Comparing the COVID-19 Vaccines: How Are They Different?

[Originally published: February 24, 2021. Updated: April 24, 2024.]

Note: The Johnson & Johnson (Janssen) COVID-19 vaccine expired as of May 6, 2023, and is no longer available in the U.S. Those who did get the J&J shot are considered up-to-date when they get one updated (2023–2024 formula) COVID vaccine.

Information in this article was accurate at the time of original publication. Because information about COVID changes rapidly, we encourage you to visit the websites of the Centers for Disease Control & Prevention (CDC), World Health Organization (WHO), and your state and local government.

COVID-19 is now in its fifth year, and the subvariants of the Omicron strain, which first emerged in 2021, continue to drive infections in the United States. The good news is that vaccines are still expected to be effective at preventing severe disease, hospitalization, and death from COVID.

In the U.S., infants, children, and adults ages 6 months and older are eligible to be vaccinated, according to the Centers for Disease Control and Prevention (CDC).

As the SARS-CoV-2 virus mutates and new variants continue to emerge, it’s important to keep up with how well the updated vaccines are performing.

We mapped out a comparison of the COVID vaccines available in the United States.

Pfizer-BioNTech

The Pfizer-BioNTech vaccine (brand name: Comirnaty) was granted full Food and Drug Administration (FDA) approval in August 2021 for people ages 16 and older. Before that, it was the first COVID vaccine to receive FDA Emergency Use Authorization (EUA) back in December 2020, after the company reported that its vaccine was highly effective at preventing symptomatic disease. This is a messenger RNA (mRNA) vaccine, which uses a relatively new technology. It must be stored in freezer-level temperatures, which can make it more difficult to distribute than some other vaccines.

Status: Pfizer’s vaccine has been updated over time to target new virus variants. First introduced in December 2020, the original COVID mRNA vaccines from both Pfizer and Moderna protected against the original SARS-CoV-2 virus. They were replaced in September 2022 by “bivalent” vaccines, which targeted both the original virus and Omicron variants BA.4 and BA.5. New updated vaccines in September 2023 replaced the bivalent shots with ones targeting the XBB lineage of the Omicron variant.

The original and bivalent vaccines are no longer in use, and it has yet to be decided whether updated shots will be administered annually, like the flu shot.

Who can get it: People 6 months and older. The CDC has specific recommendations for the following groups, noting that anyone who recently had COVID may need to consider delaying their vaccination by 3 months:

• Everyone ages 5 to 64 years (including people who are pregnant, breastfeeding, or might become pregnant) may get one dose of the 2023-2024 updated vaccine.
• Children ages 6 months to 4 years need multiple doses of COVID vaccines, including at least one dose of the 2023-2024 updated vaccine.
• Adults ages 65 and older need two doses of the 2023-2024 updated vaccine, with the second dose at least four months after the first.

• Those who are 6 months or older and moderately or severely immunocompromised (have a weakened immune system) need at least one dose of the updated vaccine and may get additional doses depending on number of doses they have previously received. Those who are immunocompromised and 65 or older should get an additional dose at least two months after their first dose.

Possible side effects: Pain, redness, or swelling at the site where the shot was administered, and/or tiredness, headache, muscle pain, chills, fever, or nausea throughout the rest of the body. If these side effects occur, they should go away in a few days. A few side effects are serious, but rare. These include anaphylaxis, a severe reaction that is treatable with epinephrine (the drug in EPIPENs®).

FDA warnings: The FDA added a warning label on the mRNA vaccines regarding serious (but rare) cases of inflammation of the heart muscle (myocarditis) and of the outer lining of the heart (pericarditis) in adolescents and young adults, more often occurring after the second dose of an mRNA vaccine. The inflammation, in most cases, gets better on its own without treatment.

How it works: It uses mRNA technology, which is a way of sending instructions to host cells in the body for making copies of a spike protein (like the spikes you see sticking out of the coronavirus in pictures). Our cells recognize that this protein doesn’t belong, and the immune system reacts by activating immune cells and producing antibodies. This will prompt the body to recognize and attack the real SARS CoV-2 spike protein if you become exposed to the actual virus.

How well it works: The 2023-2024 updated vaccines were approved based on preclinical studies of their efficacy against the latest circulating strains. Some people may still become infected even though they have been vaccinated, but the goal of the vaccines now is to prevent severe disease, hospitalization and death. Research has suggested that people who are infected after vaccination also are less likely to report Long COVID (defined as signs, symptoms, and conditions that continue or develop after acute COVID infection), compared to those who were not vaccinated.

In its preclinical data, Pfizer’s updated COVID vaccine produced strong immune responses to XBB.1.5.

In its recommendations for the most recent vaccines, the CDC also cited a study showing the risk of cardiac complications, including myocarditis (an inflammation of the heart muscle), in males 12-17 years old was 1.8–5.6 times higher after a COVID infection compared to after COVID vaccination.

In December 2020, Pfizer-BioNTech’s Phase 3 clinical data for its original vaccine showed 95% efficacy for preventing symptomatic COVID. Later data on real-world effectiveness for adults showed that the protection from the mRNA two-dose primary series waned over time, suggesting that updated vaccines would be needed to bring the immune system back to robust levels.

Moderna

The FDA granted the Moderna vaccine (brand name: Spikevax) full approval for people 18 and older in January 2022, upgrading the vaccine’s EUA, which was granted in December 2020 (a week after Pfizer-BioNTech). Moderna uses the same mRNA technology as Pfizer-BioNTech and had a similarly high efficacy at preventing symptomatic disease when the companies applied for authorization; it also needs to be stored in freezer-level temperatures.

Status: Moderna’s COVID vaccine has been updated over time to target new virus variants. First introduced in December 2020, the original COVID mRNA vaccines aimed to protect against the original SARS-CoV-2 virus. They were replaced in September 2022 by “bivalent” vaccines designed to prevent both the original virus, and Omicron variants BA.4 and BA.5. New updated vaccines in September 2023 replaced the bivalent shots with ones targeting the XBB lineage of the Omicron variant.

The original and bivalent vaccines are no longer in use, and it has yet to be decided whether updated shots will be administered annually, like the flu shot.

Who can get it: People ages 6 months and older. The CDC has specific recommendations for the following groups, noting that anyone who recently had COVID may need to consider delaying their vaccination by 3 months:

• Everyone ages 5 to 64 (including people who are pregnant, breastfeeding, or might become pregnant) may get one dose of the 2023-2024 updated vaccine.

• Children ages 6 months to 4 years need multiple doses of COVID vaccines, including at least one dose of the 2023-2024 updated vaccine.
• Adults ages 65 and older need two doses of the 2023-2024 updated vaccine, with the second dose at least four months after the first.
• Those who are 6 months or older and moderately or severely immunocompromised (have a weakened immune system) need at least one dose of the updated vaccine and may get additional doses depending on number of doses they have previously received. Those who are immunocompromised and 65 or older should get an additional dose at least two months after their first dose.

Possible side effects: The side effects are similar to Pfizer-BioNTech’s vaccine: Pain, redness, or swelling at the site where the shot was administered—and/or tiredness, headache, muscle pain, chills, fever, or nausea throughout the rest of the body. If any of these side effects occur, they should go away in a few days. A few side effects are serious, but rare. These include anaphylaxis, a severe reaction that is treatable with epinephrine (the drug in EPIPENs®).

FDA warnings: The FDA placed a warning label on the Moderna vaccine regarding a “likely association” with reported cases of heart inflammation in young adults. This inflammation may occur in the heart muscle (myocarditis) or in the outer lining of the heart (pericarditis)—it more often occurs after the second dose of an mRNA vaccine. The inflammation, in most cases, gets better on its own without treatment.

How it works: Similar to the Pfizer vaccine, this is an mRNA vaccine that sends host cells in the body instructions for making a spike protein that will train the immune system to recognize it. The immune system will then attack the spike protein the next time it sees one (attached to the actual SARS CoV-2 virus).

How well it works: The 2023-2024 updated vaccines were approved based on preclinical studies of their efficacy against the latest circulating strains. Some people may still become infected even though they have been vaccinated, but the goal of the vaccines now is to prevent severe disease, hospitalization, and death. Research has suggested that people who are infected after vaccination also are less likely to report Long COVID compared to those who were not vaccinated.

To support its 2023-2024 updated shot, Moderna shared clinical trial data that showed a strong immune response against some of the variants that are common now, including XBB.1.5, EG.5, and FL.1.5.1. Antibody responses after vaccination were about 17-times higher against XBB 1.5 and about 10-times higher against BA.2.86.

In its recommendations for the most recent vaccines, the CDC also cited a study showing the risk of cardiac complications, including myocarditis (an inflammation of the heart muscle), in males 12-17 years old was 1.8–5.6 times higher after a COVID infection compared to after COVID vaccination.

Moderna’s initial Phase 3 clinical data in December 2020 was similar to Pfizer-BioNTech’s—both vaccines showed about 95% efficacy for prevention of COVID. Later data on real-world effectiveness for adults showed that the protection from the mRNA two-dose primary series wanes over time, but booster doses brought the immune system back to robust levels.

Novavax

The Novavax vaccine (brand names: Nuvaxovid and Covovax) was the fourth COVID vaccine to be administered in the U.S (after Johnson & Johnson, which is no longer available). This vaccine, which is a protein adjuvant, had a 90% efficacy in its clinical trial, performing almost as well as the mRNA vaccines in their early trials. It is simpler to make than some of the other vaccines and can be stored in a refrigerator, making it easier to distribute.

Status: The FDA amended its earlier Novavax authorization to allow for a new adjuvanted 2023-2024 Novavax vaccine for ages 12 and older to target the XBB.1.5 strain in October 2023, a few weeks after the updated mRNA shots were approved. The Novavax vaccine is the only non-mRNA updated COVID vaccine available in the U.S.

The previous Novavax vaccine is no longer authorized in the U.S.

Who can get it: People 12 and older. There are specific recommendations for the following groups:

• Anyone ages 12 or older who was previously vaccinated with any COVID vaccine and chooses Novavax may get one dose of the 2023-24 updated vaccine and may need more depending on the number of previous COVID vaccines they’ve received.
• Those who have not been vaccinated with any COVID vaccine may get two doses of the Novavax updated vaccine, administered eight weeks apart.
• People who are 65 and older should receive two updated Novavax vaccinations, scheduled four months apart. If they are unvaccinated and choose to start with Novavax, they should follow their two doses with one additional dose of any updated 2023–2024 COVID vaccine.
• Those who are moderately or severely immunocompromised need at least one dose of the 2023-2024 updated Novavax vaccine and may need more depending on their COVID vaccination history. Those who have never been vaccinated against COVID need to start with two doses, scheduled 3 weeks apart. People in this category who are over 65 will need at least one additional dose, at least two months after their first updated dose. Further additional doses may be administered based on the judgement of a health care provider, as well as personal preference and circumstances.

Possible side effects: Injection site tenderness, fatigue, headache, muscle pain. There were rare cases of myocarditis and pericarditis (six cases in 40,000 participants) in the clinical trial.

How well it works: Novavax has reported that its updated COVID vaccine can generate an immune response against emerging strains of the coronavirus. Earlier studies of its original vaccine showed it to be 90% effective overall against lab-confirmed, symptomatic infection and 100% effective against moderate and severe disease in Phase 3 trial results published in The New England Journal of Medicine in December 2021.

As with previous COVID vaccines, the 2023-2024 updated COVID vaccines are available at participating pharmacies and provider offices. To find a location near you that carries the vaccine and to schedule an appointment, go to Vaccines.gov. You can also call 1-800-232-0233 (TTY 1-888-720-7489).

Note: None of the COVID vaccines change—or interact with—a recipient’s DNA.

The CDC provides information for each of the three vaccines in its Updated (2023–24 Formula) COVID-19 Vaccine immunization schedule.

Information provided in Yale Medicine articles is for general informational purposes only. No content in the articles should ever be used as a substitute for medical advice from your doctor or other qualified clinician. Always seek the individual advice of your health care provider with any question