As more Covid-19 vaccines become available in the U.S., it is getting tougher to run large clinical trials to test a new vaccine’s ability to prevent disease because people are less willing to take a placebo—forcing drugmakers and researchers to look for workarounds as they vet the next generation of shots and test new uses for authorized ones.
One potential workaround would be to determine what level of immune response a vaccine has to trigger to protect people from the coronavirus, as measured in blood samples, and to use that information to create smaller, faster and less-expensive clinical trials.
Instead of requiring tens of thousands of volunteers and costing several hundred million dollars, such trials could involve only hundreds of people at a fraction of the cost. They could be used to speed the availability of new vaccines targeting emerging variants.
and its partner
and a federally funded network of researchers are conducting analyses to learn what immune response is necessary for protection with current vaccines, known as an immune correlate of protection. They say it could come in handy for new studies of already-authorized vaccines—such as testing the shots in children or whether reduced doses are effective—as well as for trials of the next generation of shots, including those targeting new coronavirus strains. Over time, such knowledge could also help determine how long protection from the vaccines lasts.
Another workaround is to run future large efficacy trials outside the U.S., in places where viral transmission is high and vaccine availability is more limited.
whose Covid-19 vaccine is in mid-stage testing, may run a large Phase 3 trial of its experimental shot outside the U.S. because of the diminishing feasibility of running it in the U.S., Chief Executive
said in an interview. The company hasn’t disclosed which country or countries.
Large studies involving tens of thousands of people have been launched in the U.S. for five Covid-19 vaccines, including the two authorized for use from Moderna and Pfizer and a vaccine from
for which J&J is seeking U.S. authorization. In these studies, researchers randomly assign the volunteers to receive either the vaccine or a placebo and then compare how many get sick with Covid-19 in each group.
Vaccine vs. Placebo
But it is becoming more difficult to run these placebo-controlled efficacy trials because prospective recruits increasingly want one of the highly effective authorized shots rather than an experimental shot or a placebo, researchers say. The challenge is heightened among groups that now have access to the vaccines, like health-care workers and the elderly.
In a large study of
vaccine, about 1.5% of the volunteers who were assigned to receive a placebo subsequently decided to get one of the authorized vaccines,
the company’s head of research, said in an online scientific forum this week. More than half of those making that choice were over the age of 65.
“People in the U.S. don’t want a placebo anymore if they’re in a group that can get the authorized vaccines,” said Dr. Kathleen Neuzil, a vaccine researcher at the University of Maryland who helps lead the federally funded Covid-19 Prevention Network, made up of research sites running large clinical trials of Covid-19 shots.
Covid-19 vaccines are designed to work by inducing a person’s immune system to produce antibody proteins that can neutralize the coronavirus. The immune correlate of protection is the concentration of those antibodies at a level that prevents Covid-19 disease; antibodies below that level aren’t protective, while at or above that level are protective.
The immune correlate of protection wouldn’t be definitive proof that a vaccine is effective at protecting people from disease, but it could be sufficient to guide regulatory authorization of new vaccines or new uses for existing vaccines, said Peter Gilbert, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle and part of the Covid-19 Prevention Network. Regulators would still require reports of any side effects to determine safety and might require further studies to confirm efficacy.
A Predictive Blueprint
Such correlates of protection have been used for past vaccine development. The Food and Drug Administration has approved certain meningitis vaccines based on their ability to induce an immune response that correlates with protection, rather than requiring large placebo-controlled efficacy trials.
“It saves time, it saves money and it may be the only thing that’s logistically feasible going forward,” Dr. Neuzil said.
Covid-19 vaccines researchers expect to determine the immune correlate of protection by comparing antibody levels in blood samples taken from vaccinated people who stayed healthy with antibody levels in the relatively small number of vaccinated people in the studies who still got sick from Covid-19.
Researchers from the Covid-19 Prevention Network are running analyses to try to determine the immune correlate of protection for Moderna’s vaccine within the next couple of months. They are examining some of the blood samples taken from all subjects about one month after the second dose in the large clinical study of the Moderna vaccine.
They plan to conduct similar analyses for other Covid-19 vaccines from J&J,
PLC and Novavax, which are being tested in trials run by the researchers’ network.
Pfizer and BioNTech are conducting their own analysis to determine the correlate of protection for their Covid-19 vaccine. A Pfizer spokeswoman said the company would explore the use of immune responses in additional studies of its vaccine, such as in pregnant women, children and people with compromised immune systems.
Leaders of the Covid-19 Prevention Network expect that future vaccines could be approved based on trials of only several hundred people, if results show that they had an immune response believed to be protective.
Moderna is exploring the use of an immune correlate of protection to test whether a half-dose of its vaccine could offer sufficient protection against Covid-19 disease, Chief Medical Officer Tal Zaks said at a recent investor conference.
Expanding Vaccine Uses
An FDA spokeswoman said that when immune correlates of protection are established for these vaccines, they will be useful for a variety of studies including the evaluation of vaccines in children and assessing the response to new variants.
There are challenges for determining protective immune responses. There were relatively few cases of symptomatic Covid-19 in people who received the Moderna and Pfizer vaccines in the large studies at the time they were authorized, making statistically significant comparisons difficult. But researchers continue to follow study subjects and expect to see higher numbers.
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Write to Peter Loftus at firstname.lastname@example.org
Corrections & Amplifications
Johnson & Johnson has requested U.S. authorization of its Covid-19 vaccine. An earlier version of this article incorrectly said that J&J plans to seek authorization soon. (Corrected on Feb. 11.)
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