Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Health Care Workers | Vaccination | JAMA | JAMA Network
[Skip to Navigation]
Sign In
Table 1.  Characteristics of the Nonhospitalized Study Population of Routinely Tested Health Care Personnel With COVID-19 (N = 739)
Characteristics of the Nonhospitalized Study Population of Routinely Tested Health Care Personnel With COVID-19 (N = 739)
Table 2.  Multivariable Logistic Regression Analysis of the Association of Long COVID (N = 229) With Patient Characteristicsa
Multivariable Logistic Regression Analysis of the Association of Long COVID (N = 229) With Patient Characteristicsa
Audio Author Interview (16:38)

On August 3, 2022, the US Department of Health and Human Services released 2 major reports in response to a presidential memo calling for a whole-of-government response to the SARS-CoV-2 sequelae known as “Long COVID."

1.
Groff  D, Sun  A, Ssentongo  AE,  et al.  Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: a systematic review.   JAMA Netw Open. 2021;4(10):e2128568. doi:10.1001/jamanetworkopen.2021.28568PubMedGoogle ScholarCrossref
2.
Su  Y, Yuan  D, Chen  DG,  et al; ISB-Swedish COVID-19 Biobanking Unit.  Multiple early factors anticipate post-acute COVID-19 sequelae.   Cell. 2022;185(5):881-895.e20. doi:10.1016/j.cell.2022.01.014PubMedGoogle ScholarCrossref
3.
Chen  C, Haupert  SR, Zimmermann  L, Shi  X, Fritsche  LG, Mukherjee  B.  Global prevalence of post COVID-19 condition or long COVID: a meta-analysis and systematic review.   J Infect Dis. Published online April 16, 2022. doi:10.1093/infdis/jiac136PubMedGoogle ScholarCrossref
4.
Al-Aly  Z, Bowe  B, Xie  Y.  Long COVID after breakthrough SARS-CoV-2 infection.   Nat Med. Published online May 25, 2022. doi:10.1038/s41591-022-01840-0PubMedGoogle ScholarCrossref
5.
Levi  R, Azzolini  E, Pozzi  C,  et al.  One dose of SARS-CoV-2 vaccine exponentially increases antibodies in individuals who have recovered from symptomatic COVID-19.   J Clin Invest. 2021;131(12):149154. doi:10.1172/JCI149154PubMedGoogle ScholarCrossref
6.
Darwich  A, Pozzi  C, Fornasa  G,  et al; ICH COVID-19 Task-force.  BNT162b2 vaccine induces antibody release in saliva: a possible role for mucosal viral protection?   EMBO Mol Med. 2022;14(5):e15326. doi:10.15252/emmm.202115326PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    2 Comments for this article
    EXPAND ALL
    Confounding Between Vaccination Doses and Covid-19 Wave
    Dana Ludwig, MD, MS | UC San Francisco
    I question whether vaccination dose was such a strong factor in determining conversion to Long Covid. In Table 1, there is clearly a strong association between Covid-19 wave and Long Covid risk. In Wave 1 (2/2020-9/2020; wild-type virus but also no vaccine), there was a 48.1% chance of getting Long Covid. In Wave 3 (8/2021-3/2022; Delta and Omicron; most had 2nd vaccine dose), there was only a 16.0% chance of getting Long Covid. There is no way to untangle whether the reduced risk in Wave 3 was due to the vaccination or the decreased pathogenicity of the newer virus variants.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Confounders Interact
    Sandro Tsang, PhD | People's Open Access Education Initiative
    The comments of Dr. Dana Ludwig imply that the estimations need adjustments as herd immunity has been developed in the later wave. In the same rubric, the interaction effects between after infections and having previously vaccinated also need to be adjusted.
    CONFLICT OF INTEREST: None Reported
    Views 107,945
    Citations 0
    Research Letter
    July 1, 2022

    Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Health Care Workers

    Author Affiliations
    • 1IRCCS Humanitas Research Hospital, Milan, Italy
    • 2Department of Biomedical Sciences, Humanitas University, Milan, Italy
    • 3Politecnico di Milano, Department of Electronic, Information and Bioengineering, Milan, Italy
    JAMA. 2022;328(7):676-678. doi:10.1001/jama.2022.11691

    Survivors of COVID-19 may present with long-lasting symptoms.1 Some factors have been associated with the development of post-COVID conditions (also referred to as “long COVID”),2 including hospitalization.3 A study of older US veterans showed 15% reduction of long COVID after vaccination; however, study limitations included the low number of women and suboptimal vaccination schedules.4

    Methods

    The study was approved by the Humanitas Research Hospital institutional review board. Each participant provided written informed consent.

    We conducted an observational cohort study from March 2020 to April 2022 in individuals working in 9 Italian health care facilities.5,6 Polymerase chain reaction (PCR) tests for SARS-CoV-2 were conducted every week (in COVID wards) or 2 weeks (in other wards) for hospital personnel, or if they developed symptoms or were exposed to cases. All health care workers were required to receive 3 doses of vaccine (BNT162b2), with the first and second doses administered in January-February 2021 and the booster dose in November-December 2021.

    Between February and April 2022, each participant completed a survey including demographics, comorbidities, a list of SARS-CoV-2–related symptoms at the time of infection and their duration (survey in the Supplement), and vaccination status. We defined long COVID as reporting at least 1 SARS-CoV-2–related symptom with a duration of more than 4 weeks. Hospitalized individuals were excluded to avoid bias related to severe disease, as were individuals with a date of infection less than 28 days before the survey. We included asymptomatic infections in the acute infection group (they could not have long COVID by definition) to avoid overestimating the prevalence of long COVID. The analysis was restricted to health care workers who were tested every 1 or 2 weeks with complete demographic data and a documented positive result for SARS-CoV-2 between March 2020 and March 2022.

    By the date of infection, we divided the patients into 3 groups corresponding to the peaks in our data and circulation of variants of concern in Italy (wave 1, February-September 2020 [wild-type variant]; wave 2, October 2020-July 2021 [Alpha]; and wave 3, August 2021-March 2022 [Delta and Omicron]) (eFigure in the Supplement). A multivariable logistic regression model was used to assess the relationship between long COVID and characteristics, including participant sex, age, SARS-CoV-2 infection, wave, and vaccination status 14 days prior to infection. Time since second vaccination was assessed among vaccinated individuals.

    The Clopper-Pearson method was used to calculate 95% CIs and the Mann-Whitney U test or the t test for continuous variables and the χ2-test for categorical variables to calculate P values. The significance threshold was defined as P < .05 (2-sided). Analyses were done in Python, version 3.8.3.

    Results

    Of 2560 participants, 739 individuals (29%) had COVID-19 (89 asymptomatic), of whom 229 (31.0%; 95% CI, 27.7%-34.5%) had long COVID (Table 1). The prevalence of long COVID varied across the pandemic waves, from 48.1% (95% CI, 39.9%-56.2%) in wave 1 to 35.9% (95% CI, 30.5%-41.6%) in wave 2 to 16.5% (95% CI, 12.4%-21.4%) in wave 3. The number of vaccine doses was associated with lower long COVID prevalence: 41.8% (95% CI, 37.0%-46.7%) in unvaccinated patients, 30.0% (95% CI, 6.7%-65.2%) with 1 dose, 17.4% (95% CI, 7.8%-31.4%) with 2 doses, and 16.0% (95% CI, 11.8%-21.0%) with 3 doses. Older age, higher body mass index, allergies, and obstructive lung disease were associated with long COVID.

    With a reference group of unvaccinated females in wave 1 with no allergies or comorbidities (Table 2), male sex (odds ratio [OR], 0.65; 95% CI, 0.44-0.98, P = .04), 2 vaccine doses (OR, 0.25; 95% CI, 0.07-0.87, P = .03), and 3 vaccine doses (OR, 0.16; 95% CI, 0.03-0.84, P = .03) were associated with a lower probability of long COVID. Older age (OR, 1.23; 95% CI, 1.01-1.49, P = .04), allergies (OR, 1.50; 95% CI, 1.06-2.11, P = .02), and an increasing number of comorbidities (OR, 1.32; 95% CI, 1.04-1.68, P = .03) were associated with a higher probability. No statistically significant association with infection wave was found. Among vaccinated individuals (n = 265), time between the second vaccination dose and infection was not associated with long COVID (OR, 0.66; 95% CI, 0.34-1.29).

    Discussion

    In this longitudinal observational study conducted among health care workers with SARS-CoV-2 infections not requiring hospitalization, 2 or 3 doses of vaccine, compared with no vaccination, were associated with lower long COVID prevalence. Study limitations include that symptoms and duration were self-reported, and causality cannot be inferred.

    Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Senior Editor.
    Back to top
    Article Information

    Accepted for Publication: June 22, 2022.

    Published Online: July 1, 2022. doi:10.1001/jama.2022.11691

    Corresponding Author: Maria Rescigno, PhD, Humanitas University, Via Rita Levi Montalcini, 4, 20072 Pieve Emanuele (MI), Italy (maria.rescigno@hunimed.eu).

    Author Contributions: Dr Rescigno had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Azzolini and Levi contributed equally.

    Concept and design: Azzolini, Mantovani, Rescigno.

    Acquisition, analysis, or interpretation of data: Azzolini, Levi, Sarti, Pozzi, Mollura, Rescigno.

    Drafting of the manuscript: Levi, Sarti, Mollura, Rescigno.

    Critical revision of the manuscript for important intellectual content: Azzolini, Sarti, Pozzi, Mantovani, Rescigno.

    Statistical analysis: Levi, Sarti, Mollura.

    Obtained funding: Rescigno.

    Supervision: Azzolini, Pozzi, Mantovani, Rescigno.

    Conflict of Interest Disclosures: Dr Mantovani reported receiving personal fees for lectures from Ventana, Novartis, and Roche; consulting fees from Pierre Fabre, Verily, AbbVie, AstraZeneca, Third Rock Venture, and Merck; serving on the advisory board for Verseau Therapeutics, Myeloid Therapeutics, Imcheck Therapeutics, Ellipses, Olatec Therapeutics, Macrophage Pharma, Biovelocita, Principia, and Biolegend; grants from Novartis; and royalties for sale of reagents from Biolegend Royalties, Cedarlane Laboratories, HyCult Biotechnology, eBioscience Royalties, ABCAM Plc, Novus Biologicals, Enzo Life, and Affymetric. Dr Mantovani also reported having a patent for antihuman migration stimulating factor (MSF), a patent for NK or T cells and uses thereof, a patent for "use of SAP for the treatment of Euromycetes fungi infections,” and a patent for PTX3 as prognostic marker in COVID-19 licensed to Diasorin (prospective trial in sepsis underway). Dr Rescigno reported serving on the advisory board (with compensation) for MillBo and receiving grants from AlfaSigma, Gelesis, and Diasorin outside the submitted work. No other disclosures were reported.

    Funding/Support: Fondazione Humanitas per la Ricerca funded this research.

    Role of the Funder/Sponsor: Fondazione Humanitas per la Ricerca did not participate in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: Valeria Cento, MD, PhD, Humanitas University, Daniele Braga, PhD, IRCCS Humanitas Research Hospital, and Riccardo Barbieri, PhD, Politecnico di Milano, have contributed to the study by helping with interpretation of the data or methodologically. None received compensation for their roles.

    References
    1.
    Groff  D, Sun  A, Ssentongo  AE,  et al.  Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: a systematic review.   JAMA Netw Open. 2021;4(10):e2128568. doi:10.1001/jamanetworkopen.2021.28568PubMedGoogle ScholarCrossref
    2.
    Su  Y, Yuan  D, Chen  DG,  et al; ISB-Swedish COVID-19 Biobanking Unit.  Multiple early factors anticipate post-acute COVID-19 sequelae.   Cell. 2022;185(5):881-895.e20. doi:10.1016/j.cell.2022.01.014PubMedGoogle ScholarCrossref
    3.
    Chen  C, Haupert  SR, Zimmermann  L, Shi  X, Fritsche  LG, Mukherjee  B.  Global prevalence of post COVID-19 condition or long COVID: a meta-analysis and systematic review.   J Infect Dis. Published online April 16, 2022. doi:10.1093/infdis/jiac136PubMedGoogle ScholarCrossref
    4.
    Al-Aly  Z, Bowe  B, Xie  Y.  Long COVID after breakthrough SARS-CoV-2 infection.   Nat Med. Published online May 25, 2022. doi:10.1038/s41591-022-01840-0PubMedGoogle ScholarCrossref
    5.
    Levi  R, Azzolini  E, Pozzi  C,  et al.  One dose of SARS-CoV-2 vaccine exponentially increases antibodies in individuals who have recovered from symptomatic COVID-19.   J Clin Invest. 2021;131(12):149154. doi:10.1172/JCI149154PubMedGoogle ScholarCrossref
    6.
    Darwich  A, Pozzi  C, Fornasa  G,  et al; ICH COVID-19 Task-force.  BNT162b2 vaccine induces antibody release in saliva: a possible role for mucosal viral protection?   EMBO Mol Med. 2022;14(5):e15326. doi:10.15252/emmm.202115326PubMedGoogle ScholarCrossref
    ×