VVaccination reduces the risk of developing long Covid, according to a large new study which also found that the risk of serious complications has decreased but not disappeared as new variants of the coronavirus have emerged.
The study, published Wednesday in the New England Journal of Medicine, compared the medical records of more than 440,000 Veterans Affairs patients infected with COVID-19 with the records of more than 4 million uninfected people. The analysis found that cases of long COVID — also known as PASC (post-acute sequelae of severe acute respiratory syndrome coronavirus 2) — declined among all participants during the Delta and Omicron periods of the pandemic, but fell nearly twice as much for vaccinated people when the Omicron variant dominated cases.
The new data on the benefits of vaccination comes as Covid cases have been rising this summer across the country, and as health officials prepare to roll out an updated vaccine against new strains that Pfizer and Moderna have said they can deliver in August.
“The study is useful for validating the hypothesis that PASC incidence has declined over time and in relation to new variants (this question came up in my clinic yesterday),” Hilary Goldberg, clinical director of pulmonary and critical care medicine at Brigham and Women’s Hospital in Boston, told STAT in an email. She was not involved in the study. “It is also useful for validating that vaccination protects against the development of PASC, a question that has been somewhat unresolved,” Goldberg said.
In the unvaccinated group, 10.42 out of 100 people at the start of the pandemic (before vaccines were available) had developed long Covid one year after being infected. In the Delta era (defined as June 19 to December 18, 2021), 9.51 out of 100 unvaccinated people were diagnosed with long Covid, compared to 5.34 out of 100 vaccinated people. When the current Omicron era began (December 19, 2021), the gap widened: 7.76 out of 100 unvaccinated people got long Covid, but only 3.5 out of 100 vaccinated people.
“The vaccines are very clearly working, but it’s also clear that they’re not eliminating it completely,” Ziyad Al-Aly, the study’s lead author, said in an interview. He’s also a clinical epidemiologist at Washington University in St. Louis and a research chief at the VA St. Louis Health Care System. “What we think is really important here is that yes, long COVID has declined. But it’s not something we can completely ignore.”
Previous studies, including other research conducted by the VA, have hinted at a protective effect of vaccination as well as the detrimental impact of severe COVID infections and pre-existing medical conditions on the risk of later developing long COVID. Jai Marathe, assistant professor of infectious diseases at Boston University and director of the ReCOVer/long COVID Clinic at Boston Medical Center, points out that the new paper indicates that the type or number of comorbidities does not appear to impact PASC.
“From a research perspective, there is a strong impetus to understand the pathogenesis of PASC, given its constellation of symptoms,” she wrote to STAT. She was not involved in the NEJM article. “If vaccination alters the immune response, we need to study this in more detail to understand the interplay between viral infection and the immunologic changes that contribute to the development of PASC.”
Al-Aly is hesitant to say that these results are the final word on how well vaccination coverage is protecting people, and calls for more research. The observational study also describes how symptoms have changed with the variants in unvaccinated people.
While debilitating fatigue was once a hallmark of long Covid, more recently gastrointestinal, metabolic, and to a lesser extent musculoskeletal issues have overtaken fatigue in the unvaccinated, with gastrointestinal and metabolic issues representing twice the risk of pre-Delta and Delta combined. The study, conducted from March 2020 to January 2022, measured the duration of Covid damage across 10 disease categories: cardiovascular, blood disorders, fatigue, gastrointestinal, renal, mental health, metabolic, musculoskeletal, neurological, and pulmonary.
The risk of long Covid has not only changed with variants, but also with improved hospital care, including antivirals, Al-Aly said. Vaccination may have reduced the amount of virus circulating and therefore the risk of long Covid compared to 2020, but that is just a hypothesis. “Quantitatively, the risk has changed dynamically over time, but also qualitatively. This suggests that each strain has its own fingerprints,” he said. “Long Covid is not monolithic.”
Michael Peluso, an infectious disease physician and assistant professor of medicine at the University of California, San Francisco, said he and other doctors may see signs of the changing combination of symptoms. “This will allow me to better understand gastrointestinal and musculoskeletal symptoms in my assessment of long COVID,” Peluso, who was not involved in the study, said in an email to STAT. “We’re certainly seeing those symptoms, but I wouldn’t say they’re the most prominent.”
Goldberg wasn’t surprised by the change in symptoms. “I find that reassuring because we expect the nature of the disease to change over time. If we didn’t see that, we could potentially call into question the robustness of the data in this analysis.”
To determine the influence of vaccination versus variants, the study authors used a statistical method called decomposition analysis to conclude that 28% of the lower incidence of long Covid among vaccinated people was due to changes in variants and improved medical care, while attributing 72% of the improvement to vaccines.
The study did not specify how many vaccines a subject had received, Goldberg noted. “There are still gaps in the data — a common question patients have is what is the risk of reactivation or worsening of PASC symptoms following vaccination versus infection,” she said. “We don’t have enough information yet to answer that question, and that question often informs patients’ decision-making.”
The study’s estimate of the cumulative incidence of long COVID is lower than a June report from the Agency for Healthcare Research and Quality published in JAMA last month, which put the prevalence of long COVID at 7% of people who had already had COVID-19. That’s higher than the 3% to 4% of adults in NEJM’s Omicron era, but it reflects the agency’s survey results as opposed to the NEJM study’s reliance on medical records, Al-Aly said. Estimates of long COVID have fluctuated wildly since the start of the pandemic, before there was agreement on how to define the disease.
The Centers for Disease Control and Prevention (CDC) said Tuesday that people with disabilities are at higher risk of developing long-term COVID-19 than people without disabilities. The data shows that 11% of people with disabilities developed long-term COVID-19, while only 7% of people without disabilities experienced symptoms.
In other long-COVID research this week, a study published Wednesday in Science Translational Medicine offered an explanation for the lung damage that leads to exhausting coughs, lung disease, and shortness of breath. Researchers at the University of Virginia showed that a signaling molecule called interferon-gamma stimulated an abnormal immune response, causing inflammation and scarring in the lungs after COVID-19 infection. In mice, treatment with anti-interferon-gamma antibodies reduced inflammation and fibrosis after their acute infections. Drugs called JAK inhibitors, including one called baricitinib that has received emergency use authorization for acute COVID-19, “may be worth considering” for treating long-COVID, the authors wrote.
Despite advances in research and a decline in long-term Covid cases, the risk remains significant, Al-Aly and others have stressed.
“While the risk of long Covid is decreasing, it has not gone to zero and we will continue to see many cases of long Covid as SARS-CoV-2 continues to spread,” Peluso said. “This observation is really helpful for clinicians, researchers and advocates to make the argument that additional investment in clinical care and research for long Covid will be needed to meet the magnitude of the clinical need and to ultimately solve the problem.”
The decline in vaccination rates is concerning, likely due to COVID fatigue, Marathe said. “Living with a chronic condition like PASC can be debilitating. Therefore, educating and counseling patients and physicians to increase vaccine acceptance is a critical public health task.”
Goldberg said patients with long Covid often ask her about the risks and benefits of updating their vaccination status. “This study will help guide those of us who care for patients with PASC,” she said.
Peluso praised the study’s value in answering questions patients ask “all the time” in the clinic. “The risk associated with the Omicron variants may be lower than it was with previous variants, but it’s still significant,” he said. “And getting vaccinated is still the best thing you can do, beyond avoiding COVID, to protect yourself from developing long COVID.”
STAT’s coverage of chronic health conditions is supported by a grant from Bloomberg Philanthropies. OUR financial support are not involved in any decisions regarding our journalism.