- Experts say the current phase 3 trials for potential COVID-19 vaccines will indicate whether the vaccinations can prevent or reduce disease symptoms.
- However, researchers say the trials won’t be able to provide evidence on whether the vaccines can prevent serious illness or death.
- Experts note that researchers are trying to balance the need for information with the urgency of having a vaccine during a pandemic.
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The goal of these late-stage trials is to determine whether a vaccine is safe and effective.
But what does “effective” mean?
First, a vaccine would reduce the chances that someone who has the new coronavirus becomes severely ill with COVID-19, ends up in the hospital, or dies from the disease.
Second, a vaccine would slow the spread of the disease by preventing people from contracting the infection in the first place, or by reducing the number of particles that people with the virus shed from their airways as they breathe.
The problem is that none of the phase 3 clinical trials in progress right now are designed to examine either of those outcomes, argues
“None of the trials currently under way are designed to detect a reduction in any serious outcome such as hospital admissions, use of intensive care, or deaths,” wrote Doshi, who is also an assistant professor of pharmaceutical health services research at the University of Maryland School of Pharmacy.
“Nor are the vaccines being studied to determine whether they can interrupt transmission of the virus,” he wrote.
It’s the prevention of symptomatic infections in people who received the vaccine.
This is known as the primary endpoint.
So, every time a participant in one of these trials develops symptoms of COVID-19 and tests positive for the coronavirus, the study is one step closer to completion.
The hope of vaccine-makers is that fewer people who received the COVID-19 inoculation will develop COVID-19 compared to people who received an inactive placebo.
However, for the sake of the primary endpoint, mild infections are counted the same way as severe infections.
Doshi writes that only 150 to 160 of these “events” would need to happen before the companies can start analyzing the data to see whether the vaccines are effective.
The phase 3 trials also have secondary endpoints, which are additional measures used to determine whether a vaccine is effective.
These include severe COVID-19 illnesses, admission to an intensive care unit (ICU), or death — all of which are much less common than mild infections.
“Because most people with symptomatic COVID-19 experience only mild symptoms, even trials involving 30,000 or more patients would turn up relatively few cases of severe disease,” Doshi wrote.
This means that researchers would be unable to tell statistically whether the vaccines reduce severe disease, hospitalizations, or deaths.
The main reason for vaccine-makers not being able to determine whether a vaccine reduces more severe outcomes is a numbers game.
“To design a trial to see if a vaccine can help reduce mortality would require very large numbers of patients. I’m not sure that would be feasible in the timeline that we have currently,” said Dr. Shobha Swaminathan, an associate professor of medicine at Rutgers New Jersey Medical School and medical director of the infectious diseases practice at University Hospital, Newark.
“The study would also potentially have a much longer follow-up, which would imply that it would take longer to get the results that we’re looking for,” added Swaminathan, who is principal investigator for the Moderna COVID-19 vaccine trial at Rutgers.
Likewise, knowing whether a vaccine keeps people from spreading the coronavirus to others offers its own challenges.
Moderna’s chief medical officer told The BMJ that answering this question would require doing nasal swabs twice a week on trial participants for weeks — which isn’t easy to do with tens of thousands of people enrolled in these studies.
Does that mean when the phase 3 trials are complete, we won’t really know whether the vaccines are effective?
Not exactly. We will know whether the vaccines reduce symptomatic infections.
But we won’t know whether they reduce severe illness, hospitalizations, or deaths — at least not right away.
Additional studies would be needed to determine whether these more severe outcomes are less common in people who received a COVID-19 vaccine.
However, Swaminathan told Healthline that in the middle of a pandemic, there’s a need to get a safe vaccine to people sooner, even if we don’t know everything about its effectiveness.
“As a society, we are trying to balance the two,” she said.