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

[Originally published: February 24, 2021. Updated: Jan. 30, 2023.]

Note: 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.

As COVID-19 hits its three-year mark, the Omicron variant and its subvariants are still driving upticks 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.

Who can get it: Anyone ages 16 and older in the U.S. Infants, children, and teenagers ages 6 months to 15 years are eligible under an EUA. 

Dosage: For the primary series: two shots, 3-8 weeks apart. Dosages for infants and children are different than those for adults. 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. For some people older than 12, especially boys and men between ages 12 and 39, the CDC suggests an eight-week interval between the two shots to reduce the risk of myocarditis, an uncommon side effect (see FDA warnings below).

Who can get a booster: Most adults should get an updated Pfizer-BioNTech or Moderna bivalent booster at least 2 months after their primary series. Infants as young as 6 months, children, and teenagers are also eligible for the Pfizer bivalent booster. (Children who haven’t had the vaccine yet are now eligible for a Pfizer series that includes two doses of the monovalent vaccine followed by the bivalent booster—and those who have started the series will get the bivalent vaccine as their third dose. Children who have had all three Pfizer primary shots already are not eligible at this time for the updated booster.) The bivalent boosters authorized in August 2022 are designed to protect against disease caused by the original strain of the SARS-CoV-2 virus, as well as Omicron variants BA.4 and BA.5.

If you are immunocompromised: Children and teenagers ages 5 to 17 should receive three Pfizer-BioNTech primary doses, including a second dose three weeks after the first, and a third dose four weeks later. Teenagers 12 and older also can get a Pfizer-BioNTech booster shot three months after completing their initial series, and a second booster four weeks after the first. Adults who are immunocompromised can choose between the three available vaccines, following a schedule similar to immunocompromised teens (depending on which vaccine they choose—Pfizer or Moderna are recommended over Johnson & Johnson). More information for immunocompromised individuals is available on the CDC website.

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 new type of vaccine. It works by 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). But 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: When Pfizer-BioNTech applied for FDA authorization for its vaccine in December 2020, its initial Phase 3 clinical data surpassed expectations with 95% efficacy for the prevention of COVID-19, based on an independent analysis by the FDA. Later data on effectiveness (the vaccine's performance when used in the real world) 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 Pfizer’s primary vaccine was designed to protect against the original SARS CoV-2 virus, the new bivalent (or “updated”) booster is designed to prevent two virus strains, the original one and the Omicron subvariants BA.4 and BA.5.

In January, the New England Journal of Medicine (NEJM) published a study based on people 12 and older included in North Carolina’s state vaccine registry data. The study found the bivalent vaccine to be 58.7% effective against hospitalization compared to 25% for the monovalent one that preceded it; its effectiveness against infection was 61.8% compared to 24.9% for the monovalent. Scientists noted that this study covered a period when Omicron subvariants BQ.1 and BQ.1.1. were also circulating, which suggests the updated vaccine is more effective against those strains in addition to the ones it was designed to target.

Another study in January from the CDC assessed the bivalent vaccine’s effectiveness against the most recent Omicron subvariants, XBB and XBB.1.5, in people who had previously received two to four monovalent vaccine doses, and found it to be similar to how well it worked against BA.5 for at least the first three months after vaccination. The CDC’s study was based on COVID-19 tests performed in the pharmacy, and it found effectiveness against the XBB strains varied by age: in ages 18 to 49, it was 49% 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.

In November 2022, Pfizer announced that a clinical trial 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 new 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. 

Who can get it: Infants, children, and adults ages 6 months and older in the U.S. 

Dosage: For the primary series: two shots, 4 to 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 first positive test result. Dosages for children are different than dosages for adults. For some people older than 12, especially boys and men between ages 12 and 39, the CDC suggests an eight-week interval between the two shots to reduce the risk of myocarditis, an uncommon side effect (see FDA warnings below).

Who can get the booster: Most adults should get an updated Pfizer-BioNTech or Moderna bivalent booster at least five 2 months after their primary Moderna series. Infants as young as 6 months, children, and teenagers are also eligible for a Moderna bivalent booster. Bivalent booster shots authorized in August 2022 are designed to protect against disease caused by the original strain of the SARS-CoV-2 virus, as well as Omicron variants BA.4 and BA.5. 

If you are immunocompromised: Anyone 18 and older who is moderately or severely immunocompromised should get an additional primary shot (or third dose) of the Pfizer-BioNTech or Moderna vaccine 28 days after their second Moderna shot. They will be eligible for a booster shot five months later and can choose either a Moderna or Pfizer-BioNTech booster in most cases. Adults with certain immune deficiencies should also get a second Pfizer-BioNTech or Moderna booster; immunocompromised teenagers ages 12-17 must get this booster from Pfizer. More information for immunocompromised people is available on the CDC website.

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 the body’s cells 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: Moderna’s bivalent booster was FDA-authorized at the same time as Pfizer’s. It also targets both the original SARS CoV-2 strain and the Omicron BA.4 and BA.5 sublineages.

In January, the New England Journal of Medicine (NEJM) published a study based on people 12 and older included in North Carolina’s state vaccine registry data. The study found the bivalent vaccine to be 58.7% effective against hospitalization compared to 25% for the monovalent one that preceded it; its effectiveness against infection was 61.8% compared to 24.9% for the monovalent. Scientists noted that this study covered a period when Omicron BQ.1 and BQ.1.1. were also circulating, which suggests the updated vaccine is more effective against those strains in addition to the ones it was designed to target.

Another study in January from the CDC assessed the bivalent vaccine’s effectiveness against the most recent Omicron subvariants, XBB and XBB.1.5. in people who had previously received two to four monovalent vaccine doses, and found it to be similar to how well it worked against BA.5 for at least the first three months after vaccination. The CDC’s study was based on COVID-19 tests performed in the pharmacy, and it found effectiveness against the XBB strains varied by age: in ages 18 to 49, it was 49% 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.

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.

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.

Johnson & Johnson

The FDA authorized Johnson & Johnson’s coronavirus vaccine (brand name: Janssen) in February 2021. Unlike the first two vaccines, this is a carrier, or virus vector, vaccine, a type of vaccine that has been used before for the flu. A one-shot strategy made J&J’s vaccine easier to distribute and administer to people who found it the be the most convenient vaccine to get. But in the spring of 2021, concerns over rare blood clots associated with the vaccine prompted the government to put a pause on it, which was soon lifted. Then, in December the CDC again responded to those concerns by expressing a preference for the Pfizer and Moderna shots. In May, the FDA put new restrictions on who can get the J&J vaccine based on another review of data on the life-threatening clots.

Who can get it: Adults 18 and older who specifically request the J&J vaccine or who cannot have the other available vaccines for medical reasons.

Dosage: Single shot. Fully effective two weeks after vaccination.

Who can get the booster: Anyone who had the J&J primary shot can get a Pfizer-BioNTech or Moderna bivalent booster at least 2 months later. If you had COVID-19 recently, you might consider delaying 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.  

If you are immunocompromised: If you got the single J&J shot, you should get a second shot from either Pfizer or Moderna at four weeks, and a booster two months later (Pfizer and Moderna are preferred in most situations). Immunocompromised teenagers and adults ages 12 and older can receive a 2^nd booster (4^th dose) of an mRNA vaccine at least four months after their first booster. 

Possible side effects: Pain, redness, swelling in the arm where the shot was administered; tiredness, headache, muscle pain, chills, fever, nausea throughout the rest of the body. If any of these side effects occur, they should go away in a few days.

FDA warnings: In July, the FDA attached a warning to the Johnson & Johnson vaccine after rare cases of the neurological disorder Guillain-Barré syndrome were reported in a small number of vaccination recipients. Most of the cases occurred within 42 days after vaccination.

In April 2021, the FDA added a warning label after ending a pause on the vaccine it had recommended “out of an abundance of caution” over an uncommon, but potentially fatal, blood clotting disorder that occurred in a small number of recipients.

In December, the FDA updated its fact sheet on the shot to include information about the rare but serious blood clotting disorder called thrombosis with thrombocytopenia syndrome (TTS) that was associated with the vaccine. In May, after another review of available data on this risk, the FDA made a decision to put restrictions on access to the J&J vaccine.

How it works: This is a carrier vaccine, which uses a different approach than the mRNA vaccines to instruct human cells to make the SARS CoV-2 spike protein. Scientists engineer a harmless adenovirus (a common virus that, when not inactivated, can cause colds, bronchitis, and other illnesses) as a shell to carry genetic code on the spike proteins to the cells (similar to a Trojan Horse). The shell and the code can’t make you sick, but once the code is inside the cells, the cells produce a spike protein to train the body’s immune system, which creates antibodies and memory cells to protect against an actual SARS-CoV-2 infection.

How well it works: The data J&J submitted to the FDA in early 2021 when it applied for authorization for its vaccine showed 67% efficacy in preventing moderate to severe/critical disease by 14 days after vaccination—and 66% effective 28 days after vaccination.

How well it works against variants: At the end of 2021, J&J announced that preliminary study results from South Africa showed a J&J booster to be 85% effective against hospitalization at a time when Omicron was the dominant variant in that country. More data on the vaccine’s effectiveness against Omicron is forthcoming.

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.