To be an effective tool for fighting the COVID-19 pandemic, a vaccine will need the confidence of the public, including the doctors, nurses and pharmacists who administer the vaccine. Following part one of our series, here are frequently asked questions based on conversations I’ve had with many people about clinical trials and vaccine development.

What is a vaccine and how does it work?

A vaccine is a substance that stimulates a person's immune system to develop antibodies that produce complete or partial immunity to a specific disease. Vaccines prevent 2-3 million deaths per year. Unlike most medicines, vaccines don’t treat disease, but they can prevent it from spreading and making people sick. Many vaccines are made by taking an attenuated (or weakened) strain of a virus at a level that’s too low to cause disease, but high enough for the body to create an immune response. Some newer potential vaccines, however, use different technology that doesn’t involve direct use of the virus.

Since vaccine development usually takes years, how are scientists able to move more quickly now while doing responsible research?

COVID-19 has ushered in an unprecedented level of global collaboration and investment. Researchers mapped the virus’ genome just a month after the initial outbreak, giving vaccine developers a major head start. Additionally, advancements in science and technology mean that scientists are able to use new methods of vaccine development, like RNA vaccines.
RNA gives cells in the body instructions for creating proteins (the building blocks of DNA). Two vaccine candidates use RNA to enter a cell and stimulate the production of the SARS-CoV2 virus, which causes COVID-19 disease, creating an immune response.

Another reason why vaccine development can be slow is that funding streams can be hard to secure. Enormous amounts of funding from both public and private sources have moved the science along at unprecedented speed. U.S. Federal funding for COVID-19 vaccine development helps remove this burden. Other measures the Department of Health and Human Services (HHS) are taking include testing multiple vaccine candidates simultaneously and putting advanced manufacturing capacity in place to scale up production in the event the vaccines are found safe and effective. Normally, it would be prudent to await the trial results before scaling up to avoid the enormous investment with no assurance of success.

The issue of safety is on the minds of most people when vaccines are considered. There is no way around the fact that we will not have long-term safety data when the vaccine is initially distributed should one or more of the trials meet the criteria for EUA. Accordingly, the FDA will need to use its best judgment with limited followup. The efficacy side of the equation will be more clearcut. This means that post-market followup will be critical to fill in the needed information and the rollout of the vaccine will need to be targeted at high-risk groups in whom the benefits most likely outweigh the known and potential risks.

In order to earn public trust in COVID-19 vaccines, it will be important for findings and data from the research process to be open and transparent to the scientific community.

Why is it important for trial participation to be as broad as possible?

All vaccines and treatments must undergo testing, often involving thousands or tens of thousands of people, to ensure safety and effectiveness. Because COVID-19 is a new, global disease, it’s even more important to make sure these trials represent many types of people — including different age groups, racial and ethnic backgrounds, and health histories. The balance of benefits and risks should guide the choice to use a particular treatment, and this balance is not uniform in all people. Therefore, the recruitment of a broad population enables some assessment of the spectrum of benefits and risks.

For COVID-19, older people and those with comorbidities (especially multiple comorbidities like heart disease, chronic lung disease, diabetes and obesity) are at higher risk and may have more to gain from the vaccine, but these same people may be at higher risk of complications. In the United States, COVID-19 is also disproportionately impacting people of color and those in lower-income demographics. It’s critical that trials recruit people from these communities to ensure vaccines can benefit those that need it most or that it can be avoided if risks outweigh benefits.

What do we know about the vaccines so far?

The progress of candidate vaccines is well-covered by this NY Times website. Four vaccines made in China and one vaccine made in Russia are already in clinical use, but none of these have passed the U.S. FDA’s criteria. FDA requires that a vaccine demonstrate 30% effectiveness compared to placebo at the lower limit of the confidence interval. This means that the observed effect in a successful trial of any vaccine will be at least 50% more effective than placebo (thus the lower confidence interval falls above 30%).

Currently there are 27 vaccine candidates in Phase I evaluation, 14 in expanded safety trials and 9 in large-scale definitive clinical outcome trials. We’re still learning about the level of immunity that the COVID-19 vaccine(s) will produce, but it’s likely that the first vaccines will be most effective at preventing severe COVID-19 disease. The first set of vaccine candidates may require “booster injections” that people will likely need to receive a few months after their first dose.

What do we know about the trials?

The three trials that are most advanced in recruitment have published their protocols. This table from Eric Topol’s Twitter feed gives some relevant details. While the trials are more alike than different, each trial takes a distinct, nuanced approach to the sample size, the randomization allocation and the statistical analysis. This is not at all uncommon in clinical trials as there are literally hundreds of decisions that must be made to design a protocol. The critical point is that the FDA is overseeing the fabric of trials to make sure that the findings can be placed into context as decisions are made about marketing and labeling.