Effectiveness of COVID-19 mRNA Vaccination in Preventing COVID-19–Associated Hospitalization Among Adults With Previous SARS-CoV-2 Infection

Abbreviation: NAAT = nucleic acid amplification test.
*Initial diagnosis was based on a previous positive SARS-CoV-2 NAAT or clinical diagnosis of COVID-19 >90 days before the date of the NAAT associated with subsequent hospitalization. COVID-19 was defined as a clinical encounter with any of the following International Classification of Diseases, Tenth Revision diagnostic codes: U07.1, J12.81, or J12.82.
^†Defined as NAAT performed between 10 days before and 3 days after the date of hospital admission with a diagnosis of COVID-19-like illness. COVID-19–like illness diagnoses were defined based on others' methods (https://www.nejm.org/doi/full/10.1056/nejmoa2110362, Supplement Table S2) and included acute respiratory illness (e.g., COVID-19, respiratory failure, or pneumonia) or related signs or symptoms (e.g., cough, fever, dyspnea, vomiting, or diarrhea) using diagnostic codes from the International Classification of Diseases, Tenth Revision.
^§Patients were eligible for inclusion if the hospitalization-associated SARS-CoV-2 NAAT was performed during June 20, 2021–February 24, 2022.
^¶Cases had a positive SARS-CoV-2 NAAT result associated with hospitalization; controls had a negative SARS-CoV-2 NAAT result associated with hospitalization.
**Wilcoxon rank-sum tests and chi-square tests were used to compare medians and proportions, respectively; p-values <0.05 were considered statistically significant.
^††Other non-Hispanic includes Asian, Native Hawaiian or other Pacific Islander, and American Indian or Alaska Native persons.
^§§Underlying conditions were extracted from electronic health record clinical encounter data and were based on a CDC list of conditions associated with the highest risk for COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html, accessed March 23, 2022), and included the following: alcoholic liver disease, autoimmune hepatitis, bronchiectasis, bronchopulmonary dysplasia, cancer, cardiomyopathy, cerebrovascular disease, chronic kidney disease, cirrhosis, chronic obstructive pulmonary disease, coronary artery disease, current smoker, administration or prescription of nontopical glucocorticoids within the previous 12 months, heart failure, HIV, immune deficiency, administration or prescription of immunosuppressive medications within the previous 12 months, interstitial lung disease, nonalcoholic fatty liver disease, obesity, pulmonary arterial hypertension, pulmonary embolus, pregnancy, solid organ transplant, tuberculosis, and type 1 or 2 diabetes. Among these, diagnoses associated with immunocompromise had overall similar prevalence between cases and controls, including immunosuppressive medications other than steroids (7.9% of case-patients and 7.3% of control-patients), immune deficiencies (4.4% of case-patients and 4.5% of control-patients), solid organ transplant recipients (2.4% of case-patients and 1.8% of control-patients) and HIV (0.9% of case-patients and 0.9% of control-patients).
^¶¶Patients were categorized on the date of NAAT associated with hospitalization as unvaccinated if no COVID-19 vaccine had been received; after dose 1 if ≥14 days had elapsed since receipt of the first dose of an mRNA COVID-19 vaccine and before any second dose; after dose 2 if ≥14 days had elapsed since receipt of the second dose of an mRNA COVID-19 vaccine, and no subsequent dose was received; and after a booster dose if ≥14 days had elapsed since receipt of an mRNA booster dose administered ≥5 months after a second dose. Patients were excluded from the analysis if they received a non-mRNA COVID-19 vaccine; the day of the NAAT-associated hospitalization was <14 days after dose 1, dose 2, or a booster dose; dose 2 was received <14 days after dose 1; any booster dose was <5 months after dose 2, they received >3 doses of vaccine, or their previous positive NAAT result or COVID-19 diagnosis was after date of the most recent vaccine dose. Median time from receipt of dose 1 to dose 2 was 21 days (IQR = 21–24) for Pfizer-BioNTech and 28 days (IQR = 28–30) for Moderna vaccines. Median time from receipt of dose 2 to dose 3 was 232 days (IQR = 203–258) for Pfizer-BioNTech and 236 days (IQR = 210–261) for Moderna vaccines.
***Periods were defined as a range of dates when estimated national prevalence of a SARS-CoV-2 variant exceeded 50% as pre-Delta (before June 20, 2021), Delta (during June 20, 2021–December 18, 2021), and Omicron (from December 19, 2021). https://covid.cdc.gov/covid-data-tracker/#variant-proportions

Abbreviations: NAAT = nucleic acid amplification test; Ref = referent group; VE = vaccine effectiveness.
*Initial diagnosis was based on a previous positive SARS-CoV-2 NAAT or clinical diagnosis of COVID-19 >90 days before the date of the NAAT associated with subsequent hospitalization. COVID-19 was defined as a clinical encounter with any of the following International Classification of Diseases, Tenth Revision diagnostic codes: U07.1, J12.81, or J12.82.
^†Case-patients had a positive NAAT performed 10 days before through 3 days after the date of hospitalization with a diagnosis of COVID-19-like illness; control-patients had a negative NAAT result. COVID-19–like illness diagnoses were defined based on other methods (https://www.nejm.org/doi/full/10.1056/nejmoa2110362, Supplement Table S2) and included acute respiratory illness (e.g., COVID-19, respiratory failure, or pneumonia) or related signs or symptoms (e.g., cough, fever, dyspnea, vomiting, or diarrhea) using diagnostic codes from the International Classification of Diseases, Tenth Revision. Patients were eligible for inclusion if the hospitalization-associated SARS-CoV-2 NAAT was performed during June 20, 2021–February 24, 2022.
^§VE was calculated as [1 − odds ratio] x 100, estimated using conditional logistic regression in a test-negative design after matching by 2-week calendar period of NAAT associated with hospital admission, 10-year age group, and state of residence. Adjusted estimates accounted in addition for measured differences in sex, race/ethnicity (White non-Hispanic race: yes/no and Hispanic ethnicity: yes/no), number of clinical encounters during 2019 (0, 1–9, or ≥10), number of underlying conditions (0, 1, or >1), and days since previous infection (as a continuous variable). Underlying conditions were extracted from EHR clinical encounter data and based on a CDC list of conditions associated with the highest risk for COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html, accessed March 23, 2022), including the following diagnoses: alcoholic liver disease, autoimmune hepatitis, bronchiectasis, bronchopulmonary dysplasia, cancer, cardiomyopathy, cerebrovascular disease, chronic kidney disease, cirrhosis, chronic obstructive pulmonary disease, coronary artery disease, current smoker, administration or prescription of nontopical glucocorticoids within the previous 12 months, heart failure, HIV, immune deficiency, administration or prescription of immunosuppressive medications within the previous 12 months, interstitial lung disease, nonalcoholic fatty liver disease, obesity, pulmonary arterial hypertension, pulmonary embolus, pregnancy, solid organ transplant, tuberculosis, and type 1 or 2 diabetes.
^¶Patients were categorized on the date of NAAT associated with hospitalization as unvaccinated if no COVID-19 vaccine had been received; after dose 1 if ≥14 days had elapsed since receipt of the first dose of an mRNA COVID-19 vaccine and before any second dose; after dose 2 if ≥14 days had elapsed since receipt of the second dose of an mRNA COVID-19 vaccine and no subsequent dose was received; and after a booster dose if ≥14 days had elapsed since receipt of an mRNA booster dose administered ≥5 months after a second dose. Patients were excluded from the analysis if they received a non-mRNA COVID-19 vaccine; the day of the NAAT-associated hospitalization was <14 days after dose 1, dose 2, or a booster dose; dose 2 was received <14 days after dose 1; any booster dose was <5 months after dose 2, they received >3 doses of vaccine, or the previous positive NAAT result or COVID-19 diagnosis was after the date of the most recent vaccine dose.
**Among persons with a previous infection, adjusted VE <90 days after dose 1 was 42.0% (95% CI = 16.8%–59.5%) and ≥90 days after dose 1 was 42.2% (95% CI = 26.0%–54.8%); adjusted VE <90 days after dose 2 was 44.6% (95% CI = 28.6%–56.9%) and ≥90 days after dose 2 was 39.3% (95% CI = 32.4%–45.4%); and adjusted VE <90 days after dose 3 was 67.9% (95% CI = 60.3%–74.0%) and ≥90 days after dose 3 was 62.4% (95% CI = 48.6%–72.5%).
^††For estimation of relative VE after a booster dose, the referent group had received dose 2 (but not a booster dose) ≥5 months previously.

Abbreviations: NAAT = nucleic acid amplification test; Ref = referent group; VE = vaccine effectiveness.
*Initial diagnosis was based on a previous positive SARS-CoV-2 NAAT or clinical diagnosis of COVID-19 >90 days before the date of the NAAT associated with subsequent hospitalization. COVID-19 diagnosis was defined as a clinical encounter with any of the following International Classification of Diseases, Tenth Revision diagnostic codes: U07.1, J12.81, or J12.82.
^†Case-patients had a positive NAAT performed between 10 days before and 3 days after the date of hospital admission with a diagnosis of COVID-19-like illness; control-patients had a negative NAAT result. COVID-19–like illness diagnoses were defined based on others' methods (https://www.nejm.org/doi/full/10.1056/nejmoa2110362, Supplement Table S2) and included acute respiratory illness (e.g., COVID-19, respiratory failure, or pneumonia) or related signs or symptoms (e.g., cough, fever, dyspnea, vomiting, or diarrhea) using diagnostic codes from the International Classification of Diseases, Tenth Revision. Patients were eligible for inclusion if the hospitalization-associated SARS-CoV-2 NAAT was performed during June 20, 2021 and February 24, 2022.
^§VE was calculated as [1 − odds ratio] x 100, estimated using conditional logistic regression in a test-negative design after matching by 2-week calendar period of NAAT associated with hospital admission, 10-year age group, and state of residence. Adjusted estimates accounted in addition for measured differences in sex, race/ethnicity (White non-Hispanic race: yes/no and Hispanic ethnicity: yes/no), number of clinical encounters during 2019 (0, 1–9, or ≥10), number of underlying conditions (0, 1, or >1), and days since previous infection (as a continuous variable). Underlying conditions were extracted from EHR clinical encounter data and classified based on a CDC list of conditions associated with the highest risk for COVID-19 (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html, accessed March 23, 2022), including the following diagnoses: alcoholic liver disease, autoimmune hepatitis, bronchiectasis, bronchopulmonary dysplasia, cancer, cardiomyopathy, cerebrovascular disease, chronic kidney disease, cirrhosis, chronic obstructive pulmonary disease, coronary artery disease, current smoker, administration or prescription of nontopical glucocorticoids within the previous 12 months, heart failure, HIV, immune deficiency, administration or prescription of immunosuppressive medications within the previous 12 months, interstitial lung disease, nonalcoholic fatty liver disease, obesity, pulmonary arterial hypertension, pulmonary embolus, pregnancy, solid organ transplant, tuberculosis, and type 1 or 2 diabetes.
^¶Patients were categorized on the date of NAAT associated with hospitalization as unvaccinated if no COVID-19 vaccine had been received; after dose 1 if ≥14 days had elapsed since receipt of the first dose of an mRNA COVID-19 vaccine and before any second dose; after dose 2 if ≥14 days had elapsed since receipt of the second dose of an mRNA COVID-19 vaccine, and no subsequent dose was received; and after a booster dose if ≥14 days had elapsed since receipt of an mRNA booster dose administered ≥5 months after a second dose. Patients were excluded from the analysis if they received a non-mRNA COVID-19 vaccine; the day of the NAAT-associated hospitalization was <14 days after dose 1, dose 2, or a booster dose; dose 2 was received <14 days after dose 1; any booster dose was <5 months after dose 2, they received >3 doses of vaccine, or their previous positive NAAT result or COVID-19 diagnosis was after the most recent vaccine dose. VE was calculated using the unvaccinated group as the referent.
**Among persons with a previous infection <180 days and ≥180 days before dose 1, adjusted VE after dose 1 was 43.2% (95% CI = 25.3%–56.8%) and 36.8% (95% CI = 14.0%–53.5%), respectively; adjusted VE after dose 2 was 37.6% (95% CI = 29.6%–44.6%) for persons with a previous infection <180 days before dose 1 and 38.9% (95% CI = 28.2%–48.1%) for persons with a previous infection ≥180 days before dose 1; adjusted VE after a booster dose was 72.5% (95% CI = 65.2%–78.2%) for persons with a previous infection <180 days before dose 1 and 46.7% (95% CI = 24.9%–62.2%) for persons with a previous infection ≥180 days before dose 1.

Authors and Disclosures

Ian D. Plumb, MBBS^1,2,*, Leora R. Feldstein, PhD^1,2,*, Eric Barkley³, Alexander B. Posner, MPH³, Howard S. Bregman, MD³, Melissa Briggs Hagen, MD^1,2 and Jacqueline L. Gerhart, MD<sup>3

1</sup>Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC; ²CDC COVID-19 Emergency Response Team; ³Epic Research, Epic Systems Corporation, Verona, Wisconsin.

Corresponding author
Ian D. Plumb, iplumb@cdc.gov.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Eric Barkley, Alexander B. Posner, Howard S. Bregman, and Jacqueline L. Gerhart report support from Epic Research, Epic Systems Corporation. No other potential conflicts of interest were disclosed.

Sidebar

Summary

What is already known about this topic?

Persons with previous SARS-CoV-2 infection have some protection against reinfection leading to hospitalization, but there is limited evidence regarding the additional benefit of vaccination among these persons.

What is added by this report?

Among persons with previous infection, COVID-19 mRNA vaccination provided protection against subsequent COVID-19–associated hospitalization. Estimated vaccine effectiveness against reinfection leading to hospitalization during the Omicron-predominant period was approximately 35% after dose 2, and 68% after a booster dose.

What are the implications for public health practice?

To prevent COVID-19–associated hospitalization, all eligible persons should stay up to date with vaccination, including those with previous SARS-CoV-2 infection.