Q&A: The Differences Between a COVID-19 Vaccine Third Dose and Booster Shot

In October 2021, the FDA amended its Emergency Use Authorization (EUA) on COVID-19 vaccines to include booster shots of all three vaccines (Pfizer, Moderna and Johnson & Johnson). For Pfizer and Moderna, the parameters are patients:

• Age 65 and older.
• Age 18 through 64 at high risk of severe COVID-19.
• Age 18 through 64 whose frequent institutional or occupational exposure to SARS-CoV-2 puts them at high risk of serious complications of COVID-19 including severe COVID-19.

Additionally, the Johnson & Johnson vaccine booster was cleared for all recipients age 18 and up who received the single dose of that vaccine. The FDA is also allowing a “mix and match” system for boosters. In other words, once you’ve completed your original vaccine dose, you can receive any of the available vaccines as a booster.

Pediatrician Michelle Medina, MD, explains the differences between a third dose and a booster shot, discusses who might need these shots and shares the big questions scientists are trying to answer with the emergence of the delta variant.

Q: What’s the difference between a third dose and the booster shot? Who is eligible for the third dose and the booster shot?

I’m glad you made that distinction between a third dose and a booster shot. Currently, when we speak about third doses, we’re speaking about an extra dose apart from the first two doses of the messenger RNA vaccine because the first two doses didn’t give sufficient protection against COVID-19. And that is why some people need a third dose for them to get to a level of immunity that’s protective.

At the moment, after review by the FDA and the CDC, the portion of the population who will need a third dose includes those age 65 and up, those who are at risk of exposure through their work and those who are immune-compromised or are on any medication or treatment that makes their immune responses insufficient.

For those people, the original dose levels don’t seem to be enough. They will need a third dose to have sufficient protection. They’re eligible for the third dose at least 28 days after their second dose. We are seeing people come in and have scheduled for their third doses already.

In contrast, when we talk about booster doses, we’re talking about an additional dose, apart from the first two messenger RNA vaccines because we’re worried that over time, the protection you generated from the first two may be waning. Or it’s also possible that the protection that you got from the first two may not work as well against a new strain, such as the delta strain that’s circulating now.

A booster dose is typically given after a certain amount of time. It’s not necessarily right on top of the first two doses because we expect that your immune response will continue to generate antibodies and give you enough time to actually have a sufficient immune reaction. But over time, when your immune system needs a bit of a reminder to say, “Hey, remember, this is COVID. This is what it looks like,” that booster dose boosts whatever you have so that it amplifies the immune response that you generated the first time.

Q: Why might some people need the third dose?

It’s not dissimilar to how we have seen people react to different types of vaccines. I’ll give you an example. The HPV, or Gardasil, vaccine, when we give it to teenagers before the age of 15, they only need two doses. Because when you’re younger, it seems that you generate a very robust immune response to protect you against HPV. When you’re older — an older teen or a young adult after the age of 15 — we actually give you three doses, for you to have sufficient immunity against HPV. The difference seems to be in the way that you would respond depending on your age. When you’re younger, you seem to do better against HPV after only two doses of the vaccine. When you’re older, you need an extra dose.

The same is true for people whose immune systems are suppressed or insufficient. After two doses of the messenger RNA vaccine, they generate a certain level of immunity. But it doesn’t seem to be protective enough. We expect that the third dose will actually give them a higher level of immunity so that they can have the same level of protection as people who are healthy and only got two doses.

Q: How would a non-immune-compromised person know if they need a booster shot?

The FDA and the CDC reviewed a lot of the evidence relative to the booster doses for healthy people. We do have some signals based on all the experience that we’ve had over the past year, looking at all the people who’ve received their doses back in January and February, and then over time tracking the same people and saying, “Are they still protected?” or “Are any of them getting infected against COVID?” That is the evidence that the CDC and FDA are right now reviewing.

There does seem to be a signal that, over time, we’re seeing more people get infected with COVID, even though they’ve had the two doses back in January and February. The question remains: Are we seeing waning immunity — the protection we generated back in January doesn’t hold for more than six months? Or is it simply because we have a much more transmissible strain now, the delta strain, that we know people pass on to each other a little bit more readily?

The CDC already had a meeting on August 30 to lay out the framework of the questions we need answered. Do we really need a booster? Who needs a booster? When do we need a booster? What’s the dose of the booster?

What the FDA has now done, with their October 20 update, is to clarify those parameters to allow those most at risk, whether it’s the elderly or someone exposed to COVID-19 at their job, to receive a booster. We still don’t know if everyone will need a booster, though.

Q: Can you speak to how the Johnson & Johnson vaccine fits into all of this? That was a one-shot vaccine that isn’t using messenger RNA

Even when Johnson & Johnson was being developed, there was already thought around, “Does it really need to be just one dose? Or do we need to think about two doses?” Given the considerations that we’ve seen for the messenger RNA vaccines, Johnson & Johnson reviewed the data and conducted a study around what it will mean to have two doses, and how much more effective that will be compared to the single dose. Based on that data, the FDA determined it was necessary for everyone age 18 and up to receive a booster of that vaccine for better protection.

Q: So for all 3 kinds — Moderna, Pfizer, and Johnson & Johnson — we should hear more soon, basically?

Yes. One thing to remember is that when it comes to additional doses, whether it’s a third dose or a booster dose, timing matters. Did you have a good immune response to begin with or an insufficient response? Just because we say that a third dose may be important or necessary, may not mean that everybody should get it within a certain short timeframe. For some people, especially healthy people, sometimes a longer interval between the second and the third may be more beneficial.

Once we start hearing about third doses or booster doses, I’m sure there will be a number of people who will be very anxious to get that in, maybe even before the recommended interval is released. And we will ask people to respect that recommended interval because that is based on science. It’s a difficult concept to understand. If you think two is good, three is obviously better. But sometimes timing is an important factor, not just the number of doses.

One additional point about the FDA update on October 20 is clearing booster recipients to receive any of the three available vaccines regardless of which vaccine they originally received.

Q: If you aren’t immune-compromised, how will you know if you had a good response, or a not-so-good response?

For other vaccines that have been around for years or decades, we have what we call correlates of immunity. We know that if we measure for a certain type of antibody, it tells us that you have enough of a response. That science is still evolving for COVID. There are many types of antibodies that we could measure, but we’re not quite sure which one is really most predictive of a good response.

A lot of the data that we have is based on how groups of people are actually behaving, based on the amount of vaccination that we’ve already distributed. When you think about waning immunity, we’re looking at people who were vaccinated in January; how did they do? Vaccinated in April; how did they do? Vaccinated in June; how did they do? You make some assumptions based on how the different groups have actually behaved over time.

The big wrench in that whole scenario is the fact that delta strain came on the scene at the same time people were being vaccinated in June. And that’s why this question is still being asked. Are we dealing with waning immunity, which means we should give everybody an additional dose and say that’s it? Or are we dealing with a decreased amount of response because you’re dealing with a specific strain that’s not reacting as well? In which case, should we think of it more like the flu vaccine, where every year we give you a slightly different type of vaccine to meet the strain?

Those are two different strategies, if you think about it.

Q: What would your advice be for people who are eligible right now for a third dose?

For immune-compromised folks who are now eligible to get their third dose, absolutely, we would recommend that you go ahead and schedule that and get yourself a third dose. But as is true for anybody else who happens to be vaccinated, we still have to maintain precautions. For folks who are immune-compromised, that is even more important. So they should continue to mask; they should continue to practice good hand hygiene; they should be careful about their environment and about being in large indoor gatherings. And if it’s possible, and they’re eligible, it would be good to advocate for vaccination of all the close contacts of a person who’s immune-compromised. Anybody that they live with, anybody that they’re in touch with regularly, it would be good to also advocate for these folks to be vaccinated.

Q: Especially with the delta variant, it seems like now is more important than ever to get vaccinated if you haven’t yet, to help stop this virus from mutating and potentially getting more transmissible or more lethal?

Exactly. If you think about the pool of people who remain unvaccinated, that is the optimal playground for the virus to go around, move from one person to the next, evolve, and develop new ways to evade the mechanisms of protection we have in place. If we continue to shrink that pool of the unvaccinated, it gives the virus less and less chance to develop into something that we can’t fight off.