As the Delta variant spreads in the United States, and with studies demonstrating that the protection afforded by COVID-19 vaccines may wane over time, public health officials are evaluating the value of an additional vaccine dose to strengthen the immune response to the virus.

The U.S. Centers for Disease Control and Prevention recently authorized additional doses of the Pfizer and Moderna vaccines for Americans who have weakened immune systems, and are considering a similar booster strategy for the general public.

In this Q&A, Dr. Roy Gulick, chief of the Division of Infectious Diseases at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, and co-chair of the National Institutes of Health’s COVID-19 Treatment Guidelines panel, breaks down the science underlying booster shots and answers some frequently asked questions about the vaccines.

Question: In vaccine development, how does a determination get made about a booster schedule?

Answer: A vaccine stimulates the immune system to make a response (antibodies and/or cells) to help fight microorganisms, such as bacteria and viruses, that cause an infection. This response may only last a certain amount of time. How long the response lasts could be determined by following the immune response (for example, the amount of antibody in the blood) or by following people who have been vaccinated for the development of the actual infection. When the protection from the vaccine wears off, a booster vaccine could re-stimulate the immune system to respond again.

Q: How much of the analysis of boosters is being driven by the Delta variant, as opposed to natural changes in immunity conferred by the initial vaccine doses among the general population?

A: Both the Delta variant (which currently accounts for more than 99% of new COVID-19 cases in the United States) and concern that the immune response will wane over time are guiding the thinking exploring the vaccine booster strategy.

Q: What does the early data show about the effectiveness of an additional COVID-19 vaccine shot, particularly in the immunocompromised?

A: Immunocompromised means that the immune system is not working as well as it should. This can be caused by certain diseases such as cancer, autoimmune diseases or HIV, or by taking certain drugs, including cancer chemotherapy, steroids and drugs that affect the immune system, known as immunomodulators. We know from clinical data that immunocompromised people may not respond sufficiently to one or two COVID-19 vaccinations; some early data suggests that some will respond sufficiently with a third COVID-19 vaccination. This was the idea when the CDC recently recommended a booster with Pfizer or Moderna vaccines for moderate-to-severely immunocompromised people. We don’t know yet if non-immunocompromised people will benefit from or need an additional vaccinate dose (booster).

Q: Should vaccinated people who were previously infected with SARS-CoV-2 receive a vaccine dose?

A: Current recommendations are that people with prior COVID-19 infection should receive COVID-19 vaccination. This is because natural COVID-19 infection stimulates variable amounts of immune responses. For example, early data suggested that approximately 10% of people who had COVID-19 did not develop antibodies.

Q: How will scientists gauge the long-term effectiveness of a third COVID-19 vaccination shot?

A: People who enrolled in the original COVID-19 vaccine studies continue to be actively followed, both monitoring their immune responses (their antibody levels, for example) and to see if they acquire COVID-19 infection. Some of the original COVID-19 vaccine studies are testing booster strategies, so we will have more data to help guide clinical decisions.

Q: What’s the likelihood that COVID-19 vaccinations will be administered annually, much like the flu shot?

A: The reason that flu vaccinations are given yearly is because the most common circulating flu viruses change each year. For that reason, last year’s flu vaccine may not be effective against this year’s flu viruses. We don’t yet know if that will be the case for COVID-19 vaccinations.

Q: Have any differences been seen in side effects or risks with an additional COVID-19 vaccine shot?

A: We only have limited information on the side effects and risks of a third COVID-19 vaccination. So far, it looks like the side effects are similar to those of the first and second shots (most commonly, injection site pain or redness). More serious side effects appear rare.

Q: Is there any data about the safety and efficacy of mixing COVID-19 vaccines (i.e. two doses from Pfizer and a third from Moderna, and vice versa; first dose from J&J and second mRNA)?

A: Currently, the CDC recommends continuing the third vaccination with the same type of vaccine the person already had with the first two doses (Pfizer or Moderna). However, in unusual circumstances, the other vaccine could be given. We are still learning about the safety and efficacy of this approach.

Alyssa Sunkin-Strube is newsroom manager for Weill Cornell Medicine.