FDA Approves COVID-19 Vaccines With Postmarketing Study Strings Attached

The FDA is requiring the three manufacturers of the COVID-19 vaccines it approved today to conduct a variety of postmarketing studies.

The approval letter to Pfizer and its BioNTech mentions the companies' commitment to conduct four postmarketing studies of their vaccine, marketed under the brand name Comirnaty. The two approval letters to Moderna, one for its Spikevax vaccine and another for an updated version marketed as Mnexspike, mention a total of four postmarketing trials.

The letter to Novavax, the maker of the third approved vaccine, Nuvaxovid, mentions the company’s commitment to conducting two postmarketing studies.

FDA Commissioner Martin A. Makary, M.D., M.P.H., and Vinay Prasad, M.D., M.P.H., director of the FDA’s Center for Biologics Evaluation and Research (CBER), indicated in an opinion piece published in the New England Journal of Medicine (NEJM) on May 20, 2025, that postmarketing research would be part of the FDA’s approval of the COVID-19 vaccine. They outlined what the FDA’s preferred study design would be, including study population, primary and secondary end points and follow-up periods.

That opinion piece also foreshadowed the major change in today’s approvals. Whereas the previous approvals and recommendations had recommended the COVID-19 shots for most people, the news releases issued by the three companies today said their vaccines were approved for people 65 and older — a part of the population that, by virtue of its age, stands a greater chance of experiencing severe COVID-19—and for those younger with “at least one underlying condition that puts them at high risk for severe outcomes from COVID-19.”

In their May 20 NEJM piece, Makary and Prasad named 23 such conditions that were based on a list posted by the Centers for Disease Control and Prevention (CDC). The conditions they listed ranged from specific diseases such as tuberculosis, cystic fibrosis and asthma to broader categories, such as people who are physically inactive and current and former smokers.

The FDA did not issue a news release about the approvals. Instead, HHS Secretary Robert F. Kennedy Jr. made the announcement in a short, somewhat cryptic post on X. He said the vaccines were approved for those at “higher risk” of COVID-19 without defining what higher risk means in this context. After naming the manufacturers of the three vaccines, he said they would be “available for all patients who choose them after consulting their doctors.”

Whether that will be true depends on what is meant by "available." Insurers may be reluctant to cover the vaccines for people who do not meet the FDA’s criteria. Moreover, the CDC’s influential advisory committee, the Advisory Committee on Immunization Practices (ACIP), has yet to vote on them. Kennedy ousted the existing ACIP members in early June 25 and replaced them with a smaller group that included people who have questioned the safety and efficacy of the COVID-19 vaccines.

In their NEJM opinion piece, titled “An Evidence-Based Approach to COVID-19 Vaccination,” Makary and Prasad stated that people 50 to 64 were an “ideal population” for future trials given the “global equipoise about yearly boosters” in that age group. They said the FDA’s preferred primary end point would be symptomatic COVID-19 and called for special attention to secondary end points, which they listed as severe COVID-19, hospitalization and death. Makary and Prasad said that people who have had COVID-19 should not be excluded “since evidence is needed for the average American.” They also said the follow-up period should be at least six months to assess whether the protection of the vaccines persists.

The approval letters, which the FDA shared in an email sent out by CBER about news at the center, do not go into that level of detail about the postmarketing studies.

All four of the approved vaccines—counting Spikevax and Mnexspike as separate vaccines — will be studied in trials enrolling people ages 50 to 64 without high-risk conditions for COVID-19, according to the approval letters.

One of the studies of Pfizer and BioNTech’s vaccine, sold under the brand name Comirnaty, and of Novavax’s Nuvaxovid is a prospective, placebo-controlled study of fiercely debated post-COVID-19 vaccination syndrome. Proponents say that some people develop long COVID symptoms after vaccination and that the COVID-19 spike protein from the vaccine is to blame.

Here is a list of the postmarking studies mentioned in the approval letters and some of the barebones information in the letters about them.

Moderna’s Spikevax

Phase 3b/4, open-label, single-arm study to evaluate the immunogenicity and safety of the vaccine in people 65 and older and with risk factors for severe COVID-19. The final protocol was submitted June 20, 2025. The study is scheduled to be completed on May 31, 2026, with a final report slated for submission by Oct. 31, 2026.

A Phase 4, randomized, observer-blind, placebo-controlled trial of the vaccine and variant-containing formulations in adults, 50 to 64, without high-risk conditions for severe COVID-19. The study is scheduled to start Nov. 30, 2025, and to be completed by Jan. 31, 2027.

Moderna’s Mnexspike

The same as the types of studies and dates as those for Spikevax.

Pfizer and BioNTech’s Comirnaty

A prospective study to evaluate the safety and immunogenicity of the vaccine in people 65 years and older and people ages 12 to 64 years of age with at least one underlying condition that puts them at high risk for severe outcomes from COVID-19. The final protocol is to be submitted by Aug. 30, 2025, with interim results scheduled to be reported Feb. 28, 2026, and the study completed by July 31, 2026.

A randomized, double-blind, placebo-controlled clinical study to assess the safety and efficacy of the vaccine in adults, 50 to 64, without high-risk conditions for severe COVID-19. The companies are supposed to submit their final protocol on Sept. 30, 2025, with interim results scheduled for Feb. 28, 2026, and study completion by July 31, 2026.

A prospective study to evaluate the safety and immunogenicity of the vaccine in children 5 to 11 with at least one underlying condition that puts them at high risk for severe outcomes from COVID-19. The study is scheduled to start Sept. 30, 2025, with interim results by Feb. 28, 2026, and a completion date of July 31, 2026.

A prospective, placebo-controlled, randomized study to evaluate detection of circulating SARS-COV-2 spike antigen and self-reported symptoms of post-COVID-19 vaccination syndrome or long COVID symptoms at months 1, 3, 6, and 12 in the vaccine and control arms.

Novavax’s Nuvaxovid

A phase 3, open-label, single-arm study to evaluate the safety and immunogenicity of the vaccine. The schedule in the approval letters calls for the final protocol to be submitted on Aug. 30, 2025, interim results on Feb. 28, 2026, and completion of the study on July 31, 2026.

A phase 4, observer-blind, placebo-controlled randomized clinical trial to assess circulating, vaccine-derived spike protein in people 50 to 64 with no history of post-vaccination syndrome or long COVID. The protocol is scheduled to be submitted March 31, 2026, with a study completion date of Nov. 30, 2027.