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If you’re immunocompromised, you likely have a lot of concerns about breakthrough infections — i.e., COVID-19 infections among people who are fully vaccinated. Are you more likely to get a breakthrough COVID-19 infection? If so, are you at a greater risk of getting very sick or needing to be hospitalized? When can you get a third COVID-19 vaccine dose to garner more protection against the virus? What else can you do to stay safe in this new chapter of the pandemic?

While data is still emerging and recommendations are changing quickly, initial research shows that people who are immunocompromised are more likely to experience breakthrough infections than those who are not. However, breakthrough infections are still uncommon — and those that lead to serious complications are much rarer still.

Here’s everything you need to know about the latest research, and what you can do to stay safe.

What Is a Breakthrough Infection of COVID-19?

 For research purposes, the U.S. Centers for Disease Control and Prevention (CDC) has defined a COVID-19 vaccine breakthrough infection as the detection of SARS-CoV-2 or antigen in a respiratory specimen from a person 14 days or more after receipt of all recommended doses of FDA-authorized COVID-19 vaccines.

If someone receives two shots of the Pfizer or Moderna vaccine or one shot of the Johnson & Johnson vaccine — but still contracts COVID-19 two weeks or more later — they have a breakthrough infection.

The CDC is not tracking all breakthrough infections; only those that lead to hospitalization or death. As of August 23, 2021, the CDC reports that 11,050 patients with breakthrough infections were hospitalized or died — out of more than 171 million people who are fully vaccinated.

This does not consider breakthrough infections that do not lead to hospitalization or death, so it’s challenging to get a full picture of how common breakthrough infections are and who is more likely to get them — say, immunocompromised people vs. not.

Last month, the Kaiser Family Foundation, which has been reviewing data on breakthrough infections at the state level, issued a report that showed that the share of COVID-19 infections among those who are fully vaccinated ranges from less than 1 percent in states such as Connecticut, Nebraska, New Jersey, and Virginia to around 3 percent in states such as Arkansas, Montana, and Utah. Arizona and Alaska had the highest shares at 5.9 percent and 4 percent, respectively.

Experts have stated that breakthrough infections were exceedingly rare earlier in the pandemic, before the rise of the Delta variant. But according to the New York Times, “recent outbreaks suggest that numbers may be higher” and that it’s unclear how common breakthrough infections are, especially considering that most estimates rely on data that predates the rise of the Delta variant.

It’s likely that breakthrough infections are becoming more common than they were earlier in the pandemic, but those that lead to serious complications are very, very rare.

Breakthrough Infections vs. Breakthrough Disease

It’s worth noting that there’s a huge difference between “breakthrough infections” and “breakthrough disease.”

“The first important thing to know is that infection is objective — are you infected or not?” says Sarah Fortune, MD, Chair of the Department of Immunology and Infectious Diseases at Harvard T.H. Chan School of Public Health. “Meanwhile, disease is subjective — do you feel sick? And disease can be anywhere from not feeling well to intubation. The complexity of that is we don’t look for infection in the absence of disease.”

In other words, if you don’t have any symptoms, you likely won’t get tested for COVID-19.

Getting the COVID-19 vaccine remains very important for preventing severe disease. Vaccines not only protect against getting infected with COVID-19, but also serious outcomes from it like severe symptoms, hospitalization, or death, according to the CDC.

According to the Kaiser data, the numbers for hospitalization and death rates among those who are fully vaccinated are very reassuring. “Hospitalization rates among those fully vaccinated ranged from effectively zero (0.00 percent) in California, Delaware, D.C., Indiana, New Jersey, New Mexico, Vermont, and Virginia to 0.06 percent in Arkansas. Death rates were even lower at 0.00 percent for all but two states, Arkansas and Michigan, where they were 0.01 percent.”

According to a study released by the CDC in August, unvaccinated people are about 29 times more likely to be hospitalized with COVID-19 than those who are fully vaccinated. The study, which is based on data collected from Los Angeles County between May 1 and July 2, also found that unvaccinated people have five times the number of COVID-19 infections than those who are fully vaccinated.

That said, there is an increasing percentage of vaccinated people among those hospitalized with COVID-19 — especially as Delta continues to spread. The vaccinated can also develop long-COVID, a mysterious continuation of symptoms experts are still learning about.

In a July 2021 New England Journal of Medicine study, researchers tested 1,497 fully vaccinated health care workers from December 19, 2020 to April 28, 2021 in Israel and detected 39 breakthrough cases. (The study was conducted before the country’s surge of cases caused by the Delta variant.)

Of the breakthrough infections, 31 percent had symptoms lasting more than 14 days and 19 percent had symptoms lasting more than six weeks (long COVID), which included prolonged loss of smell, persistent cough, fatigue, weakness, difficulty breathing, and/or muscle pain. Nine people took more than 10 days off work, and one person hadn’t returned to work after six weeks. That said, none of the people with breakthrough infections required hospitalization. Only one of the 39 individuals with breakthrough infections was immunocompromised.

Why Are Breakthrough Infections Occurring?

Even though it’s very important to get vaccinated to protect yourself from COVID-19 — a particularly severe illness — no vaccine is perfect, which we’ve known from the beginning.

The Delta variant may be more likely to cause infections among the vaccinated because of how this particular strain takes hold in the body, explained journalist Apoorva Mandavilli in a New York Times article. COVID-19 vaccines are injected into the muscle of your arm, where they rev your immune system to produce antibodies in your blood.

Some of these antibodies wind up in your nose, but “because the Delta variant seems to flourish in the nose,” and the amount of virus transmitted is much higher, according to the Times, there may not be enough antibodies to sufficiently fight it off, which could “explain why more people than scientists expected are experiencing breakthrough infections and cold-like symptoms.”

However, the vaccine does equip your immune system to fight off the virus before it can infect the lungs or damage other organs, which explains why the vaccine is still critically important and lifesaving.

Emerging research shows the Delta variant may slightly affect vaccine efficacy. For those who received two doses of the Pfizer vaccine, efficacy was 93.7 percent with the alpha variant and 88 percent with the Delta variant, per a July 2021 study in The New England Journal of Medicine. For those who only received one dose of the vaccine, efficacy was 48.7 percent for the alpha variant and 30.7 percent for the Delta variant another reason it’s important to get your second shot.

“Only modest differences in vaccine effectiveness were noted with the delta variant as compared with the alpha variant after the receipt of two vaccine doses,” write the researchers. “Absolute differences in vaccine effectiveness were more marked after the receipt of the first dose.”

Breakthrough Infections in Immunocompromised People

Not surprisingly, breakthrough infections appear to be more common among those who are immunocompromised. According to data presented at a CDC Advisory Committee on Immunization Practices meeting in July, immunocompromised patients represent 44 percent of hospitalized COVID-19 breakthrough cases — even though they only make up 2.7 percent of the population. This includes people with cancer, HIV, and organ transplants, as well as those who take immunosuppressant medication for inflammatory conditions.

Although this sounds scary, keep in mind that hospitalization from breakthrough infection is very rare to begin with. Even among people who are immunocompromised, vaccines still work to prevent severe disease.

It’s important to get vaccinated even if you are immunocompromised, because some protection is better than none.

“You can imagine with vaccination that the immune response is creating a screen and it’s blocking the virus from being able to set up shop,” says Dr. Fortune. “The more robust your immune response, the denser that screen. For somebody who’s on an immunosuppressive drug regimen, they may still have a little response — they might have a screen, but that screen might have bigger holes. It’s providing a layer of protection, but it’s not providing protection to the same degree as someone who’s not on immunocompromising medications.”

According to the research published by the CDC in July, vaccine breakthrough cases will occur more frequently in group settings (such as long-term care facilities) and in groups at risk of primary vaccine failure, including the immunocompromised.

Just how much less effective is the COVID-19 vaccine in people who are immunocompromised than in those who are not? Additional research published by the CDC highlights key data points from research about vaccine efficacy in the immunocompromised:

  • 75 percent vaccine efficacy against symptomatic COVID-19 seven to 27 days after second dose of Pfizer vaccine among immunosuppressed people versus 94 percent overall, per a May 2021 study in Clinical Infectious Diseases.
  • 80 percent vaccine efficacy against SARS-CoV-2 infection seven or more days after second dose of mRNA vaccine among people with inflammatory bowel disease on immunosuppressive medication, per a May 2021 study in Gastroenterology.
  • 59 percent vaccine efficacy against COVID-19 hospitalization among immunocompromised patients 14 days or more after second dose of mRNA vaccine versus 91 percent without immune compromise, per a July 2021 pre-print study (meaning it hasn’t been peer-reviewed yet) on MedRxiv.

Of course, the meaning of “immunocompromised” can vary dramatically from person to person. A lot will depend on the specific condition you have and what immunosuppressive medications you’re taking — some, like TNF inhibitors, seem to have little impact on vaccine efficacy. And for instance, one study found that biologics don’t interfere with the COVID-19 vaccine in inflammatory bowel disease patients.

“It’s important to know that in people who are immunocompetent, it’s very clear that vaccines protect against severe infection, hospitalizations, and death, even with the newer variants that are circulating,” says David Aronoff, MD, Director of the Division of Infectious Diseases at Vanderbilt University School of Medicine in Nashville, Tennessee. “But we have less confidence in the degree of that protection in people whose immune systems are depressed or not working at a normal level.”

How Can Immunocompromised People Reduce Their Risk of Breakthrough Infections?

Even though you’re hearing about a lot about breakthrough infections right now, keep in mind that vaccines, masks, and other mitigation efforts can make a big difference in your risk.

Vaccinations and Additional Doses

If you’re immunocompromised and fully vaccinated because you received two doses of the Pfizer or Moderna COVID-19 vaccine, you should get a third dose of the Pfizer or Moderna COVID-19 vaccine to further bolster your body’s response. (There is not yet an additional dose available for people who received the one-dose Johnson & Johnson vaccine.)

Per the American College of Rheumatology’s COVID-19 vaccine guidance, it’s crucial for people on immunosuppressive or immunomodulating medication to receive a third dose of the COVID-19 vaccine. Because this group of individuals did not garner full protection from the initial vaccine, the additional dose could help immunocompromised patients mount a more robust response.

In fact, an August 2021 study found immunocompromised people who did not garner a response from the first series of mRNA could develop antibodies after a third COVID-19 vaccine dose. According to the study, which assessed organ transplant patients who received the Moderna vaccine, 33 to 50 percent of patients developed an antibody response after receiving an additional dose of the COVID-19 vaccine.

For people with inflammatory or autoimmune conditions, getting the third dose applies to anyone on immunosuppressive or immunomodulating medication. The only exception is people taking only hydroxychloroquine (Plaquenil), as this medication does not suppress the immune system and, therefore, does not affect patients’ response to the first two vaccine doses.

In preparing to get your third COVID-19 vaccine dose, talk to your health care provider about any necessary adjustments to your medications.

The ACR recommends that patients temporarily stop taking many immunosuppressant or immunomodulating medications for one to two weeks after receiving the third dose to help improve the immune system response, if disease activity allows. This includes medications such as methotrexate and JAK inhibitors but does not necessarily apply to most biologic drugs.

For other medications, experts recommend timing when you get the vaccine around your medication dose. For example, with the medication rituximab, you should try to get the third dose close to your next infusion, which is when your immune system will likely have the best response.

Read more here about the ACR’s COVID-19 vaccine guidance, including medication adjustments.

Knowing which medications to adjust and for how long can be complicated and confusing. It’s important to discuss your personal situation with your doctor to decide what’s right for you. Don’t stop taking medications on your own.

Monoclonal Antibodies

Another important option to help reduce complications from breakthrough infections particularly for immunocompromised people is monoclonal antibodies. This therapy essentially revs your immune system with antibodies that can make it easier to fight off COVID-19. Getting treatment like monoclonal antibodies immediately could have a significant impact on the disease course.

Initially, this therapy was only approved for people who were infected with COVID but not yet hospitalized. But the U.S. Food and Drug Administration (FDA) recently authorized the use of REGEN-COV, a monoclonal antibody treatment, to prevent COVID-19 in adults and children (age 12 and older, who weigh at least 88 pounds) who have been exposed to coronavirus and are at high risk for progression to severe COVID-19.

This treatment is not a substitute for getting vaccinated, but it can be an important tool for people who are immunocompromised to reduce their risk of COVID complications. Read more here about monoclonal antibody treatment. .

Masks and Other Mitigation Efforts

You’ve likely stayed vigilant about your COVID-19 mitigation efforts if you’re immunocompromised, even after the CDC relaxed its recommendations for fully vaccinated individuals earlier this year. Recommendations have since shifted back and the CDC now recommends that everyone, including fully vaccinated people, wear masks in public indoor spaces to help reduce the spread of COVID-19.

Wearing a mask in public indoor settings as well as in crowded outdoor settings is a smart idea particularly if you’re immunocompromised.

“The more people wear masks in public spaces, the less people who are wearing masks become or feel stigmatized,” says Dr. Aronoff. “For the most vulnerable members of our community, it is certainly easier for them to engage in mask wearing if they know that doesn’t mark them as different in some way, shape, or form from other people in their community.” (Here’s how to deal with feeling victimized for wearing a mask.)

But masks are just one part of the equation. The more mitigation efforts society takes as a whole, the more protected immunocompromised people will be.

For those who are immunocompromised, it is more crucial now than ever that their family members, coworkers, friends, and community members get vaccinated if they’re eligible. Here’s how to talk to loved ones about getting the vaccine.

And of course, other mitigation efforts to prevent COVID-19 remain the same:

  • Maintain a social distance of six feet or more from people outside of your household whenever possible.
  • Wear face coverings when out in public and when you can’t be socially distant.
  • Wash or sanitize your hands frequently and disinfect commonly touched surfaces.
  • Avoid large groups or situations when it will be hard to be socially distant.
  • When spending time with others, being outdoors is safer than indoors.

“People who are immunocompromised need to understand that they need to take all the precautions and really need to be careful,” says Dr. Fortune. “It’s a time to be very vigilant.”

“The best way we will protect the most vulnerable among us is to do as many things as we can to make it very difficult for this virus to spread,” says Dr. Aronoff. “Right now, vaccines are the best ways to do this, but masks and distance and paying close attention to public health guidance are key elements of what should hopefully be a successful strategy.”

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Bernal JL, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. The New England Journal of Medicine. July 21, 2021. doi: https://www.doi.org/10.1056/NEJMoa2108891.

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FDA authorizes REGEN-COV monoclonal antibody therapy for post-exposure prophylaxis (prevention) for COVID-19. U.S. Food and Drug Administration. August 10, 20201. https://www.fda.gov/drugs/drug-safety-and-availability/fda-authorizes-regen-cov-monoclonal-antibody-therapy-post-exposure-prophylaxis-prevention-covid-19.

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Hall et al. Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients. New England Journal of Medicine. August 11, 2021. doi: https://doi.org/10.1056/NEJMc2111462.

Interview with says David Aronoff, MD, Director of the Division of Infectious Diseases at Vanderbilt University School of Medicine in Nashville, Tennessee

Interview with Sarah Fortune, MD, Chair of the Department of Immunology and Infectious Diseases at Harvard T.H. Chan School of Public Health

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