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Who needs to get a third dose of the COVID vaccine?

contributed by Mary Clare Fischer

We know more now about how immunocompromised people — including organ transplant recipients, certain cancer patients and those on medications that severely suppress the immune system — respond to the COVID vaccine.

stock image of three syringes
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As the COVID-19 pandemic has continued, scientists have gathered more data about the coronavirus that’s been waging chaos on a global scale as well as what might need to be done to keep the COVID vaccines effective for various populations on a long-term basis.

For those who are immunocompromised, either because of a condition or a medication, there’s been much to learn.

Other than those with HIV, immunocompromised people were not included in the large clinical trials that studied the COVID vaccines. So researchers often had to make educated guesses about how this population — and subgroups within it — would respond to the shots that were intended to protect people from not only contracting and spreading the coronavirus but from becoming severely ill with COVID-19 or dying from it.

Now that more studies have been conducted that feature this group, we have more information, which led the FDA to authorize a third dose of the mRNA vaccines for immunocompromised people.

The following is a discussion with Daniel Kaul, M.D., director of the Transplant Infectious Disease Service at Michigan Medicine, to find out what scientists have gleaned about COVID vaccines and those who are immunocompromised and what answers they’re still hoping to find.

What evidence has emerged when it comes to how protected immunocompromised patients, specifically organ transplant recipients, are against COVID-19 once they’re vaccinated?

How protected immunocompromised people are remains a bit unclear.

What we can discern from some messy data is that clearly people who are immunosuppressed, who have been vaccinated, are getting admitted to the hospital with severe COVID.

There’s a network of 21 large adult hospitals under the umbrella of the CDC, called the IVY network, that University of Michigan Medical School associate professor of microbiology and immunology Adam Lauring, M.D., Ph.D., did all the sequencing for.

Their study saw that there was an efficacy against hospitalization of immunocompromised people of about 50% instead of the 95% or more that we saw in immunocompetent people, those whose immune systems aren’t weakened. That certainly isn’t definitive — there are some other studies that may demonstrate a bit better protection than that — but that created some concern.

We also didn’t expect the Delta variant to be so contagious and to cause so many more cases, which has created an increased risk to transplant patients.

Finally, we saw that in other countries, in Israel and in the United Kingdom, for example, and then also starting in the United States, there did seem to be a decrease in the ability of the vaccine to prevent infection, although the vaccine still maintained a tremendous ability to protect immunocompetent people from hospitalization and severe disease.

But that did create some concern that immunocompromised folks may be even more vulnerable, both because vaccinated people could potentially spread it (not nearly as much as unvaccinated people, but could still potentially spread it) and also, if that waning of the vaccine’s protection was seen in immunocompetent people, perhaps it would be worse in immunocompromised people.

All of which led to more testing of third doses of the COVID-19 vaccine for immunosuppressed people. What did we learn from those studies?

It’s not surprising that the vaccine works less well in immunocompromised people than the immunocompetent. That's generally true of other vaccines. But because immunocompromised people weren't included in the clinical trials of the COVID-19 vaccine, there was no idea to know how much less well it worked, whether additional doses would be helpful and so forth.

When Michigan Health published its explainer, “Should I still wear a mask if I’m immunocompromised?” a few months ago, we had just a hint from a very small, not very well standardized report, where people got third doses that were immunocompromised, and the researchers checked antibody levels and saw that there was some response in people who didn't respond initially. It was hard to know exactly what to make of that in terms of how meaningful that was.

There have since been two major pieces of data that have helped fill in the story in different ways.

One was in France, where they just decided to give everybody who was immunosuppressed and had a transplant a third dose, usually 28 days after the second dose of the Pfizer-BioNTech vaccine. And what they saw was that there was a significant increase in the number of people who received the third dose who developed antibodies after the third dose, but not the second dose. Again, we didn’t really know what that meant.

After that, in Toronto, they did a very nice study where they actually randomized people who'd had transplants to either not get a third dose or to get a third dose 28 days after the second dose, and they measured T cell responses and antibody responses, which are different elements of the immune system. They found that even in people who responded to the second dose, the antibody responses were significantly higher.

And they additionally found that for people who didn't respond to two doses, that a significant proportion of them responded to the third dose, again in terms of antibody levels, and they attempted to define a certain threshold of antibodies because we haven’t known what level of antibodies you need to be protected from developing COVID-19.

Do antibody levels seem to correlate with protection? Given the different components of the immune system, the CDC and health systems across the country were stressing not to put too much weight on antibodies as a metric of immunity for a while.

We are now seeing more data about what levels of antibody correlate with protection against COVID-19. It’s become pretty clear that if you have higher antibody levels, you're a lot less likely to develop symptomatic disease.

And that's not terribly surprising, because if you think about how COVID works, it's this virus, and it gets in your nose or your mouth or your eyes and then it wants to attach to these receptors. If there's a whole bunch of antibody running around that interferes with that process, it's going to be hard for the virus to establish a productive infection.

But in the background to that, it's important to know that there are human coronaviruses that circulate every year, and they give us colds.

You can contract one of these coronaviruses and then contract the same one a year later. But you don’t get really sick; you just get a cold. That’s because that’s how our immune system works. The antibody levels go down, so they don’t necessarily protect us against infection, but as soon as it’s there they know what it is, they ramp up quickly and they prevent the development of severe disease by and large.

That’s what so far our COVID vaccines have done in immunocompetent people. You may get sick, but you’re very unlikely to get severe pneumonia and wind up in the hospital. And that’s because our immune systems have been educated.

It’s just harder to educate an immune system in an immunosuppressed person.

Hence the FDA’s authorization of a third dose for this population. What are your thoughts about this decision?

The FDA was in a very difficult position, one they rarely have to face. They’re a very data-driven organization, and they want to make sure that drugs are safe and effective and they want to see large studies to confirm that before they make a recommendation.

But in this case, they were not particularly concerned about safety since we're not talking about a new drug. We’re just talking about giving essentially a third dose of the same drugs (which probably is better thought of as a third dose in the primary series rather than as a booster dose since you're trying to generate an immune system response rather than boost a previous response.)

So they looked at the data and made the decision to expand the emergency use authorizations to allow a third dose of the Moderna or the Pfizer vaccine. (If you’ve received Pfizer, and you can't get access to a third dose of it, you can get Moderna and vice versa.)

Left out of all this are the people who are immunocompromised who have received the single-shot Johnson & Johnson/Janssen vaccine. I think this is really troubling because that vaccine works, but not as well. And there really isn't a legal mechanism under the emergency use authorization for people who received Johnson & Johnson to get an additional dose of an mRNA vaccine or, for that matter, the Johnson & Johnson vaccine.

Not very many of our patients at Michigan Medicine fall into this category. I don't have numbers, but the vast majority of our immunocompromised patients received an mRNA vaccine as did the vast majority of Americans in general. But still, that's a real concern and hopefully we'll get further guidance on that soon, but those people are left hanging in the breeze right now.

What about antibody tests? Should immunocompromised people get those now?

No, we still don’t recommend checking antibody levels before a third dose. Anyone who’s immunocompromised should get the third dose because their antibody levels will go up regardless of whether they developed antibodies initially. And that’s a good thing.

Who is eligible for the third dose?

The way the FDA did this (and I think it’s appropriate) is that it doesn’t require a prescription.

This isn't so much about being at an increased risk for severe COVID; it's about that these people need a three-dose vaccine to respond as well as the general population did to a two-dose vaccine, and that’s determined by the nature of your immune system.

Some people who should definitely get a third dose are those with solid organ or bone marrow transplants, cancer or autoimmune disease that require immunosuppressive medications.

And if you’re not sure whether you qualify, talk to your doctor.

The Biden administration just recommended that everyone who received an mRNA vaccine get a booster shot about eight months after their second dose, regardless of whether they’re immunocompromised or not. Is there enough data to support this?

People who are immunocompetent, who have received two doses of mRNA vaccine, are currently still very well protected against serious disease and hospitalization. I don't think there's a justification or need to run out and try and get a booster dose in that circumstance, so I wouldn't be too concerned about that right now. I’m certainly not going to get a third dose myself at the moment. The evidence for this remains incomplete.

And there’s this issue of vaccine equity. There’s a desperate need for it around the world. I think it's a little hard to justify going outside of any FDA or CDC recommendations to get a booster dose. But I don't mean that at all for immunocompromised folks, for whom I think a third dose is totally appropriate.

Are there people who may still not respond to a third dose?

Yes. Even a third dose still leaves a significant number of solid organ transplant recipients with relatively low or unmeasurable levels of antibody. So unfortunately, continuing to practice social distancing and being careful to avoid exposure remains appropriate for that group of people.

But none of this should discourage people from getting vaccinated. Transplant patients in particular are at considerable risk of bad outcomes if they get COVID. Even though we can't guarantee that the vaccine will be fully protective, it's really the best thing that we have available.

Anything else to add?

In the future, when we have urgent problems like this, a broader array of people should be considered for early trials. That could include pregnant women and children, for instance, as well as immunocompromised people. It can be fraught to think about those things – ideally, you like to test things in the group that would be able to tolerate unanticipated side effects more. But nonetheless, I think it's worth discussing or, at least when early safety data is available, to start trials a little bit quicker, so we have actual answers.

Get more information about COVID-19 from the Michigan Medicine Health Blog

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