By Emma Yasinski

Last winter, the three Covid-19 vaccines authorized in the U.S. promised to be successful beyond even the most optimistic of expectations. Last year, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said that a vaccine that was 50 to 60 percent effective would be enough.

The FDA was willing to approve anything with more than 50 percent efficacy. Yet clinical trials showed the vaccines from Moderna and Pfizer were 95 percent protective against a symptomatic infection and nearly 100 percent effective against hospitalization and death. Johnson and Johnson’s single dose vaccine was slightly less protective at 67 percent but was also 100 percent effective against hospitalization and death.

Still, many scientists worried that that powerful immunity might wane over time. Since the vaccines were authorized after patients in the trials were followed for about two months, it wasn’t clear how long that protection would last. Some scientists pointed to the fact that some vaccines, like the influenza vaccine are required every year while others provide lifelong protection, and wondered which category Covid shots would fall into. While no one could say definitively when or if we’d need to add extra shots to the dosing regimen, when Pfizer planned to ask regulators to approve a third shot in July, the CDC and FDA said “not yet.” But, just a couple weeks later, the agencies have decided it’s time to act.

On August 12, the FDA announced that third doses of Pfizer and Moderna’s vaccines would be made available for patients with compromised immune systems. A few days later, the CDC followed up with detailed recommendations about who would qualify. Then, just another few days after that, the Biden administration announced that everyone will eventually need booster shots, and they may be available to the general public as early as September.

Kartik Cherabuddi who treats patients with complex infectious diseases like HIV at the University of Florida, says that since July, he’s seen more and more immunocompromised patients admitted to the hospital with Covid-19. “That’s why it’s more important to look at this third dose in immunocompromised patients. We’re starting to see them be admitted to the hospital.”

After all that, World Health Organization (WHO) chief scientist Soumya Swaminathan suggested that prioritizing booster shots in wealthier countries like the U.S. could lead to more variants, and other scientists have come out saying it’s still too soon. The onslaught of new information has caused some confusion. These are some of the most pressing questions.

Who will need a third shot and when?

First up for the third shots are a limited number of individuals the CDC considers moderate to severely immunocompromised. The third shots are available for these individuals today.

For the rest of the population, for whom the vaccine is gradually losing some efficacy, the Biden administration hopes to start offering the shots near the end of September, starting with the same groups that were vaccinated earliest during the first vaccine rollout: healthcare workers and people over the age of 65. You’ll become eligible for your third shot eight months after you received the second jab, so aside from the immunocompromised patients going first, it’ll look a lot like the previous rollout. The administration still needs an advisory committee from the CDC to review evidence and make recommendations and for the FDA to authorize the plan.

The immunocompromised patients are going first, explains Onisis Stefas, a chief pharmacy officer at Northwell Health in New York City, because they’re not losing immunity—many of them never mounted a strong immune response to begin with. Additionally, if you’re immunocompromised “you have less of a chance of fighting off an infection like the coronavirus.” meaning if you do get infected, you’ll likely fare worse than a someone with an intact immune system.

Studies published in the spring of this year hinted that individuals who received solid organ transplants or certain cancer treatments often produced few or no detectable antibodies after vaccination than healthier individuals, suggesting that their protection from disease was limited. Another small study suggested that immunocompromised patients make up about 44 percent of breakthrough cases that send patients to the hospital. Overall, the study, which was conducted before the Delta variant was dominant, showed that vaccine was about 60 percent effective in immunocompromised patients.

“A lot of the patients that are classified as immunocompromised never really got full coverage from the two-dose regimen,” says Stefas.

The good news is that one trial showed that solid organ transplant patients who received a third shot of Moderna’s vaccine two months after the second showed substantial increases in antibody levels, which implies they also gained more protection from the disease. That’s why these patients have been put at the front of the booster line.

Many conditions and medications can weaken your immune system, but for now, the CDC is recommending third shots for patients who are taking immunosuppressants after a solid organ transplant, are actively receiving treatment for tumors or blood cancers, have received a stem cell transplant within the last two years, have an advanced or untreated HIV infection, are taking high-dose corticosteroids or have certain diseases such as DiGeorge Syndrome or Wiscott-Aldrich syndrome that suppress the immune system.

The August 18 announcement that everyone will need a third shot came on the heels of two main findings. The first is that immunity gained from the vaccines seems to wane over time. Data from Israel, which was the first to vaccinate most of its population with the Pfizer vaccine shows that more than half of infections are occurring in individuals who have been vaccinated. A preprint suggests that the more time has passed since a person’s second shot, the higher the chances that they’ll experience a breakthrough infection. The CDC released data showing that immunity to infection has begun waning in the U.S. as well, though most vaccinated individuals in both countries remain protected from severe disease and hospitalization.

The second major finding is that while the vaccines still protect most patients from hospitalization and death, the new Delta variant can infect vaccinated individuals. And those individuals can spread the disease to others, albeit for a shorter period than unvaccinated individuals who are infected.

How does a third shot help build immunity?

Your body has several weapons to fight an infection. When your immune system first recognizes a new invader like Sars-CoV-2, the virus that causes Covid-19, it mobilizes an all-out attack, producing unique immune cells designed to kill this virus it has never seen before, but this takes time and in many cases, the disease causes serious damage before our immune systems have had time to respond.

Your first dose of vaccine introduces your immune system to a protein found on Sars-CoV-2. Your cells recognize that this protein doesn’t belong, and builds up an army to fight it off. That army includes antibodies which are specifically-tailored to neutralize that protein, and B and T cells which work together to produce said antibodies. If you don’t see the virus again for a long time, your body may start to get rid of the circulating antibodies, but the B and T cells might still be there, able to produce new ones.

“These cells remain in hiding and when they are exposed to the [virus] they'll actually come out and do their function and produce more antibodies,” says Catherine Liu, a vaccine and infectious disease researcher at the Fred Hutchinson Cancer Research Center. Those antibodies can help protect you.

When you get a second dose of the vaccine, your B and T cells recognize the protein and can mount a faster, stronger immune response, rapidly producing neutralizing antibodies and ridding your body of the invader. The third dose works the same way, by reminding your immune system what the virus looks like, so it stays alert and ready to amount a response if you ever come in contact with the real thing.

“That third dose is just additional support for your body to see the vaccine and continue to mount an immunologic response, which would give you more antibodies,” says Stefas. “Then, in the event that you do come in contact with the coronavirus, your body can fight it off a little bit easier.”

Are there any risks?

For most individuals, the safety data of a third shot appears no different than that of the first and second. Pain at the injection site was extremely common, and others experienced fevers, headaches, muscle pain and other flu-like symptoms for up to two days. In seven out of a million women aged 18-49 who received the Johnson & Johnson vaccines, the shot triggered dangerous, abnormal blood clots. Odds of severe side effects like blood clots or anaphylactic reactions are extremely rare. However, neither safety nor efficacy data on third shots for healthy people has been reviewed yet by the FDA.

Over a million individuals are thought to have already gotten third shots in the U.S. along with others in Israel. So far, no new safety concerns have emerged.

Experts recommend that immunocompromised patients discuss the vaccine with their doctors. First, if you’re taking immunosuppressants, stimulating your immune system with a vaccine may cause undesirable effects. Stimulating your immune system to respond to Covid-19 could spark it to attack a transplanted organ, for example, explains Peter Gulick, an infectious disease specialist at Michigan State University. Despite that possibility, Liu says that in the small studies on organ transplant patients so far, this hasn’t happened, “but obviously, that’s something people will follow,” she adds.

Depending on your condition, your physician may suggest that you pause or reduce the immunosuppressant treatment before getting the vaccine, to give your immune system the best chance at building a robust response.

Does it have to be the same shot I got before?

The CDC currently recommends that you stick with the same shot you originally received. If your first two doses came from Pfizer, your third should as well. While some studies mixed and matched the AstraZeneca vaccine (which is not authorized in the U.S.) and the Pfizer vaccine, researchers haven’t fully explored how Pfizer, Moderna and Johnson & Johnson’s vaccines might work together.

Right now, all of the vaccines are authorized under an emergency use authorization from the FDA. The agency has authorized a third dose of Moderna and Pfizer for immunocompromised individuals and is expected to authorize third doses for everyone within the next few days.

What if I got the Johnson & Johnson shot?

The FDA and CDC say they don’t currently have enough data to recommend extra doses of the Johnson & Johnson vaccine, but that data is expected soon.

“We also anticipate booster shots will likely be needed for people who received the Johnson & Johnson (J&J) vaccine. Administration of the J&J vaccine did not begin in the U.S. until March 2021, and we expect more data on J&J in the next few weeks. With those data in hand, we will keep the public informed with a timely plan for J&J booster shots as well,” said CDC, NIH and FDA officials in a prepared statement on August 18.

Could I still get infected after a third shot?

No vaccine is 100 percent protective, but breakthrough cases tend to be mild compared to normal cases. It’s always possible that you could experience a breakthrough infection even after a third shot, though it’s thought to be less likely.

Even after a third dose, some immunocompromised patients may be left with little protection. Liu emphasized that in addition to continuing to take other safety measures like masking and distancing, individuals who come in close contact with immunocompromised patients, such as family and caretakers, should prioritize getting vaccinated as well. “Having any of their close contacts protected will form a cocoon to protect the immunocompromised individuals,” she says.

Cherabuddi adds that in many cases, “they’ve done everything right and it’s not their fault that they’re hospitalized. I think we as a community, as a nation, should do more to shield them from infection.”