It’s a question on many people’s minds these days: Do I need a booster dose of a COVID vaccine?

The answer, like many aspects of this pandemic, is complicated. And in some ways, it depends on what we mean by “need.” The three vaccines approved or authorized in the U.S. generally provide very good protection against severe disease and death from COVID. Yet some people, especially those who are immunocompromised, may not mount a strong response to the initial doses. And although there is not much evidence of waning immunity among young, healthy individuals, some reports from Israel, the U.K. and the U.S. suggest protection may erode somewhat over time, especially among the elderly. Breakthrough infections do happen even in healthy vaccinated people, though they are very unlikely to cause severe disease.

Officials in the U.S. and several other countries have now authorized booster shots for various subsets of their populations. As of October 20, the U.S. Food and Drug Administration has authorized a third dose of the Pfizer or Moderna shot for certain people who previously got those vaccines: those aged 65 or older, those aged 18 to 64 who have underlying health conditions that put them at risk of severe COVID and people in the latter age group who are at high risk of occupational exposure, such as health care workers and teachers. Earlier the Centers for Disease Control and Prevention’s director recommended the Pfizer booster shot for all three groups—overruling the agency’s own advisory panel, which had not recommended people receive an extra dose based on their occupation. On October 14 an FDA advisory panel voted to recommend authorizing boosters for the Moderna vaccine. And on October 15 it voted to recommend a booster of the Johnson & Johnson (J&J) vaccine for anyone aged 18 or older at least two months after the first dose. The FDA has also now authorized the J&J booster and allowed providers to mix and match different vaccines.

Yet many questions remain: Do people in high-exposure jobs really need a booster? Should we mix and match vaccines? And most importantly, what are we trying to achieve with a booster dose?

Scientific American posed these questions to Celine Gounder—an infectious disease specialist and epidemiologist at New York University and Bellevue Hospital in New York City, who was a member of the Biden-Harris transition’s former COVID-19 Advisory Board—and to Alessandro Sette, a professor at the La Jolla Institute for Immunology.

[An edited transcript of the interview follows.]

Who needs a booster shot?

GOUNDER: It goes back to “What is it you’re trying to accomplish? What is the outcome of interest?” I don't think we’ve actually agreed on that, which is why there’s so much disagreement. Are you trying to prevent transmission? Are you trying to prevent breakthrough infection? Are you trying to prevent symptomatic disease? Are you trying to prevent severe disease, hospitalization, death? Because those will all have different policies.

If we’re trying to prevent symptomatic disease, and we’re trying to prevent transmission, that raises the question: Do our current vaccines do that? By giving a third dose, will you provide that level of protection indefinitely? Or will you see a waning of that protection over time? Unless you’re planning to keep boosting over and over and over again, I think it’s going to be very difficult to prevent all infections.

That said, do you need a perfect vaccine—a vaccine that perfectly prevents breakthrough infection and transmission—to prevent or to shrink the epidemic? No. I mean, your goal here is really to get the reproductive rate, R0, below one: in other words, one infected person transmits COVID on average to fewer than one other person. So if you can get to that point with even imperfect vaccines and other mitigation measures, eventually, you will suppress transmission to very low levels.

SETTE: Whether we need a booster shot has a very nuanced answer. It’s not black-and-white. I tend to try to rephrase the question. “Need” is probably not the best way to phrase it. The question is, first of all: What data do we have that it is safe, or is it associated with greater side effects or greater risks? Second, does it do anything—both in terms of protection and in terms of immune response? Third, in what conditions is it recommended to deploy a booster? And last but not least, what are some of the other considerations? There is obviously a lot of debate regarding global vaccine supply worldwide and even within the U.S. Are there other groups that should receive a vaccine?

Are there any groups of people you think should get a third shot?

GOUNDER: I think there are data to support third doses or additional doses for people older than, depending on the study, 60 or 65. There are data for the highly immunocompromised—for example, organ transplant recipients, people who are on highly immunosuppressive medications, AIDS patients, and the like. And then there are good data for nursing home residents or other long-term care facility residents. For the first two of those groups, the elderly and the highly immunocompromised, this seems to be related to a poor immune response to the COVID vaccine up front. And this has been shown: there was a JAMA paper by Dorry Segev of Johns Hopkins University looking at organ transplant recipients that found that if you give two doses, many of them have zero response. A subsequent study found that with a third dose, you’re finally able to elicit a response.

In the elderly, you have this phenomenon of immunosenescence, where, you know, just like your bones and joints at the age of 80 are not what they were at 20, similarly, your immune system at the age of 80 is not what it was at the age of 20. You just don’t have as good of an immune response. And then if you have any waning of immunity over time, if you start off at a lower level, you know that that could put you at risk, right? So what we’ve seen (and it’s not just out of Israel—we’ve seen this with the Public Health England data, with the Kaiser Permanente data and with others) is that there is waning of immunity, particularly protection against disease, and more severe outcomes among people older than 60 or 65. You don’t see that reduction in the younger age groups, in terms of protection against severe disease.

SETTE: If someone is immunocompromised or very old, a booster is certainly highly advisable. But then it becomes a gradient. And when it gets to other categories, do these categories need it? Probably not. Would it be beneficial to have everybody have a third administration of a vaccine? It probably would be beneficial: it would cut down on the amount of virus that was circulating, it would cut down on the small amount of severe infection even in vaccinated people, and so forth. So, at some point, it becomes a risk-benefit calculation.

Do you agree with the CDC’s decision to recommend boosters for people at high risk of exposure through their job, such as health care workers?

GOUNDER: I would argue: if you’re going to say it’s to keep health care workers on the job, then your recommendation should really be “You should get vaccinated,” not “may get vaccinated.” If you think they’re truly higher-risk in terms of individual health—then maybe it makes more sense, because then that health care worker can weigh the risks and benefits and say, “Well, you know, I am somebody who’s obese, so I should probably get that extra dose” or “Yeah, I’m young and healthy, and I don’t need it.” That’s where I disagree with the CDC recommendation, because they seem to be saying it’s really for the protection of the health care worker. And I don’t think you can make that case based on the data.

What is your reaction to the FDA advisory panel’s recommendations on Moderna boosters?

GOUNDER: It especially aligns with the CDC recommendations for boosters for the Pfizer vaccine. So from an operational, logistic, communications perspective, it certainly makes sense. Where I disagree is: I’m not entirely convinced that the categories eligible for boosters should have been quite so broad. The Moderna vaccine does seem to be holding up better than the Pfizer vaccine. And I’m not convinced that the Moderna vaccine needs to be authorized for as wide a range of people as was done for the Pfizer vaccine.

Honestly, I wasn’t convinced about recommending boosters for people in high-risk occupations for the Pfizer vaccine either. I mean, I fall into that “high-risk” group as a health care worker, and I’m not currently planning on getting an additional dose. We’re not seeing evidence that there’s a higher risk of severe disease, hospitalization and death among health care workers or other “high-risk” groups if they have been fully vaccinated. So, you know, it feels like it’s more about assuaging anxieties among some of those groups. And to me, that’s not really data-driven.

Is the Moderna vaccine more effective than the other vaccines?

GOUNDER: I think the data we have would say that the Moderna vaccine appears to be more durable [meaning it produces longer-lasting immunity]. And so, you know, it may be that even older persons may not need a third dose if they got Moderna as their initial regimen.

SETTE: The data with Moderna that we have seen suggested a durable immune response for at least seven months’ time. And certainly there are multiple reports that suggest that maybe the Moderna vaccine immunity may be dropping less in terms of antibodies over time. Again, it goes back to the thing that it is difficult to say “need” as opposed to “Does it help?” Another consideration that I heard being raised is that there is also a need for simplicity, to have a simple single message delivered to people that could potentially get a third shot. Otherwise it could get very complicated.

Should people mix and match vaccines?

GOUNDER: The National Institutes of Health has been doing studies of mix and match where they’ve literally done all nine potential combinations. So you start with Moderna, Pfizer, or J&J as your first vaccination, and then you follow up with an additional dose of one of the others. [Editor’s Note: Results from the NIH study—which has not yet been peer-reviewed—suggested that a Moderna or Pfizer booster produced a stronger immune response (a higher increase in the number of antibodies) than an additional Johnson & Johnson shot in people who had previously received the J&J vaccine. The Moderna shot produced the largest increases in antibodies of all the vaccines tested, including when it was given as a booster for the Pfizer or J&J vaccine. The sample sizes were too small to make definitive comparisons, however. In addition, the Moderna booster used in the study was a full dose, whereas the company is applying for FDA authorization for a half-dose booster.]

I would say, based on those data, the recommendation I would make is that if you got Pfizer or Moderna, you should get a boost with either Pfizer or Moderna. And it doesn’t need to be the exact same one: either mRNA can be used to boost you. And if you got Johnson & Johnson, similarly, you should get a boost with one of the two mRNA vaccines. [Editor’s Note: This interview was conducted prior to the FDA advisory panel’s vote to authorize a second dose of the J&J vaccine as a booster. The option of mixing vaccines was not voted on at this time.]

SETTE: There are data to suggest that, in some cases, mixing and matching may actually yield an even better response. On the other hand, the data that we have regarding safety and duration of immune responses are from one vaccine, and so then it becomes difficult to know “If I take vaccine A and boost with vaccine B, am I doing a good thing?” So to keep it uniform and simple has its own appeal.

What are you telling your own family and friends about whether they need a booster?

GOUNDER: My mom is the only one left in our family who’s older—she is older than 65. She got Moderna. [Before the FDA advisory panel recommendation] what I told her was, “Let’s wait and see—there’s no rush right now.” It’s not going to really change her behavior. In terms of those of us in my family who are younger, we’re waiting. None of us are getting extra doses right now.

Editor’s Note (10/20/21): This article was edited after posting to include updated information about the FDA’s decision to authorize Moderna and Johnson & Johnson boosters and to allow mixing and matching of vaccines. The text had previously been amended on October 15 include updated information about the FDA advisory panel’s recommendation for boosters of the J&J vaccine.