How You Will Know If a Coronavirus Vaccine Is Safe and Effective

Mostly, by the government helping to pay for the expensive clinical trials needed to show a vaccine is safe and effective, and also by helping to cover the cost of jump-starting production.

Though large human trials and vaccine production are generally costly and time-consuming, the first few stages of developing a vaccine can be accomplished relatively quickly. That includes the initial preclinical lab work and animal studies, as well as the phase one and phase two clinical trials, which involve giving the vaccine to relatively small numbers of people—from dozens to a few hundred—to see whether they raise any immediate red flags about safety and side effects and whether they trigger an immune response indicating that they might help prevent people from getting ill.

Where things really start to slow down is when a vaccine is ready to move to stage three clinical trials. These are much larger, usually involving at least 30,000 people, and can cost hundreds of millions of dollars. Because they are so expensive, pharmaceutical companies generally won’t move to a phase three trial until they are confident it will pan out.

But in this current emergency, manufacturers can move faster because the federal government has said “we’ll pay for phase three trials, and if the vaccine is unsafe, we’ll throw it away,” Offit says.

Another roadblock is how long it takes to scale up the infrastructure needed to produce millions or even billions of doses. But in the case of a potential coronavirus vaccine, that process has already begun for certain products, just in case they turn out to be effective.

“The only way to do vaccine development fast is to compress it, and the only way to compress it is to spend money on stuff that you might not use,” says Paul Duprex, a professor of microbiology and molecular genetics and director of the Center for Vaccine Research at the University of Pittsburgh. “You’re building a factory to make something that you don’t even know whether or not it works.”

Because of the elimination of financial and time barriers, there are already at least eight potential products that are close to or have begun phase three trials, Offit says.

From a safety standpoint, stage one and stage two clinical trials are meant to make sure that a vaccine doesn’t cause any obvious, serious problems. But safety issues often don’t emerge until thousands of people receive a vaccine, which is one reason stage three trials are so critical.

In these trials, half of the volunteers are typically given the real vaccine and the other half a placebo shot. Both groups then continue on with their day-to-day lives. In the months that follow, researchers track how many people develop side effects that could be attributed to the vaccine.

Given the potential seriousness of COVID-19, some minor side effects of a coronavirus vaccine, such as low-grade fever and headache, would likely be considered acceptable, Offit says. But because vaccines are given to healthy people, it’s especially important for manufacturers to demonstrate that they don’t cause serious side effects.

By the end of the phase three trial, thousands of people—say, 20,000—are going to have received the vaccine, which is a big enough number that most common side effects should become clear.

If problems emerge, those trials will be paused and can be stopped. One of the current phase three trials was at least temporarily voluntarily paused, for example, after an unexplained illness occurred in one study participant.

It’s possible or even likely that a vaccine will work differently for different populations, Offit says. Some vaccines might not work as well in older populations, for example, or may provide more or less protection to different racial or ethnic groups. Because of that, it’s essential that these trials enroll participants that represent different ages, ethnicities, and health conditions, he says.

Historically, clinical trials have underrepresented racial and ethnic minorities, despite legislative efforts to increase the diversity of trial populations, according to a study reviewing the diversity of participants in trials for early coronavirus therapeutics. This is an especially relevant concern when evaluating interventions against COVID-19 because people of color have been disproportionately more likely to suffer severe complications from the virus.

The Food and Drug Administration’s guidelines for coronavirus vaccine development encourage manufacturers to recruit study participants who are racially and ethnically diverse and to include elderly individuals and individuals with preexisting conditions. But these are not mandatory guidelines.

Two of the vaccine manufacturers that are likely to first report vaccine efficacy data are publicly reporting data on the racial and ethnic diversity of study participants. So far, Moderna has reported that approximately 63 percent of those enrolled in its trial are white, 20 percent are Hispanic or Latinx, 10 percent are Black, four percent are Asian, and three percent are from other backgrounds. Pfizer has said that approximately 42 percent of global participants and 30 percent of U.S. participants in its trial have “diverse backgrounds.” In August, Moderna’s CEO told CNBC that the company had slowed enrollment to ensure that the trial sufficiently represented communities most affected by COVID-19.

Children, however, are not currently included in phase three trials. FDA guidance says that manufacturers should plan on ways to study younger populations, but it’s likely that a vaccine will first be authorized for adults before it is studied in younger populations.

Consumers won’t be able to figure out what works best in a given group until there is more data publicly available. Offit says that as long as his subgroup had been adequately represented in the phase three trial, he’d feel fine getting the vaccine himself.

Of course, it’s not enough that a vaccine is safe. It also has to prevent disease.

The FDA says that for a coronavirus vaccine to be approved, it should prevent infection or severe disease in at least 50 percent of people. That’s the minimum level of efficacy that could help us achieve “herd immunity,” which is when enough people are immune that the virus stops spreading through the population. But it would be far better if the vaccine is at least 70 to 75 percent effective, something Offit says he thinks is achievable with COVID-19. Pfizer and Moderna have both reported that their vaccines appeared to be at least 90 percent effective at preventing symptoms—better than that 70 to 75 percent—but that needs to be confirmed; and it's not yet clear whether the vaccines also prevent asymptomatic infection.

To speed up testing of the vaccine, phase three trials are prioritizing candidates who have a good chance of being exposed to the virus, such as healthcare personnel and other essential workers.

Scientists should be able to see how well a vaccine is working by the time about 150 people enrolled in a phase three trial get the coronavirus, Dean says. It will be especially clear if the vast majority of the group that got sick received the placebo, and if there are only a handful of cases in the group that received the potential vaccine.

Before the FDA officially approves a vaccine, a panel of outside experts should review the safety and efficacy data from the trials, Dean says. That panel would then issue a recommendation to the FDA for or against approval. While that recommendation is nonbinding, these deliberations are generally public. “Then everyone can see the process play out and everyone feels onboard,” she says.

Once a vaccine is approved, it will first be made available to people at a higher risk of infection or of complications from COVID-19, according to Offit.

Initial estimates put this number at more than 100 million people in the U.S. alone, he says. That group includes healthcare workers, people who work in long-term-care facilities, and individuals with health conditions that make them more susceptible to complications from a coronavirus infection.

Rolling out a vaccine to this first group will be a complex process that will take months, Offit says, especially because many of the products furthest along need to be stored at subzero temperatures, and people would probably need to get two doses, spaced out.

Scott Gottlieb, former FDA commissioner, says the agency may also decide to authorize the use of a vaccine for certain populations before it’s fully approved for the general public.

Most of the potential vaccines that are furthest along right now rely on new technologies that haven’t been used before, according to Duprex. It will therefore be important to keep development and testing going, even if one of the first candidates appears to be effective.

Even after a vaccine has been approved and is being used, it’s important to continue to track people who receive it, to learn more about its safety and efficacy. “Six months of efficacy isn’t four years of efficacy,” Offit says. Once a vaccine is rolled out to millions of people, rarer side effects can still emerge, so researchers continue to closely follow the real-world results.

Though it’s possible that one of the vaccine candidates that’s currently or about to be in phase three trials will be safe and effective enough to distribute, it may be that one of the later candidates works better, according to Offit.

“We could be lucky, all of the stars could align,” and one of the first products could work extremely well, Duprex says. But products also fail, and there’s no guarantee that a new technology will work as well as we hope, he says.

Still, “because there are so many different approaches, I think most of us feel confident that there’s something out there,” Dean says.

For now, we need to focus on other interventions that we know help. Once we know a vaccine is effective, “it’s not like you’re going to flip a switch and everything is going to be better,” she says. We need to continue to try to increase mask wearing, improve contact tracing, prioritize ventilation, and develop rapid tests that quickly identify infectious people. A vaccine “has to be part of an integrated response,” she says.