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

[Originally published: February 24, 2021. Updated: May 22, 2023.]

Note: The Johnson & Johnson (Janssen) COVID-19 vaccine is no longer available in the U.S. The CDC says that people ages 18 years and older who received one dose of the J&J vaccine should be considered to have received a single-dose J&J primary series. Adults ages 18 years and older who received one or two J&J COVID-19 vaccine doses are recommended to receive one bivalent mRNA dose (Moderna or Pfizer-BioNTech) at least two months after completion of the previous dose.

Information in this article was accurate at the time of original publication. Because information about COVID-19 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 fourth year, and the Omicron variant and its subvariants are still driving infections in cases 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-19.

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 vaccines are performing, but it’s also a daunting task, given the flood of information (and misinformation) coming at us from so many directions.

We mapped out a comparison of the most prominent COVID-19 vaccines.

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-19 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.

Options for getting the Pfizer-BioNTech vaccine changed in April 2023, when the U.S. recommended updated mRNA (bivalent) shots for most inoculations, including primary vaccinations and additional (booster) shots. The bivalent shots, first authorized in 2022, are now the only mRNA COVID-19 shots available in the U.S. They are called bivalent because they were updated to protect against two virus strains: the original one and the BA.4/BA.5 Omicron subvariants. The original shot (called the monovalent, because it targeted only one strain) is no longer available in the U.S.

Who can get it: People 6 months and older.

Dosage: Varies by age and other factors.

• Children between 6 months and 4 years: If your child is unvaccinated, they are eligible for three doses of the bivalent vaccine with the first two doses three weeks apart and the third dose at least eight weeks later. If they have received one dose of the monovalent Pfizer vaccine, they are eligible for two doses of the bivalent vaccine with the first dose three to eight weeks after the monovalent dose, and the second shot at least eight weeks later. Those who have received two doses of the monovalent Pfizer vaccine are eligible for one dose of the bivalent vaccine, which should be given at least eight weeks after receiving the monovalent vaccine. Children who have gotten three doses of the monovalent Pfizer vaccine are eligible for a single dose of the bivalent shot starting eight weeks after receiving the monovalent vaccine.

• People ages 5 and older: If you are unvaccinated, you are eligible for a single dose of the bivalent Pfizer vaccine. If you have received one or more doses of a monovalent vaccine, you are eligible to get one dose of the bivalent Pfizer vaccine starting at least eight weeks after receiving your last monovalent shot. People ages 65 years and older who have gotten one dose of a bivalent vaccine are eligible for another dose of the bivalent Pfizer vaccine to be given at least four months after getting the previous one.

If you are immunocompromised: If you are 6 months or older and unvaccinated, you are eligible for three doses of the bivalent Pfizer vaccine. Those who have received one dose of the monovalent Pfizer vaccine are eligible for two doses of the bivalent Pfizer vaccine, and those who have received two or three doses of the monovalent Pfizer are eligible for one dose of the bivalent Pfizer vaccine.

People in this group have the option to get an additional shot of a bivalent vaccine to be given at least two months after their last bivalent vaccine. Children 5 years of age and younger who have previously gotten a Pfizer vaccine dose are only eligible for the bivalent Pfizer vaccine. People in this group may also be eligible for additional doses of a bivalent vaccine at the discretion of a health care provider.

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: Pfizer-BioNTech’s initial Phase 3 clinical data for its vaccine in December 2020 showed 95% efficacy for preventing symptomatic COVID-19 in adults after two doses. Later data on real-world effectiveness showed that the protection from the mRNA two-dose primary series waned over time, but booster doses brought the immune system back to robust levels.

How well it works against variants: While Pfizer’s primary vaccine was designed to protect against the original SARS CoV-2 virus, the new bivalent vaccine is formulated to protect against both the original strain and Omicron subvariants BA.4 and BA.5. Studies have shown these vaccines to be effective against both infection and (to a greater degree) severe disease, hospitalization, and death. Some key studies include:

• A New England Journal of Medicine (NEJM) study published in January 2023 focused on people 12 and older in North Carolina’s state vaccine registry data. It found bivalent vaccines from Pfizer and Moderna to be 58.7% effective against hospitalization compared to 25% for the monovalent ones that preceded them, and 61.8% effective against infection compared to 24.9% for the monovalent vaccine. Scientists noted that this study covered a period when Omicron subvariants BQ.1 and BQ.1.1. were circulating, which suggests the updated vaccine was effective against those strains in addition to the ones it was designed to target.
• A CDC study, also published in January, evaluated the effectiveness of the bivalent mRNA vaccines’ effectiveness against Omicron subvariants XBB and XBB.1.5 in people who had previously received two to four monovalent vaccine doses. Researchers found effectiveness to be similar to the vaccine’s effectiveness against BA.5 for at least the first three months after vaccination. The study, based on COVID-19 tests performed in pharmacies, found effectiveness against the XBB strains varied by age: In ages 18 to 49, it was 49% effective against the XBB strains versus 52% against the BA.5 viruses; in ages 50 to 64, it was 40% compared to 43% for BA.5; and in people 65 and older, 43%, compared to 37%, for the BA.5 viruses.
• Pfizer reported updated clinical trial data in November 2022 that showed levels of neutralizing antibodies in the bivalent booster were fourfold higher in people 55 and older than in people of similar ages who got a monovalent booster, which targeted only the original virus. (Antibodies are known to provide protection against infection or reinfection and severe disease.) But Pfizer’s data did not show whether bivalent recipients were less likely to become infected.

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.

As with Pfizer, options for getting the Moderna vaccine changed in April 2023, when the U.S. recommended updated bivalent mRNA shots for most inoculations. These shots from Moderna and Pfizer, first authorized in 2022 as boosters, are now the only mRNA COVID-19 shots available in the U.S. They are called bivalent because they protect against two virus strains: the original one and the BA.4/BA.5 Omicron subvariants.

Who can get it: People ages 6 months and older.

Dosage: Varies by age and other factors.

Children between 6 months and 5 years of age: If your child is unvaccinated, they are eligible for two doses of the bivalent Moderna vaccine with the second dose given four to eight weeks after the first. Children who have received one dose of the monovalent Moderna vaccine are eligible for one dose of the bivalent Moderna vaccine four to eight weeks after the monovalent vaccine. Those who have received two doses of the monovalent Moderna vaccine are eligible for a single dose of the bivalent Moderna vaccine at least eight weeks after getting the monovalent vaccine.

People ages 6 and older: If unvaccinated, you are eligible for one dose of the bivalent Moderna vaccine. People who have received one or more doses of a monovalent vaccine are eligible for one dose of the bivalent Moderna vaccine starting eight weeks after getting a monovalent vaccine dose. Those ages 65 and older who have received one dose of a bivalent vaccine are eligible for a single dose of the bivalent Moderna vaccine starting four months after getting the previous dose of a bivalent vaccine.

If you are immunocompromised: Unvaccinated people 6 months and older are eligible for three doses of the bivalent Moderna vaccine. Those who have received one dose of the monovalent Moderna vaccine are eligible for two doses of the bivalent Moderna vaccine. Immunocompromised people 6 months and older who have received two or three doses of the monovalent Moderna vaccine are eligible for one dose of the bivalent Moderna vaccine.

People in this group have the option to get an additional shot of a bivalent vaccine to be given at least two months after their last bivalent vaccine. Children between 6 months and 4 years of age who have previously gotten a Moderna vaccine dose are only eligible for the bivalent Moderna vaccine. People in this group may also be eligible for additional doses of a bivalent vaccine at the discretion of a health care provider.

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: Moderna’s initial Phase 3 clinical data in December 2020 was similar to Pfizer-BioNTech’s—at that point, both vaccines showed about 95% efficacy for prevention of COVID-19. 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 bring the immune system back to robust levels.

How well it works against variants:

While Moderna’s primary vaccine was designed to protect against the original SARS CoV-2 virus, the new bivalent vaccine—similar to Pfizer’s—is formulated to protect against both the original strain and Omicron subvariants BA.4 and BA.5. Studies (mentioned above in the Pfizer section) have shown the mRNA vaccines to be effective against both infection and (to a greater degree) severe disease, hospitalization, and death.

Novavax

The Novavax vaccine (brand names: Nuvaxovid and Covovax) was the fourth COVID-19 vaccine to be administered in the U.S. 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 vaccine was authorized in the U.S. in July 2022 and a booster was announced a few months later in October. The CDC says people should consider getting the Novavax vaccine if they are unable or choose not to get an updated Pfizer-BioNTech or Moderna COVID-19 vaccine.

Who can get it: People 12 and older.

Dosage: 2 doses, 3-8 weeks apart. If you had COVID-19 recently, you might consider delaying your second primary dose or your booster by 3 months from when you started to experience symptoms or (if you had no symptoms) the date of your positive test result.

Who can get the booster: The Novavax booster protects against the original SARS CoV-2 virus and may not protect against recent Omicron subvariants. Adults who have not received a booster shot previously may choose to get it six months after completing their primary vaccination if they are unable to receive the bivalent booster for a medical or any other reason. Alternatively, adults are eligible for a Pfizer-BioNTech or Moderna bivalent booster at least two months after their primary Novavax vaccination, and teenagers ages 12 through 17 must get a Pfizer-BioNTech bivalent booster.

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 it works: Unlike the mRNA and vector vaccines, this is a protein adjuvant (an adjuvant is an ingredient used to strengthen the immune response). While other vaccines trick the body’s cells into creating parts of the virus that can trigger the immune system, the Novavax vaccine takes a different approach. It contains the spike protein of the coronavirus itself, but formulated as a nanoparticle, which cannot cause disease. When the vaccine is injected, this stimulates the immune system to produce antibodies and T-cell immune responses.

How well it works: 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. While the efficacy was similar among participants from several demographic groups (the study looked at subgroups based on demographic characteristics, coexisting conditions, and those at high risk for COVID), efficacy was lower—at about 67%—in Hispanic or Latino participants, as compared to participants who were not Hispanic or Latino. Notably there were few infections among people in the study who were Hispanic or Latino overall (just 8 in the Novavax group and 11 in the placebo group), making these results somewhat difficult to interpret.

How well it works on virus variants: The data presented to the FDA was gathered before Omicron or its recent subvariants started to circulate, but the company says it expects to have a vaccine that will protect against the recent Omicron subvariants in 2023.

Note: None of the COVID-19 vaccines change—or interact with—a recipient’s DNA.

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 questions you have regarding a medical condition.

This article was reviewed by Yale Medicine infectious diseases specialist Jaimie Meyer, MD, MS.