How — and When — We’ll Know If a Covid-19 Vaccine Is Working

Phase 3 trials explained


There are more than 150 experimental Covid-19 vaccines in development right now, and a handful of those have recently entered the final stages of human testing.

Initial findings show a glimmer of promise: In early trials, these vaccines appear safe and seem to spur an immune response in the body. But how will we know that a vaccine is actually working? And how soon could that be?

Despite President Trump’s rosy predictions that a vaccine will be ready by Election Day on November 3, experts say that timeline is unlikely.

“I don’t see how that’s possible,” said Paul Offit, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, during a National Press Foundation briefing for journalists on August 10. “I think that would be a mistake. You want to make sure that we have clear efficacy data before we put this vaccine out there, because there is fragile vaccine confidence in this country.”

Moderna and Pfizer kicked off late-stage trials at the end of July, with both companies hoping to enroll 30,000 people. In an Aug. 7 email from Moderna obtained by CNN, investigators said they have so far enrolled 4,536 trial subjects. Meanwhile, AstraZeneca is expected to begin a large trial in the U.S. soon. It will take time to screen people to first learn whether they’re eligible to participate. Plus, the vaccines being tested by these companies each require two doses, an initial shot and a “booster” given about a month later.

After that, researchers will need to follow people for several weeks to learn whether they get sick with Covid-19 while going about their daily lives. Investigators will also need to take blood samples from people and analyze them for antibodies against SARS-CoV-2, the virus that causes Covid-19. Specifically, they’re hoping that a vaccine prompts the body into making antibodies that can neutralize the virus. Looking for neutralizing antibodies is more difficult and time-consuming than other antibody tests because scientists need to test the antibodies against the actual virus in a biosafety lab.

“I just have a hard time thinking that any of that information can be ready by October or November,” Thomas Denny, chief operating officer of the Duke Human Vaccine Institute, tells the Coronavirus Blog.

Vaccine development is typically a slow process, often taking a decade or more. But the urgency of the coronavirus pandemic and the advent of new vaccine technology mean that a Covid-19 vaccine could be produced in record time. Still, vaccine studies can only go so fast.

Researchers first need to conduct phase 1 trials, in which they give a vaccine in different doses to a small number of people, usually just a few dozen, to test for safety. They want to find the highest dose they can give people with the least side effects. The bar for safety in a vaccine study is much higher than in a trial of a drug or therapy for a specific disease because vaccines are given to huge populations of healthy people.

“Vaccine effectiveness is typically lower in the real world.”

Next are phase 2 trials, where investigators give a vaccine to a few hundred people and widen the groups of people included, such as the elderly. They’re looking for safety issues in a larger number of people, as well as determining whether the vaccine can stimulate the immune system.

Then come large phase 3 trials, which typically include thousands or tens of thousands of people. This is the final stage of testing before a vaccine can be approved for use. In these trials, researchers randomly give a vaccine or placebo to participants and look for efficacy — the reduction in disease among the vaccinated group. The gold standard for these trials is known as a “double blind” trial, which means neither the participants nor the investigators know whether a person has received the vaccine or placebo.

This last phase can take years to conduct because investigators need to wait for people to be naturally exposed to the pathogen that the vaccine is meant to protect against.

“Prior to Covid, these types of trials would take a much longer period of time,” says Denny, who’s run HIV vaccine trials. “We’re in a different setting today than we traditionally are. We have a highly infectious agent that spreads efficiently and easily.”

In the U.S., phase 3 trials are happening in many places that have become hot spots of infection, like Florida, Texas, and California. In those places, the likelihood of being infected with the virus is great. By enrolling people in these places who are at high risk of getting infected — like health care workers and essential workers — we won’t have to wait years until we know whether a Covid-19 vaccine works.

The speed of a trial is determined by three major factors: the rate of enrollment, the number of people needed to draw a conclusion about the vaccine efficacy, and the frequency of disease in the population where the trial is being conducted.

“We are all hoping that the alignment of those factors will lead to results as soon as possible,” Katherine O’Brien, MD, director of the immunization, vaccines and biologicals program at the World Health Organization, tells the Coronavirus Blog.

In a phase 3 trial, investigators determine whether a vaccine is working by comparing the number of infections in the non-vaccinated group to those who have received the vaccine, explained O’Brien. Vaccine efficacy is measured as the difference in the rate of disease in the placebo group minus the rate of disease in the vaccinated group, all divided by the rate in the placebo group.

Risk also factors into the equation. With wearing masks and social distancing encouraged or required in many places, how likely is it that people in the trial will be exposed to the virus? Researchers want to make sure both the placebo group and vaccinated group have an equal risk of exposure.

Consider a trial of 200 people — 100 who get a vaccine and 100 who get a placebo. If all 100 people in the placebo group get sick and no one in the vaccinated groups does, the vaccine would have a 100% efficacy rate. If there are 100 infections in the placebo group and 50 in the vaccinated group, the efficacy would be 50%. If there are the same number of infections in both groups, the efficacy would be 0%.

In June, the U.S. Food and Drug Administration released guidance for the approval of a Covid-19 vaccine. The agency said in a statement that to win regulatory approval, a vaccine will need to either prevent disease or decrease its severity in at least 50% of people who are vaccinated. For comparison, the flu vaccine is about 40% to 60% effective, and it varies every year. This year’s flu vaccine is about 45% effective, according to the Centers for Disease Control and Prevention.

“We would of course like to see much higher levels,” says Wayne Koff, PhD, the president of the Human Vaccines Project, a New York-based nonprofit with the goal of decoding the human immune system.

That’s because efficacy rates, which are calculated from a clinical trial run under ideal conditions, differ from the actual effectiveness of a vaccine, which is how well it performs in real-world conditions. Vaccine effectiveness is typically lower in the real world. A major reason is because clinical trials may exclude elderly people, who don’t respond as well to vaccines because of their weakening immune systems. Vaccine trials also tend to enroll people who are generally healthy, and scientists know that chronic illnesses can decrease the effectiveness of a vaccine.

Another reason for this discrepancy is that the vast majority of trial volunteers get the full regimen of doses that a vaccine requires. In real life, vaccination rates drop off after a first dose, making the vaccine less effective.

Phase 3 trials could also reveal whether a Covid-19 vaccine will be able to just prevent symptoms of Covid-19 disease or protect against infection entirely. According to a July 10 estimate from the Centers for Disease Control and Prevention, about 40% of people who get infected with the virus are asymptomatic.

So, when’s the soonest we could learn whether a coronavirus vaccine is working? Koff and Denny think we could know by the end of the year at the earliest, but the beginning of 2021 is more likely.

“We may get a little bit of a hint sooner,” Denny says.

Former staff writer at Medium, where I covered biotech, genetics, and Covid-19 for OneZero, Future Human, Elemental, and the Coronavirus Blog.

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