This story was last updated on Jan 10, 2022.
Scientific teams around the world have developed successful Covid-19 vaccines in incredibly short order. In a feat that even a couple of years ago would have seemed completely out of reach, vaccines to protect against the new disease were being used before the first anniversary of the disclosure that a new threat existed. This is truly extraordinary.
In the United States, three vaccines are available. Two — those from Moderna and Johnson & Johnson — have emergency use authorizations, which are green lights from the Food and Drug Administration to be put into use, even though they have not yet been fully licensed. In August 2021, the FDA gave full approval to the vaccine developed by the partnership of Pfizer and German manufacturer BioNTech for people 16 and older. The EUA for the Pfizer vaccine remains in place for younger teens and children aged 5 and older. It is the only one of the three vaccines currently available for use in individuals under the age of 18.
The Pfizer shot first received emergency authorization in mid-December 2020, followed closely by the one developed by Moderna with assistance from the National Institute of Allergy and Infectious Diseases.
In late February came a third. Janssen Pharmaceuticals, the vaccine division of Johnson & Johnson, secured an emergency use authorization for its one-dose vaccine. The vaccine was seen as a potential game-changer. It doesn’t require the fussy cold-chain needed to keep the Pfizer and Moderna vaccines from spoiling. It is cheaper, both on a per-dose basis and because only one dose is needed. Plus it was thought a one-and-done option might entice some people who couldn’t easily get two doses to roll up their sleeves.
But since the J&J vaccine’s arrival on the scene it has faced a number of challenges. A production snafu in the hands of a contract producer contaminated 15 million doses, which had to be destroyed. In mid-April, the FDA and CDC paused use of the vaccine as they investigated whether it triggered a rare but dangerous side effect — diffuse blood clots that formed even though affected people had low levels of clot-forming platelets. Continuing concern about that condition, called thrombosis with thrombocytopenia syndrome, or TTS, led the CDC on Dec. 16 to advise people to choose Moderna or Pfizer over the J&J vaccine.
The Pfizer and Moderna vaccines are made using messenger RNA, or mRNA, a technology that delivers a bit of genetic code to cells — in effect, a recipe to make the surface protein (known as spike) on the SARS-2 virus. The proteins made with the mRNA instructions activate the immune system, teaching it to see the spike protein as foreign and develop antibodies and other immunity weapons with which to fight it.
The J&J vaccine uses a different approach to instruct human cells to make the SARS-2 spike protein, which then triggers an immune response. It is what’s known as a viral vectored vaccine. A harmless adenovirus — from a large family of viruses, some of which cause common colds — has been engineered to carry the genetic code for the SARS-2 spike protein. Once the adenovirus enters cells, they use that code to make spike proteins. J&J employed this same approach to make an Ebola vaccine that has been authorized for use by the European Medicines Agency.
The Pfizer vaccine has been approved for use for people aged 16 and older, though its EUA also extends to children and teens aged 5 to 15. Children aged 12 to 15 are given the adult dose of the vaccine; those aged 5 to 11 receive one-third of the adult dose. The company is testing smaller doses in infants aged six months to 19 months and kids 2 to 4 years of age; it expects those results either later this year or early in 2022.
Moderna’s vaccine has been cleared for use in people 18 and older, though the company has submitted an application to have the vaccine’s emergency authorization extended to youths down to the age of 12. On Oct. 29, the FDA informed Moderna that it would need more time to study that application, given concerns about the higher rate of myocarditis in Moderna recipients. The agency said that decision might not come until January 2022. In light of the FDA’s announcement, Moderna indicated it would delay applying for an extension of its EUA to include children aged 6 to 11, until the decision on 12- to 17-year-olds has been issued.
At this point J&J’s vaccine is only authorized for people 18 and older. It has recently started a Phase 3 efficacy trial in youths aged 12 to 17, but is substantially behind its two competitors in getting into the pediatric market.
We should note off the top that the randomized controlled trials conducted to determine if and how well the mRNA vaccines worked were done before the emergence of what now seems like an endless stream of variants, the latest of which is the highly mutated Omicron. So the figures listed below are indications of how well these vaccines protected people from the original SARS-2 virus, called the Wuhan strain. It has since been shown that some of the mutations acquired as the virus evolves have eroded the vaccines’ protective powers to a greater or lesser degree, depending on the variant.
That said, the Pfizer and Moderna vaccines displayed astonishing — and essentially equivalent — degrees of efficacy, at least in the early stages after vaccination.
The Pfizer vaccine showed efficacy of 95% at preventing symptomatic Covid infection after two doses. The vaccine appeared to be more or less equally protective across age groups and racial and ethnic groups.
The Moderna vaccine was 94.1% effective at preventing symptomatic Covid-19 after the second dose. The vaccine’s efficacy appeared to be slightly lower in people 65 and older, but during a presentation to the Food and Drug Administration’s advisory committee in December, the company explained that the numbers could have been influenced by the fact there were few cases in that age group in the trial. The vaccine appeared to be equally effective across different ethnic and racial groups.
But comparing the efficacy of those vaccines to the efficacy of Johnson & Johnson’s is challenging because of differences in the designs of the Phase 3 clinical tests — essentially the trials were testing for different outcomes. Pfizer’s and Moderna’s trials both tested for any symptomatic Covid infection. Pfizer started counting cases from seven days after receipt of the second dose of vaccine, while Moderna waited until day 14 to start counting cases.
J&J, by contrast, sought to determine whether one dose of its vaccine protected against moderate to severe Covid illness — defined as a combination of a positive test and at least one symptom such as shortness of breath, beginning from 14 or 28 days after the single shot. (The company collected data for both.)
Because of the difference in the trials, making direct comparisons is a bit like comparing apples and oranges.
The J&J vaccine was still being tested when the variants were making the rounds. Much of the data generated in the South African arm of the J&J trial involved people who were infected with the variant first seen in South Africa, called Beta.
The J&J one-dose vaccine was shown to be 66% protective against moderate to severe Covid infections overall from 28 days after injection, though there was variability based on geographic locations. The vaccine was 72% protective in the United States, 66% protective in South America, and 57% protective in South Africa.
But the vaccine was shown to be 85% protective against severe disease, with no differences across the eight countries or three regions in the study, nor across age groups among trial participants. And there were no hospitalizations or deaths in the vaccine arm of the trial after the 28-day period in which immunity developed.
The vaccines all appear to have lost some efficacy against infection with the Delta variant, which became dominant in the United States in summer 2021 — though it’s not clear how much of the efficacy decline is due to the mutations of Delta or waning immunity as the months since initial vaccination accumulate.
It also appears that, while the vaccines are preventing many infections, vaccinated people who have breakthrough infections with the Delta variant can transmit the virus to others (though they are not as infectious as unvaccinated people). Still, even with Delta, studies indicate that the vaccines have maintained their protectiveness against severe disease and death.
Number of doses/amounts of vaccine per dose
The primary series of both the Moderna and the Pfizer vaccines is two shots: a priming dose, followed by a booster shot. The interval between Moderna doses is 28 days; for the Pfizer vaccine, it’s 21 days.
Each dose of Pfizer’s contains 30 micrograms of vaccine. Moderna went with a much larger dose of vaccine, 100 micrograms. It means the company is using a little more than three times as much vaccine per person as Pfizer is. While Moderna’s initial results didn’t seem to justify the much larger dose, data suggest the protection the company’s vaccine generates is declining at a slower rate than Pfizer’s is; some experts believe the higher dose may be at least partially responsible.
The J&J vaccine is, as mentioned, a single-dose vaccine. The company has also tested a two-dose regimen, with the two shots given 57 days apart. The results from that 30,000-person trial were presented during an Oct. 15 meeting of FDA’s Vaccines and Related Biological Products Advisory Committee, as part of its application for an EUA for its booster dose. (More on this later.)
Durability of protection
Concerns about waning immunity are driving a number of countries to offer their citizens booster shots, despite the fact that the director-general of the World Health Organization, Tedros Adhanom Ghebreyesus, called for a moratorium on giving vaccine boosters until 2022 in order to speed up first doses of vaccine to low-income countries.
What appears to be happening is that as more time passes after vaccination, protection against all Covid infections starts to decline. Breakthrough cases — which are mostly mild — have started to increase. The decline has been most pronounced among Pfizer recipients. Data from the large health system Kaiser Permanente of Southern California suggests the waning is most pronounced against the Delta variant — the main family of SARS-CoV-2 viruses circulating in the U.S. — but even against other variants protection has declined.
All three vaccines continue to offer solid protection against severe illness, though there is concern within the Biden administration that this too will weaken if boosters are not given.
A key question at this point is whether the booster shots will solidify protection in a way that is more sustained, or if these additional doses mark the start of a regular booster shot effort.
For the purposes of this discussion, there are two sorts of boosters.
The first is boosters or third shots for people who are moderately to severely immunocompromised — because they are undergoing chemotherapy for cancer, because they have had an organ transplant and are on immunosuppressive therapy, or because they have advanced or untreated HIV. These were authorized in August by the FDA for the Pfizer-BioNTech and Moderna vaccines, because of growing evidence that immunocompromised people might not be protected by the standard vaccine regimen.
The policy did not apply to the one-dose J&J vaccine. It is unlikely many immunocompromised people would have opted for this vaccine.
The second type of booster is designed to top up protection from the initial shot, in the case of J&J, or series of shots, in the cases of Pfizer and Moderna. All three companies have received authorizations for booster shots from the FDA.
Pfizer was the first to file with the agency, and its booster was authorized in late September. At that time, boosters were made available to people 65 and older, people 18 to 64 with medical conditions that raise their risk of severe Covid, and people aged 18 to 64 whose jobs or living arrangements put them at higher risk of severe Covid.
On Oct. 20, the FDA issued EUAs for Moderna and J&J’s boosters — and in the process, created a very interesting situation. (More on this in the next section.)
Unique among the companies, Moderna’s third shot contains half as much antigen as its first two. (This is not the case for people who are immunocompromised. Their third dose of Moderna is a full dose.) The emergency authorization states that the Moderna booster can be given to the same groups of people as the Pfizer booster.
On Nov. 19, the FDA broadened the eligibility for Covid vaccine boosters to all adults 18 and older. On Dec. 9, the FDA and the CDC announced that people who are aged 16 and 17 can receive a booster shot. The Pfizer booster is the only one authorized for people under age 18.
Both the Pfizer and Moderna boosters are available to people five months or later after the second dose in the series.
Not so with the J&J booster. The company had wanted the booster to be given six months or more after the initial shot, except in rare circumstances. But FDA’s vaccine advisers rejected that idea, expressing concern about the level of protection people get from the single shot. They recommended that everyone who got the J&J vaccine should be vaccinated two months after the first dose — with a catchup period for people who are already further out from their first shot.
Mix and match boosters
It appears getting a booster shot is going to be a “choose your own adventure” type of experience after the FDA stipulated that people eligible for boosters can choose any of the jabs, regardless of what brand they initially received.
There is a growing body of evidence that boosting with a different vaccine could induce a broader and longer-lasting immune response — though some combinations may work better than others.
In announcing the emergency authorizations for the Moderna and J&J boosters, the FDA stated no preference for who gets what, or in what order. People who got J&J can get a second shot of Moderna (the half dose) or Pfizer. People who got one of the mRNA vaccines can get the J&J vaccine as their booster, the agency said.
Not stated in the FDA’s announcement is the fact that this new policy will make life much easier for folks delivering booster shots, especially those trying to boost people living in long-term care, homeless shelters or prisons. They will need to bring only one vaccine when they go to administer booster shots, rather than trying to match people to their original vaccination brand.
The first vaccine to be put into use in the U.S. remains the most popular of the vaccines in use here. As of Jan. 10, of the more than 519 million vaccine doses administered, 58% have been Pfizer shots, 38% were Moderna jabs, and 3.4% were made by J&J.
Despite the fact that the FDA and the CDC announced that people could choose any of the three vaccines when they get a booster shot, to date most have opted to be boosted with vaccine with which they were first vaccinated; 93% of people who got the Pfizer vaccine as their primary series chose that vaccine for their booster dose, and 92.5% of people who got the Moderna vaccine as their primary series went on to choose the Moderna booster.
The exception was the one-dose J&J vaccine. Of the 3.9 million people who got J&J as their primary vaccine and were boosted by Jan. 10, only 33% stuck with J&J for their booster; the other 67% chose one of the mRNA vaccines.
Side-effect and adverse event profile
In the vernacular of vaccinology, shots that trigger a range of transient side effects in a lot of recipients are known as reactogenic.
All of these vaccines — in fact, most if not all the Covid-19 vaccines that have reported data so far — fall into the reactogenic category. The Advisory Committee on Immunization Practices, the CDC’s expert panel on vaccines, advised hospitals early in the rollout that they might want to stagger vaccinations among employees in case some feel too unwell to work the day after being vaccinated.
The most common side effects are injection site pain, fatigue, and headache. Some people in the clinical trials have reported fever. With the Pfizer and Moderna vaccines, side effects have been more common after the second dose so far. Younger adults, who have more robust immune systems, reported more side effects than older adults.
To be clear: These side effects are a sign of an immune system kicking into gear. They do not signal that the vaccine is unsafe. To date there are no serious, long-term side effects associated with receipt of these vaccines, which will be closely monitored as their use expands. There is zero evidence to support claims that getting vaccinated against Covid will affect one’s future fertility.
There have been reports of severe allergic reactions to the mRNA vaccines. Both the Pfizer and Moderna vaccines appear, on rare occasions, to trigger anaphylaxis, a serious and potentially life-threatening reaction. People who develop anaphylaxis must be treated with epinephrine — the drug in EpiPens — and may need to be hospitalized to ensure their airways remain open. The CDC says people should be monitored for 15 minutes after getting a Covid-19 shot, and 30 minutes if they have a history of severe allergies. J&J recently revealed that a single case of anaphylaxis has been reported in someone who received its vaccine.
The most recent data from the CDC suggest that anaphylaxis occurs at a rate of between two to five cases per one million people vaccinated in the U.S. Many of the people who have developed anaphylaxis have a history of severe allergies and some have had previous episodes of anaphylaxis.
The mRNA vaccines carry a small risk of myocarditis and pericarditis, two types of heart inflammation that are most commonly seen soon after people receive their second shots, health officials have said. Males under 30 seem to be at highest risk, particularly those aged 12 to 17. Most cases reported have been mild and resolved.
The J&J also appears to have a serious — thought different — problem. A small number of individuals who received the vaccine have gone on to develop thrombotic events in the week or two after vaccination; one has died. The condition is called thrombosis with thrombocytopenia syndrome (TTS) in the United States; in Europe, it is generally referred to as vaccine-induced immune thrombotic thrombocytopenia or VITTS.
The thrombotic events include diffuse clots and low platelet levels, an unusual combination that can be dangerous if treated improperly. The normal treatment for clots — a blood thinner called heparin — would make the problem worse, the FDA said, warning doctors to ask for a Covid-19 vaccination history if they see patients with that configuration of symptoms.
TTS occurs most commonly in women between the ages of 30 and 49. The CDC says from March 2 to Aug. 31 there were 54 confirmed cases, nine of whom died.
Safety for those who are pregnant, lactating, or planning a pregnancy
Early on in the Covid vaccine rollout, there were no data on which to determine if the vaccines were safe for people who are pregnant or lactating. But after several studies, experts have concluded the vaccines are safe during pregnancy and lactationand furthermore, they are important for these two groups to receive. This study in the New England Journal of Medicine, for instance, looked at the safety of Pfizer and Moderna vaccines in pregnant and lactating people.
The CDC and the American College of Obstetricians and Gynecologists advise that people who are pregnant or lactating should get vaccinated, because of the risk Covid infection poses to them.
There are a lot of rumors making the rounds that getting vaccinated against Covid will negatively impact a person’s ability to conceive a child. ESPN football reporter Allison Williams recently announced she was quitting the network — which has a vaccine mandate — because she wants to have another child.
There is no evidence that getting vaccinated against Covid threatens fertility. In fact, a study published in September compared pregnancy rates among patients undergoing in vitro fertilization, looking to see if there were differences among people who had been vaccinated, who had Covid antibodies from infection, or had neither. “The current study failed to identify the difference in the implantation or pregnancy rates between women with documented seropositivity to the spike protein and women without seropositivity,” the authors reported.
The mRNA vaccines require an elaborate cold chain, the term used to describe the conditions under which vaccines must be stored during distribution and when they are in the doctors’ offices, pharmacies, or public health clinics where they’ll be administered.
The J&J shot does not, which means this vaccine can be given easily anywhere — in doctors’ offices, pharmacies, mass vaccination sites, public health clinics. It can be stored for at least three months at the temperature of a regular refrigerator.
Of the mRNA vaccines, Pfizer’s was originally the more difficult to use. It had to be shipped and stored in ultra-cold freezers — ones that could keep the vials at -94 degrees Fahrenheit. But recently, the FDA announced that the vaccine can be shipped and stored — for one month only — at temperatures of normal pharmacy freezers, between -13 and 5 degrees Fahrenheit. That should make the final stage of the vaccine’s journey from production plant to syringe ready to plunge into an arm somewhat easier.
And Pfizer’s pediatric vaccine will be easier still to administer, which may make it more likely pediatricians will become involved in the vaccine rollout. The 10-dose pediatric vaccine vial can be stored for up to 10 weeks at refrigerator temperatures. The bounds of trust between pediatricians and parents will be key in getting people who are uncertain about whether they want to vaccinate their children to agree to do so.
Moderna’s vaccine must be shipped at -4 degrees Fahrenheit, which is within the range of a regular refrigerator freezer. The Moderna product is stable at fridge temperature for 30 days and at room temperature for 12 hours. J&J’s vaccine can be stored at room temperature — not to exceed 77 degrees Fahrenheit — for 12 hours when the vial hasn’t yet been punctured. After the first dose is withdrawn, the vial can be stored in a fridge for six hours or at room temperature for two hours.
Andrew Joseph contributed reporting.
An earlier version of this story mischaracterized the way in which viral vectored vaccines work and incorrectly stated that the single dose J&J vaccine contains more antigen than the doses in its two-dose regimen.