge it is built to discover. In the Moderna and Pfizer trials, even a mild case of Covid-19 — for instance, a cough plus a positive lab test — would qualify and muddy the results. AstraZeneca is slightly more stringent but would still count mild symptoms like a cough plus fever as a case. Only moderate or severe cases should be counted.

There are several reasons this is a problem.

First, mild Covid-19 is far more common than severe Covid-19, so most of the efficacy data is likely to pertain to mild disease. But there is no guarantee that reducing the risk of mild Covid-19 will also reduce the risk of moderate or severe Covid-19.

The reason is that the vaccine may not work equally well in frail and other at-risk populations. Healthy adults, who could form a majority of trial participants, might be less likely to get mild Covid-19, but adults over 65 — particularly those with significant frailty — might still get sick.

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