Vaccines and Long COVID: What Do We Know?

Vaccines are now a key tool in preventing acute, severe COVID-19. But less is known about their effect on long COVID. Does vaccination against SARS-CoV-2 protect against long COVID? And what effect, if any, does vaccination have on pre-existing long COVID?

Preventing Long COVID

Because COVID-19 vaccines are effective in both preventing the disease and lessening its severity, the CDC recommends vaccination to prevent long COVID.

“If you don’t get COVID, you don’t get long COVID,” Lisa Sanders, MD, medical director of the Yale New Haven Long COVID Consultation Clinic in Connecticut, told MedPage Today.

“Second, if you do get COVID after you’ve been vaccinated, it reduces your chance of getting severe COVID — and the worse your infection, the more likely you are to get long COVID,” she explained.

Observational data seem to bear this out. One recent meta-analysis of six studies found that having at least one dose of a COVID-19 vaccine prior to infection was associated with about 50% lower odds of developing long COVID (OR 0.539, 95% CI 0.295-0.987, P=0.045), when compared with no vaccination.

In one study of more than 20 million participants in the U.K., Spain, and Estonia, COVID-19 vaccines reduced the risk of long COVID by approximately 29-52%. In another analysis of over 2.3 million vaccinated and 1.5 million unvaccinated Norwegian individuals, vaccination with any COVID-19 vaccine, including mRNA vaccines or AstraZeneca’s ChAdOx1 vaccine (never authorized in the United States), reduced the risk of developing long COVID by 36% (subdistribution HR 0.64, 95% CI 0.55-0.74).

CDC data presented at the 2023 IDWeek annual meeting suggested mRNA vaccines are effective in children as well. Those who received mRNA COVID-19 vaccines during the Omicron variant wave were up to 48% less likely to develop post-COVID conditions following infection. The vaccines also cut the risk of respiratory post-COVID conditions by 47%.

In contrast to these studies, however, one earlier large observational study using Veterans Affairs data found that vaccination had a less robust effect on reducing the risk of long COVID. That study found vaccination reduced post acute sequelae of COVID-19 by only 15% (HR 0.85, 95% CI 0.82-0.89) in people with breakthrough infection.

One bright note is that the incidence of long COVID seems to be decreasing over time, primarily due to vaccination, according to one recent analysis of Veterans Affairs data. Among those who were infected after vaccination, post acute sequelae incidence decreased from about 5.3% in the Delta era to 3.5% in the Omicron era. Researchers also found that about 72% of the decrease in the cumulative risk of long COVID between the Omicron era and earlier eras could be attributed to vaccines, and about 28% could be attributed to era-related effects, such as changes in virus pathogenicity.

Treating Long COVID

What effect COVID-19 vaccines have on improving or worsening existing long COVID symptoms is a much more murky question with few, if any, answers.

One meta-analysis of 11 studies from fairly early on in the pandemic found some evidence of improvement in long-COVID symptoms among people who got at least one dose of vaccine after full vaccination. However, several of the studies reported no change or even worsening in long COVID symptoms with vaccination.

In another analysis of studies from 2021, seven studies found that most individuals with long COVID experienced no changes to their symptoms following one or more doses of the COVID vaccine.

In a revealing survey that included over 800 people in the U.K. with long COVID, about 58% of participants reported improvements in symptoms after vaccination, 18% reported deterioration, and the remainder reported no change. Of note, however, larger improvements in symptom severity scores were seen in those receiving the mRNA vaccines compared to adenoviral vector vaccines.

If vaccines do have a positive or negative effect on long COVID symptoms, there are no definitive answers as to why that might be or whether it’s a placebo effect, Otto Yang, MD, an infectious disease specialist at the University of California Los Angeles’s David Geffen School of Medicine, told MedPage Today.

“Some people believe that at least a subset of people with long COVID actually have ongoing viral replication, so you could hypothesize that vaccination and boosting the immune response could reduce that,” he said.

“On the other hand, some people with long COVID may have some kind of autoimmune condition caused by COVID and you can imagine that … vaccination could increase those immune responses and make things worse,” he posited.

“You can wave your hands any way you want to come up with any mechanism that you want. We’re really just kind of in the dark right now about it, and it’s possible that both of those things are true or quite possibly that neither of those are true,” he emphasized.

Getting Better Answers

Current studies about vaccine effects on long COVID are entirely observational. There are no randomized controlled trials on the topic — and probably never will be for several reasons, Yang told MedPage Today.

The first problem in studying vaccines and long COVID is that there is no agreed-upon definition of long COVID and no objective measures of the disease, such as laboratory tests, biomarkers, or imaging. “What we’re calling long COVID is probably a constellation of different types of processes,” Yang said. “If you don’t have a clear definition of a condition, that makes it very difficult to study.”

Also, the majority of people have been vaccinated or had COVID-19 infections multiple times, further complicating the ability to study effects of vaccines on long COVID. “It’s going to be very, very difficult,” Yang commented. “The slate is not clean, so to speak, in terms of studying this, because people are going to be very heterogeneous in terms of how much exposure they’ve had in the past.”

Sanders tells her patients to get vaccinated against COVID to limit the risk of post-acute sequelae. “I’m not afraid of COVID, but I’m quite anxious about long COVID,” she said.

“Every time you get COVID, it’s the same risk,” she commented. “I’ve had patients who’ve had COVID six, seven, eight times, and they finally got long COVID … It’s a crap shoot every time.”

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