A Third COVID-19 Vaccine (NUVAXOVID) Wins FDA Approval

In May 2025 the Food and Drug Administration (FDA) approved a third COVID-19 vaccine (NUVAXOVID).[1] Previously available under an Emergency Use Authorization,[2] a single 0.5 milliliter dose of Nuvaxovid is delivered by intramuscular injection.[3] In people who have not previously received a COVID-19 vaccine, a second dose is administered three weeks after the first.[4]

According to the product label, the vaccine is indicated for adults 65 years and older and people 12 through 64 years of age with at least one medical condition that puts them at high risk of severe COVID-19 outcomes. Nuvaxovid can further be used to boost immunity in people previously vaccinated with any COVID-19 vaccine if the booster is administered at least two months after the second dose of the initial series.

About COVID-19 vaccines

Unlike the previously approved messenger ribonucleic acid (mRNA) vaccines for COVID-19 (COMIRNATY [Pfizer],[5] SPIKEVAX [Moderna]), the main active ingredient of Nuvaxovid (Novavax) is the viral-surface spike protein of SARS-CoV-2. In the mRNA vaccines, the active ingredient is the RNA code that a recipient’s cells use to make viral-surface spike proteins that the immune system recognizes, leading to the development of protection against SARS-CoV-2. By comparison, the genetically engineered (recombinant) spike protein in Nuvaxovid directly acts as an antigen that similarly stimulates the immune system to produce antibodies.[6]

As of September 2025 the Spikevax mRNA vaccine was approved for individuals 6 months through 64 years of age with at least one underlying condition that increases their risk of severe COVID-19 outcomes and for all adults 65 years and older.[7] The Comirnaty mRNA vaccine was approved for all adults 65 years and older and individuals age 5 through 64 years who are at increased risk of severe COVID-19.[8]

Clinical studies[9]

Seven clinical studies supported the approval of Nuvaxovid.

Study 301 was a randomized, observer-blinded trial of the vaccine based on the original (Wuhan) strain of SARS-CoV-2 evaluating the primary two-dose series and a booster dose administered six months later. The study enrolled 29,943 adults; 9,982 were in the placebo group. The primary immunization series was 90% effective at preventing laboratory-confirmed COVID-19 cases. Three cases of myocarditis or pericarditis (heart-related inflammation) were observed within 14 days of vaccination; one case was in the placebo group.

A pediatric version of study 301 enrolled 2,247 participants age 12-17 years; vaccine efficacy was 80%, and there was one case of serious myocarditis two days after the second Nuvaxovid dose.

Study 311 enrolled 1,719 adults who had received two or three doses of a mRNA vaccine at least 90 days previously. Participants were randomized to receive a Nuvaxovid booster based on the original strain, an Omicron BA strain, or both (bivalent). FDA reviewers concluded that the effectiveness and safety of Nuvaxovid against the newer and older SARS-CoV-2 strains was comparable.

Study 313 was an open-label trial that gave a booster dose of Nuvaxovid (Omicron XBB) to adults who were previously vaccinated with an mRNA COVID-19 vaccine (n=332) or were seropositive (blood test showing previous infection) and COVID-19 vaccine naïve (n=338). FDA reviewers concluded that the booster dose with the newer strain performed reasonably, regardless of prior vaccine or infection history.

The FDA reviewers determined the other four trials provided “supportive evidence of safety” for Nuvaxovid based on the original Wuhan strain. Study 307 randomized 911 “medically stable” adults (aged 18-49 years) to one of three different manufacturing lots of the vaccine. Study 101 randomized 823 “healthy adults” (aged 18-84 years) to receive the vaccine with and without an adjuvant ingredient to enhance the recipient’s immune response (in the approved Nuvaxovid vaccine, in addition to the spike protein). Study 302 randomized 15,185 “healthy and clinically stable” adults (aged 18-84 years) to receive Nuvaxovid or placebo. Similar in design to study 302, study 501 included 4,418 participants (aged 18-64 years), many of whom had medically stable human immunodeficiency virus (HIV) infection.

As of October 2024 there had been 1,017 reports to the FDA’s Vaccine Adverse Event Reporting System database related to Nuvaxovid. Fifty-five percent of these were classified as serious, with the most common (33 to 77 reports each) being headache, chest pain, dyspnea (shortness of breath), dizziness, fatigue, myalgia (muscle aches), pyrexia (fever), nausea, cellulitis (skin infection) and cough. Thirty-three deaths were reported, although none were apparently caused by the vaccine. There were 39 reports of myocarditis or pericarditis; 12 of the cases were classified as serious, and none were fatal.

After reviewing the risks of myocarditis and pericarditis from COVID-19 vaccination, Public Citizen’s Health Research Group previously concluded that the risk is rare and is strongly outweighed by the benefits of COVID-19 vaccination.[10]

As is the case with other vaccines, the most common adverse reactions to Nuvaxovid are injection-site tenderness or pain.

Narrowed indications for Nuvaxovid

The FDA approval of Nuvaxovid requires the company to conduct several post-marketing studies. Moreover, the approval was for a narrower population than the manufacturer had requested and the FDA staff had recommended. Overruling the staff, the newly appointed director of FDA’s Center for Biologics Evaluation and Research (CBER) issued a “decision memo” restricting the vaccine’s indications.[11] The CBER director denied approval for people age 12 through 64 years unless they had at least one underlying condition that put them at high risk of severe outcomes from COVID-19. The CBER director justified countermanding his staff based largely on three arguments: 1) insufficient data, 2) uncertainty about coronavirus variant evolution and 3) the decreasing incidence of severe COVID-19.

The review process for the Nuvaxovid vaccine, which included the involvement of the FDA’s Office of the Commissioner and possibly the Department of Health and Human Services, was very troubling. The process deviated from standard practice at the agency and has implications for federal vaccine policy and future regulatory decisions about COVID-19 vaccines.[12]

What You Can Do

To prevent death or serious complications from COVID-19, Nuvaxovid is the third good vaccine option available in the United States, either as an initial two-dose series or as a booster immunization. COVID-19 vaccination is particularly important for adults 65 years and older, younger individuals with underlying medical conditions that put them at high risk of severe outcomes, children between 6 and 23 months, and people who are pregnant.[13]
 

References

[1] Barnswell H. Novavax wins narrowed approval for its Covid-19 shot after delay. STAT. May 17, 2025. https://www.statnews.com/2025/05/17/fda-approves-novavax-covid-shot-with-conditions-after-delay/. Accessed September 10, 2025.

[2] Katella K. Novavax’s COVID-19 vaccine: your questions answered. YaleMedicine. May 20, 2025. https://www.yalemedicine.org/news/novavax-covid-vaccine. Accessed August 5, 2025.

[3] Novavax, Inc. Label: COVID-19 vaccine, adjuvanted (NUVAXOVID). June 2025. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1a20513c-d255-46d7-8e6b-294cec4b44f4&type=display. Accessed August 3, 2025.

[4] Food and Drug Administration. Novavax COVID-19 vaccine, adjuvanted. November 4, 2024. https://www.fda.gov/vaccines-blood-biologics/coronavirus-covid-19-cber-regulated-biologics/novavax-covid-19-vaccine-adjuvanted. Accessed August 5, 2025.

[5] Update on COVID-19 vaccination. Worst Pills, Best Pills News. April 2025.  https://www.worstpills.org/newsletters/view/1656. Accessed August 3, 2025.

[6] Novavax, Inc. Label: COVID-19 vaccine, adjuvanted (NUVAXOVID). June 2026. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1a20513c-d255-46d7-8e6b-294cec4b44f4&type=display. Accessed August 3, 2025.

[7] Moderna receives U.S. FDA approval for updated COVID-19 vaccines targeting LP.8.1 variant of SARS-CoV-2. August 27, 2025. https://feeds.issuerdirect.com/news-release.html?newsid=6729249760870595&symbol=MRNA. Accessed September 10, 2025.

[8] Pfizer and BioNTech’s Comiranty receives U.S. FDA approval for adults 65 and older and individuals ages 5 through 64 at increased risk for severe COVID-19. August 27, 2025.  https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontechs-comirnatyr-receives-us-fda-approval. Accessed September 10, 2025.

[9] Food and Drug Administration. Summary basis for regulatory action, BLA STN: 125817/0, NUVAXOVID. April 1, 2025. https://www.fda.gov/media/186879/download?attachment. Accessed August 3, 2025.

[10] Very low risk of heart inflammation with COVID-19 mRNA vaccines. Worst Pills, Best Pills News. November 2022. https://www.worstpills.org/newsletters/view/1498. Accessed August 3, 2025.

[11] Food and Drug Administration. Center director decision memo: BLA: 125817, NUVAXOVID. May 16, 2025. https://www.fda.gov/media/186905/download?attachment. Accessed August 3, 2025.

[12] Zettler PJ, Cha S, Despres S, Lurie P. FDA Review of Novavax's COVID-19 vaccine-regulatory integrity and deviations from standard practice. JAMA. 2025;334(6):479-480.

[13] Centers for Disease Control and Prevention. People with certain medical conditions and COVID-19 risk factors. June 11, 2025. https://www.cdc.gov/covid/risk-factors/index.html. Accessed August 3, 2025.