This week the Biden administration announced it would begin offering COVID booster shots to most Americans eight months after their second dose of Pfizer’s or Moderna’s messenger RNA (mRNA) vaccines. Pending authorization from the U.S. Food and Drug Administration and the Centers for Disease Control and Prevention’s vaccine advisory panel, people will start receiving boosters on September 20. Health care workers and nursing home residents will be among the first to be eligible.

The announcement came even as scientists have been debating whether such boosters are needed, who should get them and when they should be administered. It was made less than a week after the CDC recommended that moderately or highly immunocompromised people should receive an additional shot because evidence had emerged that they may not mount an adequate response to two doses. The latest recommendation was issued in light of data from Israel, vaccine makers and several U.S. studies suggesting that vaccine-induced immunity to COVID wanes after six months—and that the vaccines are less effective at preventing mild or moderate disease from the coronavirus’s notorious Delta variant than they were against earlier strains. Two doses of the mRNA vaccines still appear to provide excellent protection against severe disease and death, however.

“If you wait for something bad to happen..., you’re considerably behind your real full capability of being responsive...,” said Anthony Fauci, chief medical adviser to President Joe Biden, in a White House press briefing on Wednesday. “You want to stay ahead of the virus.”

Not all experts are convinced that most healthy people will need boosters. And the World Health Organization has said it is unethical for rich countries to distribute shots to already vaccinated people when so much of the global population has yet to receive a single dose. But the Biden administration has defended its decision, saying the U.S. government should not have to choose between protecting its own citizens and protecting the rest of the world. At the same time, several experts contend that getting more shots in the arms of so far unvaccinated Americans would be a much more effective strategy for protecting the population than administering booster shots to those who are already vaccinated.

Scientific American asked Shane Crotty, a virologist and professor at the La Jolla Institute for Immunology, and Céline Gounder, an infectious disease specialist and epidemiologist at NYU and Bellevue Hospital in New York City and a member of the Biden-Harris Transition COVID-19 Advisory Board, about whether booster shots are warranted and other questions.

[An edited transcript of the interview follows.]

Do we need booster shots? And if so, who needs them most?

GOUNDER: The data are clear that vaccines remain highly protective against severe disease, hospitalization and death, even with time and against the Delta variant. We’re not seeing waning protection against hospitalization and death. What we are seeing is reduced immunity against the Delta variant with respect to infection.

The groups it is clear should be getting additional doses include highly immunocompromised people: recipients of solid organ transplants, those with AIDS, those taking highly immunosuppressive drugs for cancer or autoimmune disease—these people have less of a response to vaccination. Some will respond to an extra dose but not all. Also, people in nursing homes, where we have seen breakthrough infections turn bad and lead to severe disease and death. Unvaccinated caregivers can introduce the virus to nursing homes. It makes sense to give additional doses to nursing home residents, but you would probably have a bigger impact giving them to caregivers. Beyond that, there’s really no clear data to support giving additional doses to the general public in the U.S. at this time.

CROTTY: It comes down to the word “need.” People mean different things. The data over the past month have generated enough uncertainty about Delta and how long protection lasts that I think a government decision to take a “better safe than sorry” approach to boosters is a reasonable approach. You don’t want to make the decision too late.

Definitely immunocompromised people need a booster. There were tidbits of data in May, June and July that there were many immunocompromised individuals who didn’t make good responses to two shots but had better responses to three. Now there’s been a clinical trial that shows clearly that a third dose helps certain categories of immunocompromised people. If people had good T cells [a type of immune cell] after one to two doses, they had a good antibody response to a third dose. Should we give boosters for people older than 80? That completely makes sense. It’s not that large a population, and we know they are at very high risk. What about people older than 70, 60, 50? Those are really policy decisions.

How good is the immune response generated by the vaccines?

CROTTY: It looks like the vaccine generates high-quality immune memory. There was a paper in Science last week on the Moderna vaccine showing antibodies at six months from the second vaccination, and there wasn’t that much of a decline. We’ve made public the first data on T cell memory six months after an mRNA vaccine (a low dose of Moderna). There was almost no change in T cell memory between one and six months after vaccination. It will probably last pretty well for one year plus. Look at the data from England—they had a ton of Delta, and the vaccines worked great against it. There was a massive difference in hospitalizations and deaths in the Delta wave, compared with the winter wave [when the Alpha variant first identified in the U.K. was widely circulating]. Are boosters needed? Not for hospitalizations or deaths.

Are boosters going to work? Yeah, the Moderna clinical trial data show that, as well as data from Pfizer. They’re going to top up antibody titers. But do we need them? Uncertain.

What do you make of the data from Israel that suggest vaccine immunity decreases significantly over time?

CROTTY: The Israel data is the best available in terms of the vaccine waning. But Israeli officials haven’t published anything [in a scientific journal]. I take my cue from epidemiologists. Confounding factors are a big deal. Israel had a lot of [apparent] problems with vaccine efficacy in February and March. They finally published a paper showing the vaccine worked great. Now it looks like there’s a decline [in effectiveness] and potentially a big decline. It’s possible we’ll never know.

GOUNDER: There are real issues with the Israel data. They are confounded by age and other factors. They need to be shared not in PowerPoint slides; the raw data need to be shared. I would not make any decisions based on the Israeli data.

Laboratory data also pose a problem. So-called neutralizing antibodies are the best correlate of protection. But when you measure them six months to a year later, it’s not clear. If you had antibodies to every infection you’ve ever had, your blood would literally be sludge. If you saw immune cells called memory B and T cells disappear, that’s a different question. You expect antibodies to decline, though.

Should people who got the Johnson & Johnson vaccine get a booster?

CROTTY: In my opinion, it is now time for those who had the Johnson & Johnson vaccine to get a second dose. The Delta variant is so much faster-spreading than previous strains. The available data suggest weakening immunity against Delta. A huge Johnson & Johnson COVID-19 vaccine study has just been released that includes Delta variant cases—a 500,000 person study in South Africa. The vaccine provides 93 percent protection from death, and 71 percent protection from Delta hospitalizations. This looks consistent with it being reasonable for people who have had one dose of the Johnson & Johnson vaccine to want a booster dose. [Editor’s note: This answer was adapted from severalTwitter threads Crotty referred us to.]

GOUNDER: We should soon have data from a clinical trial looking at low- versus high-dose and single- versus two-dose regimens of the Johnson & Johnson vaccine. This data will help guide recommendations about giving additional doses of vaccine to people who’ve gotten one dose of the Johnson & Johnson vaccine.

Should we mix and match vaccines—for example, an adenovirus vaccine, such as AstraZeneca’s or Johnson & Johnson’s, plus an mRNA vaccine?

CROTTY: For people who got the viral vector vaccines [such as the AstraZeneca or Johnson & Johnson vaccines], it’s pretty clear-cut that a follow-up dose of mRNA is better than a second dose of AstraZeneca and also better than two mRNA doses. There are data supporting mixing vaccines going back [at least] 20 years—it’s called a heterologous prime-boost. The order matters. I would not get Pfizer and then J&J. But you could consider getting Pfizer and then a protein vaccine [a vaccine that contains fragments of SARS-CoV-2 proteins, such as one made by Novavax, which has not yet been authorized in the U.S.].

GOUNDER: We need to talk more about heterologous prime-boost: An adenovirus vaccine followed by an mRNA or adenovirus followed by a protein vaccine—we may well be headed in that direction. We should also consider intranasal inhaled vaccines. Those would be better at initiating mucosal immunity [immunity in the nose and upper respiratory tract].

Will a third shot produce side effects? And if so, how severe might they be?

GOUNDER: Probably more of the same: mild fever, achiness, fatigue. But not everybody is going to have those.

Is it ethical to give booster shots to vaccinated people when so much of the world is still unvaccinated?

CROTTY: I think it’s a false dichotomy. The vaccines are going to expire; you’re not going to move them around. The best-case scenario in the U.S. would be if we got all unvaccinated people vaccinated. It would be far better than dealing with boosters. The math is not even close.

GOUNDER: Clearly just giving people additional doses has diminishing returns. You could have a lot more impact by reducing transmission in the community [by vaccinating the unvaccinated].

How often will we need boosters? Will it be just one, or will we need one every year like the flu shot?

GOUNDER: I really hate the word “booster” because it implies an annual vaccine. I think of the COVID vaccine as most similar to the hepatitis B vaccine. We don’t give an annual hepatitis B vaccine. It’s really optimizing the dosing regimen—how many doses with what spacing. I don’t think it will be yearly at all. I think we’re looking at this becoming an endemic virus. The idea is to convert this from something that will land you in the hospital or kill you to something like the common cold.