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Vaccinated individuals with breakthrough infections were not immune to long COVID and also saw higher risks for death and comorbidities compared to those without any evidence of an infection, according to data from the U.S. Department of Veterans Affairs (VA).

In the pre-Omicron study, there was a higher risk of at least one incident post-acute sequelae within 30 days of a breakthrough infection -- such as pulmonary complications, coagulation or hematologic disorders, and fatigue -- compared with controls (HR 1.50, 95% CI 1.46-1.54), reported Ziyad Al-Aly, MD, of Washington University in St. Louis, Missouri, and colleagues.

Moreover, risk of death beyond 30 days of illness was higher for those with breakthrough infection (HR 1.75, 95% CI 1.59-1.93), the authors wrote in

"Getting COVID-19, even among vaccinated people, seems almost unavoidable nowadays," Al-Aly said in a statement. "Now that we understand that COVID-19 can have lingering health consequences even among the vaccinated, we need to move toward developing mitigation strategies that can be implemented for the longer term since it does not appear that COVID-19 is going away any time soon."

The authors noted that to their knowledge, this was "the first large study to characterize the risks of post-acute sequelae of [breakthrough infection] at 6 months."

The team examined data from Jan. 1, 2021 to Oct. 31, 2021 in the VA's electronic healthcare databases, and found 33,940 individuals with breakthrough infection, defined as a positive COVID test and a prior record of complete vaccination with one of the FDA's authorized vaccines. There were also 4,983,491 controls with no record of a positive COVID test.

There was more than a twofold higher risk of pulmonary complications (HR 2.48, 95% CI 2.33-2.64), coagulation and hematologic disorders (HR 2.43, 95% CI 2.18-2.71), and a twofold increased risk of fatigue (HR 2.00, 95% CI 1.82-2.21) among 30-day survivors of breakthrough infection compared with controls. The authors also documented higher risks of cardiovascular, gastrointestinal, kidney, mental health, musculoskeletal, and neurologic disorders.

The researchers added that there was no statistically significant difference by vaccine type in risk of death among those with breakthrough infection, but that Moderna's COVID vaccine (Spikevax) and Pfizer's (Comirnaty) were linked to a lower risk of at least one post-COVID condition.

Not surprisingly, Al-Aly's group found that compared with individuals who had COVID infection without prior vaccination, those with breakthrough infection had a lower risk of death (HR 0.66, 95% CI 0.58-0.74), and lower risk of 24 out of 47 post-COVID sequelae. The authors noted a "consistently reduced risk" of hematologic and coagulation disorders and pulmonary disorders in those with breakthrough infection.

Limitations to the data include that only those with a positive COVID test were included, meaning the sample did not include those who had COVID but were not tested, which could bias the estimates. The VA population is at least 90% men, which may limit the study's generalizability, and the authors acknowledged the possibility of unmeasured confounders.

Al-Aly called for a more layered approach for protection other than vaccination, masking, and social distancing, calling it "not sustainable."

"Our current approach will likely leave a large number of people with chronic and potentially disabling conditions that have no treatments," he said. "We need to urgently develop and deploy additional layers of protection that could be sustainably implemented to reduce the risk of long COVID."

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