Covid-19 Vaccine: The Most Important Questions to Ask
By: Tara Haelle
Tags: Pandemic, Six Months In, Covid 19, Coronavirus, Vaccines

It’s Okay to Have Questions About a Covid-19 Vaccine. Here’s What to Ask.

The approval process, interpreting clinical trial results, and how to be confident in your choice to get the vaccine

This story is part of “Six Months In,” a special weeklong Elemental series reflecting on where we’ve been, what we’ve learned, and what the future holds for the Covid-19 pandemic.

Depending on whom you ask, anywhere from half to 70% of Americans plan to get the Covid-19 vaccine when it’s available. But that means a lot of folks likely have questions before they’ll decide to line up for it. It’s entirely reasonable for people to be skeptical about a new vaccine. In fact, concern about a potential Covid-19 vaccine is healthy, particularly given the speed of its development, and is shared by many scientists and public health experts. “We tell people all the time to get involved in your health and ask questions, and then we act surprised when people ask questions about vaccines,” says Holly Witteman, PhD, an associate professor of medicine at Laval University in Quebec City, Canada, who studies vaccine hesitancy. So, what should you be asking? Ahead, recommendations from the experts.

Did the vaccine successfully go through all appropriate regulatory channels?

Above everything else, a Covid-19 vaccine must make it through the gauntlet of approvals at the FDA and CDC that any other vaccine, at any other time, for any other diseases, would be expected to pass through.

“I do think if a vaccine is approved through a science-based process, the public can have a lot of trust that the vaccine is safe and effective,” Witteman says.

But most people aren’t familiar with all those processes or which ones might involve shortcuts that could make them uneasy. Generally speaking, a vaccine goes through three clinical trials. Then the vaccine must receive FDA approval based on the clinical trial data. After the FDA licenses the vaccine, the CDC makes recommendations on who should get it and when. The FDA could also issue an Emergency Use Authorization, but only if the data strongly shows high efficacy and no safety issues. And there is an inherent expectation that public health and regulatory officials and manufacturers will ensure a vaccine goes through the right processes.

“I do think if a vaccine is approved through a science-based process, the public can have a lot of trust that the vaccine is safe and effective.”

“The promise is that all the safe measures will still be taken, but it’s okay to have questions about how that is done,” says Maya Goldenberg, PhD, an associate professor of philosophy at the University of Guelph in Ontario, Canada. Goldberg specializes in vaccine hesitancy research and has a book on it coming out in spring 2021. “The extent to which people trust vaccines is going to depend on the extent to which they trust the system that supports vaccines.”

Questions about regulatory processes are especially valid when evidence of political interference already exists, such as attempts by the administration to edit the CDC’s Morbidity and Mortality Weekly Report.

“We are seeing significant damage to precisely those U.S. institutions and government agencies that are supposed to be protecting public health. If the system doesn’t work, there’s no reason to trust the product,” Goldenberg says.

Take, for example, the influence the executive branch had on FDA decisions about hydroxychloroquine and convalescent plasma, notes Paul Offit, MD, director of the Vaccine Education Center and an infectious disease pediatrician at Children’s Hospital of Philadelphia, who co-developed the rotavirus vaccine. “There’s evidence that this administration [influences federal regulatory agency processes], so you wonder if that would be true here also,” Offit says.

Fortunately, several aspects of the approval processes are transparent and immune to political influence. Data safety monitoring boards, composed of academics independent from the government and pharmaceutical companies, closely observe the clinical trials to watch for possible safety problems and assess the evidence for efficacy.

Then, two committees within the FDA and CDC, both composed of independent experts, meet publicly to make recommendations to the parent agency. The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) meets in open, publicly broadcast meetings where anyone can hear the experts discuss the data. The next one for the Covid-19 vaccine will be October 22.

“If that group says they don’t think it’s ready, and then it gets approved, that’s worrisome, or if they’re skipped,” Offit says. “I don’t think they should be skipped.”

So far, FDA Commissioner Stephen M. Hahn has vowed that Covid-19 vaccine candidates “will be reviewed according to the established legal and regulatory standards for medical products,” including VRBPAC.

The other committee is the CDC’s Advisory Committee on Immunization Practices (ACIP), which created a Covid-19 Vaccines Work Group in April that includes 41 experts from a wide range of different fields. At its open June meeting, the work group established its guiding principles for decision-making, starting with safety being “of paramount importance,” including across different populations. Following safety were “the importance of diversity in clinical trials” and the “efficient and equitable distribution of vaccines.” Again, open meetings of ACIP will allow the public to hear what these independent experts think about the vaccine’s safety and efficacy based on the data. If the committee expresses any concerns, those concerns will be immediately public in real time.

What was found during the clinical trials?

While many people will feel comfortable relying on those committees, even if they feel the larger agencies are suspect, others will want to study the data themselves. Here’s how to interpret it.

Where do you find the data?

All clinical trial data submitted to the FDA is publicly available, without a paywall. You should be able to find this data by searching online for “FDA Covid-19 vaccine approval” and clicking on the result in the FDA’s “Vaccines, Blood & Biologics” section. The approval page will include links to all the supporting documents in the vaccine’s approval application. For example, the HPV vaccine’s page includes the clinical reviews that contain all the evidence on the Gardasil 9 trials. If you have trouble finding it this way, you may need to do some digging on ClinicalTrials.gov, but news articles will likely link to the data as well.

“Look at the tables, where the data are summarized,” Witteman advises. “Also, there will be supplemental material and data with extra tables, and sometimes that’s where you get those details you’re interested in.”

How large were the trials?

It’s important that the later (phase 3) trials have enough people to detect rarer adverse events that might not show up in only a couple thousand people. The FDA requires a minimum of 3,000 people in these trials, but more than 10,000 is ideal. So far, most trials for Covid-19 vaccines have 15,000 to 20,000 people.

Who was in the trials?

Thousands of people in a trial doesn’t mean much if all the participants are demographically similar. Participants need to be diverse in terms of age (including older adults), race, ethnicity, comorbidities, and sex. Additional trials may be needed to establish safety and efficacy for children and pregnant people.

Witteman said she would especially want to look at differences in safety and efficacy between males and females and among different racial and ethnic groups.

How effective is the vaccine?

How many people received the vaccine and how many received a placebo (a “fake” vaccine)? How many people who received the vaccine got sick with Covid-19? How serious were those infections? How many people who received the placebo got sick with Covid-19? These numbers will be summarized in tables, and the researchers use them to calculate the efficacy of the vaccine. Ideally, they will also calculate the efficacy for different subgroups, such as by age, race, and sex.

The FDA has issued detailed guidance to vaccine manufacturers on development of a Covid-19 vaccine, including a required minimum efficacy of 50%. That means the FDA won’t approve a vaccine unless it prevented Covid-19 infections in at least 50% of vaccinated people in the clinical trials. (Efficacy refers to how well the vaccine works in the clinical trials; effectiveness refers to how well it works in the general population after licensure.) For comparison, the measles vaccine is about 97% effective, and the annual influenza vaccine is usually 40% to 60% effective.

Another helpful question is how severe the illness is in people who got the vaccine and still got sick. Did the vaccine reduce the severity of disease compared to those in the placebo group? (In other words, were there more mild illnesses overall in the vaccine group?) A harder question to answer, but one that the researchers should hopefully try to address, is whether people who get the vaccine and test positive for Covid-19 without symptoms are still contagious.

What are the side effects?

The biggest issue for most people will be the vaccine’s safety profile. “We need to know what the benefit/risk trade-off is,” Goldenberg says. “Of course, the lower the risk, the better, and the higher the efficacy, the better.”

To learn about side effects, first look at the list of all adverse events that were reported and how common each was. An adverse event isn’t always an actual side effect: Any negative health event occurring during a trial is an adverse event, even if clearly unrelated to the vaccine (such as getting hit by a car). Side effects are the adverse events that evidence shows were caused by the vaccine.

If the vaccine is an injection, common side effects will almost certainly include soreness, redness, and swelling at the injection site, and possibly fainting (listed as syncope), because these are common with any vaccine injection. The frequency of other side effects will give you an idea of the vaccine’s overall safety and whether there are any substantial risks.

What systems are in place to find side effects after approval?

After FDA licensure (meaning the agency has approved the vaccine for use) and after people begin getting the Covid-19 vaccine, safety surveillance doesn’t stop. Several programs specifically look for adverse events as the vaccine is distributed. Physicians and even individuals can (and should) report adverse events to the Vaccine Adverse Event Reporting System (VAERS), which enables researchers to watch for any upticks in certain types of reports. (A VAERS report does not mean the vaccine caused the problem, but if a problem is reported over and over, it’s a red flag for researchers to investigate.) The Vaccine Safety Datalink is a collaborative research project that involves studies to investigate possible links between a vaccine and negative effects. Finally, the Post-licensure Rapid Immunization Safety Monitoring System analyzes health insurance claims data to look for possible vaccine safety concerns.

“It’s never a matter of when you know everything because you never know everything. The question is when do you know enough?”

How should I interpret the trial results as a layperson?

It’s okay if you dig up the PDF of a clinical trial and have no idea where to begin. Most people have little experience interpreting clinical trial data on their own, so Witteman recommends watching for explainers in the news and listening to experts who offer their assessments.

How do you know if someone is actually an expert? Look them up on their institution website or on PubMed. They should have publications or other experience in vaccine trials, vaccine safety, or evaluating clinical trials. Many epidemiologists who specialize in infectious disease will have valuable perspectives as well. If you’re reading a news article, search for other articles by that journalist. Have they covered vaccines and clinical trials before?

“Ideally, everyone would have access to a well-informed health professional who can help them with that decision, but I know that is not the reality, especially not in the U.S.,” Witteman says. If you don’t have a doctor you trust to answer your questions about the vaccine, Witteman recommends seeking out experts in the news or on social media who acknowledge the limits of the data and their own knowledge. Ideally, they’ll have experience in vaccine development or safety.

“You’re not looking at people who appear 100% certain about everything,” she says. “You’re looking for people who are saying, ‘These are the limits of what we know.’ That’s an indication of someone who has the confidence to be really honest.”

The bottom line

One of the challenges of making decisions based on scientific evidence is that the evidence is never complete — but you still have to make a decision.

“You never eliminate uncertainty, you just reduce it,” Offit says. “So, when people ask the question, ‘Is it absolutely safe?’ No, nothing is absolutely safe.”

For example, it’s impossible to have data on long-term side effects from a brand-new vaccine. No vaccines licensed in the United States have ever shown long-term effects that weren’t discovered during clinical trials or within a year after licensure, but it’s still not possible to guarantee that will never happen.

“It’s never a matter of when you know everything, because you never know everything,” Offit says. “The question is when do you know enough? With the information we have now, do the benefits outweigh the risks?”

If the vaccine makes it through VRBPAC, FDA approval, and ACIP and is recommended by the CDC, that means the experts believe the benefits outweigh the risks. Being able to ask these questions and find the answers can help you feel confident about agreeing with them.