Long COVID after breakthrough SARS-CoV-2 infection
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Abstract
The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary ( n = 4,983,491), historical ( n = 5,785,273) and vaccinated ( n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated ( n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.
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mRNA-1273 vaccination is associated with a lower incidence of long COVID compared with Ad26.COV2.S (OR 0.87; 95% CI 0.80-0.93).
“Only one study compared (therefore, meta -analyses could not be performed) different types of vaccines (i.e., BNT162b2 vs mRNA-1273 vs Ad26.COV2.S), in which BNT162b2 and mRNA-1273 were associated with lower incidences of long COVID compared to Ad26.COV2.S (OR, 0.86; 95 % CI, 0.800.93 and OR, 0.87; 95 % CI, 0.80-0.93, respectively) whereas no difference was seen between BNT162b2 vs mRNA-1273 (OR,”
From Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis (2023) · cites this paper as [16]
The Results section (page unavailable) reports a decreased risk of at least one post-acute sequela among mRNA-1273 recipients, and the Discussion explicitly compares that reduction with Ad26.COV2.S. Our copy does not report the claimed OR of 0.87 or its 95% CI of 0.80–0.93, so the numerical part cannot be verified. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBNT162b2 vaccination is associated with a lower incidence of long COVID compared with Ad26.COV2.S (OR 0.86; 95% CI 0.80-0.93).
“Only one study compared (therefore, meta -analyses could not be performed) different types of vaccines (i.e., BNT162b2 vs mRNA-1273 vs Ad26.COV2.S), in which BNT162b2 and mRNA-1273 were associated with lower incidences of long COVID compared to Ad26.COV2.S (OR, 0.86; 95 % CI, 0.800.93 and OR, 0.87; 95 % CI, 0.80-0.93, respectively) whereas no difference was seen between BNT162b2 vs mRNA-1273 (OR,”
From Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis (2023) · cites this paper as [16]
The Results (page not available) report a decreased risk of at least one post-acute sequela among BNT162b2 recipients, and the Discussion explicitly describes greater risk reduction with BNT162b2 than with Ad26.COV2.S. Our copy does not give the claimed OR of 0.86 or 95% CI of 0.80–0.93, so the numerical part is not verified. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNo difference in incidence of long COVID was seen between BNT162b2 and mRNA-1273 vaccination (OR 1.00; 95% CI 0.95-1.05).
“Only one study compared (therefore, meta -analyses could not be performed) different types of vaccines (i.e., BNT162b2 vs mRNA-1273 vs Ad26.COV2.S), in which BNT162b2 and mRNA-1273 were associated with lower incidences of long COVID compared to Ad26.COV2.S (OR, 0.86; 95 % CI, 0.800.93 and OR, 0.87; 95 % CI, 0.80-0.93, respectively) whereas no difference was seen between BNT162b2 vs mRNA-1273 (OR,”
From Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis (2023) · cites this paper as [16]
The Results section (page unavailable) reports no statistically significant difference in post-acute sequelae risk between BNT162b2 and mRNA-1273 recipients with breakthrough infections. Our copy does not give the claimed OR of 1.00 or its 95% CI of 0.95–1.05, so those figures cannot be verified. (LLM, conf=0.85)
Experimental — accuracy not yet measuredA nationwide database study revealed that vaccinated patients were less likely to develop long COVID than unvaccinated patients, even in those non-hospitalized.
“A nationwide database study revealed that vaccinated patients were less likely to develop long COVID than unvaccinated patients, even in those non-hospitalized [16].”
From Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis (2023) · cites this paper as [16]
Patients with two-dose vaccination were more likely to have pre-existing comorbidities than those without/one-dose vaccination.
“Notably, other studies showed that patients with two-dose vaccination were more likely to have pre-existing comorbidities than those without/one-dose vaccination [16,24,25].”
From Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis (2023) · cites this paper as [16]
The Results section on breakthrough infection versus infection without prior vaccination compares post-acute outcomes and says the weighted cohorts had balanced baseline characteristics; it does not report that the vaccinated group had more pre-existing comorbidities. The Methods sections on covariates and statistical analysis identify prior conditions and describe baseline comparisons, but the searched passages do not establish a two-dose versus no-dose/one-dose comorbidity difference (page numbers unavailable). (LLM, conf=0.73)
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- Authors
- Al-Aly, Z., Bowe, B., & Xie, Y.
- Affiliations
- VA St. Louis Health Care System (US)
- Venue
- Nature Medicine
- Published
- 2022-05-25
- Volume
- 28
- Issue
- 7
- Pages
- 1461-1467
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC9307472
- OpenAlex
- W4281476185
- Cited by
- 866
- References
- 7
- Citations by year
- 2026: 85 · 2025: 130 · 2024: 217 · 2023: 292 · 2022: 142
- FWCI
- 103.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Medicine (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- Funders
- U.S. Department of Veterans Affairs
- American Society of Nephrology
- Topics
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- long COVID, post-acute sequelae, COVID-19 vaccination, vaccine effectiveness, mortality, cardiovascular complications, coagulopathy, mental health, musculoskeletal disorders, neurological disorders, veterans, post-acute care
- MeSH terms
- COVID-19, SARS-CoV-2, Post-Acute COVID-19 Syndrome, Humans, Nervous System Diseases, Cohort Studies
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