Effectiveness of COVID-19 mRNA Vaccination in Preventing COVID-19–Associated Hospitalization Among Adults with Previous SARS-CoV-2 Infection — United States, June 2021–February 2022

Previous infection with SARS-CoV-2, the virus that causes COVID-19, has been estimated to confer up to 90% protection against reinfection, although this protection was lower against the Omicron variant compared with that against other SARS-CoV-2 variants (1–3). A test-negative design was used to estimate effectiveness of COVID-19 mRNA vaccines in preventing subsequent COVID-19–associated hospitalization among adults aged ≥18 years with a previous positive nucleic acid amplification test (NAAT) or diagnosis of COVID-19.^† The analysis used data from Cosmos, an electronic health record (EHR)–aggregated data set (4), and compared vaccination status of 3,761 case-patients (positive NAAT result associated with hospitalization) with 7,522 matched control-patients (negative NAAT result). After previous SARS-CoV-2 infection, estimated vaccine effectiveness (VE) against COVID-19–associated hospitalization was 47.5% (95% CI = 38.8%–54.9%) after 2 vaccine doses and 57.8% (95% CI = 32.1%–73.8%) after a booster dose during the Delta-predominant period (June 20–December 18, 2021), and 34.6% (95% CI = 25.5%–42.5%) after 2 doses and 67.6% (95% CI = 61.4%–72.8%) after a booster dose during the Omicron-predominant period (December 19, 2021–February 24, 2022). Vaccination provides protection against COVID-19–associated hospitalization among adults with previous SARS-CoV-2 infection, with the highest level of protection conferred by a booster dose. All eligible persons, including those with previous SARS-CoV-2 infection, should stay up to date with vaccination to prevent COVID-19–associated hospitalization.

Data were obtained from Cosmos (4), an EHR data set that includes information from more than 135 million patients and 154 health care organizations in the United States.^§ Patients eligible for inclusion in the analysis met the following four criteria: 1) age ≥18 years, 2) residence in the United States, 3) at least one hospital admission for a COVID-19–like illness,^¶ with a hospitalization-associated NAAT performed from 10 days before through 3 days after admission during June 20, 2021–February 24, 2022, and 4) a previous positive NAAT result or diagnostic code of COVID-19 (with or without hospitalization) >90 days before the date of the NAAT associated with the subsequent hospitalization.** Patients under the billing category of “observation” and patients who were admitted and discharged on the same day were excluded. Vaccination status was categorized on the day of the NAAT associated with the hospitalization as 1) unvaccinated, 2) after dose 1, 3) after dose 2, or 4) after a booster dose^††; patients were excluded if they did not meet one of these definitions or if the previous positive NAAT result or COVID-19 diagnosis was after the date of the most recent vaccine dose. Vaccination information was collected during the 14 days after hospitalization or other health care visit from a patient’s health system, other health systems via clinical record exchanges, state registries, and patient-reported history.^§§

VE was estimated using conditional logistic regression, comparing the vaccination status among case-patients and control-patients. VE after each vaccine dose was estimated using the unvaccinated group as a referent. For estimation of relative VE after a booster dose, the referent group had received dose 2 (but not a booster dose) ≥5 months previously. Eligible case-patients were matched with control-patients using a 1:2 ratio by 2-week period of the hospitalization-associated NAAT, 10-year age group, and state of residence. After matching, estimates were adjusted for sex, race/ethnicity, number of clinical encounters during 2019, number of underlying health conditions, and days since the previous infection.^¶¶ The period June 20–December 18, 2021, was categorized as Delta-predominant, and the period December 19, 2021–February 24, 2022, as Omicron-predominant; periods were defined as range of dates when estimated national prevalence of a SARS-CoV-2 variant exceeded 50%.*** In a sensitivity analysis, VE was also estimated defining previous infection as a positive NAAT result. Wilcoxon rank-sum tests and chi-square tests were used to compare group medians and proportions, respectively; p-values <0.05 were considered statistically significant. Data were analyzed using R software (version 4.1.2; R Foundation). This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.^†††

Among 5,116,024 adults aged ≥18 years with an initial positive NAAT result or diagnosis of COVID-19, 51,609 patients were hospitalized with COVID-19–like illness associated with a NAAT result >90 days after the previous infection,^§§§ including 5,048 (9.8%) with a positive NAAT result. Among these 5,048 case-patients, 2,436 (48.3%; median = 67 reinfections per week) were admitted during the Delta-predominant period, and 2,612 (51.7%; median = 343 reinfections per week) during the Omicron-predominant period (Supplementary Figure, https://stacks.cdc.gov/view/cdc/116026).

After 7,569 patients were excluded, 11,283 of 44,040 eligible patients were matched and included in the analysis, 3,761 (87.1%) of 4,319 eligible case-patients and 7,522 (18.9%) of 39,721 eligible control-patients. Case- and control-patients were demographically similar, with fewer underlying conditions and previous health care encounters among case-patients (Table 1). Overall, 61.2% of case-patients were unvaccinated, 4.3% had received 1 vaccine dose, 27.6% had received 2 doses, and 6.9% had received a booster dose, compared with 47.5%, 5.5%, 33.2%, and 13.9% of control-patients, respectively.

During the Delta-predominant period, estimated adjusted VE was 58.8% (95% CI = 41.3%–71.1%) after dose 1, 47.5% (95% CI = 38.8%–54.9%) after dose 2, and 57.8% (95% CI = 32.1%–73.8%) after a booster dose; during the Omicron-predominant period, adjusted VE was 33.0% (95% CI = 15.0%–47.2%) after dose 1, 34.6% (95% CI = 25.5%–42.5%) after dose 2, and 67.6% (95% CI = 61.4%–72.8%) after a booster dose (Table 2). VE estimates were similar whether hospitalizations were <90 days or ≥90 days after the most recent vaccine dose. Similar estimates were obtained in a sensitivity analysis that included 2,146 case-patients and 4,887 control-patients with previous infection confirmed by NAAT (Supplementary Table, https://stacks.cdc.gov/view/cdc/116025).

During the analysis period, among persons who had a previous positive NAAT result or COVID-19 diagnosis before the first vaccine dose, estimated VE was 43.1% (95% CI = 30.7%–53.2%) after dose 1, 41.7% (95% CI = 35.5%–47.3%) after dose 2, and 70.3% (95% CI = 64.1%–75.4%) after a booster dose (Table 3). Among persons whose initial infection occurred between dose 2 and a booster dose, VE after the booster dose was 50.0% (95% CI = 26.9%–65.8%). Estimated VE of a booster dose was similar among persons aged <65 years (67.7%; 95% CI = 57.7%–75.3%) and ≥65 years (64.5%; 95% CI 56.0%–71.4%). Relative VE of a booster dose compared with ≥5 months after dose 2 was 55.9% (95% CI = 43.6%–65.5%).

Acknowledgments

Caleb Cox, Joseph Deckert, Joseph Haddock, Paul Jacobs, Epic Research, Epic Systems Corporation, Verona, Wisconsin; Adi Gundlapalli, Ruth Link-Gelles, Claire Midgley, Tamara Pilishvili, Heather Scobie, CDC.

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

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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.