key: cord-1026924-ex9pf675
authors: Plumb, Ian D.; Feldstein, Leora R.; Barkley, Eric; Posner, Alexander B.; Bregman, Howard S.; Hagen, Melissa Briggs; Gerhart, Jacqueline L.
title: 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
date: 2022-04-15
journal: MMWR Morb Mortal Wkly Rep
DOI: 10.15585/mmwr.mm7115e2
sha: 010756cafa92a764c2775cea78d61fa8ba183f88
doc_id: 1026924
cord_uid: ex9pf675

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.

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 § Cosmos is an aggregated EHR data platform of participating health systems that use software provided by Epic Systems Corporation that includes more than 135 million patients with similar demographics to U.S. Census data. Of 154 health systems included in the Cosmos dataset, 130 health systems that had data available since 2019 were included in the current analysis. https:// epicresearch.org/about-cosmos ¶ COVID-19-like illness diagnoses included acute respiratory illness (e.g., COVID-19, respiratory failure, or pneumonia) or related signs or symptoms (cough, fever, dyspnea, vomiting, or diarrhea) using diagnosis codes from the International Classification of Diseases, Tenth Revision. ** 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, and J12.82. A difference of >90 days was used consistent with the Council of State and Territorial Epidemiologists case definition of COVID-19: https://ndc.services.cdc.gov/case-definitions/coronavirus-disease-2019-2021/. † † 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; and after dose 2 if ≥14 days had elapsed since completion of a second mRNA vaccine dose, and no subsequent dose was received. To limit early additional doses (for example, among immunocompromised persons), patients were categorized as after booster if ≥14 days had elapsed since receipt of an mRNA booster dose administered ≥5 months after a second dose, and if no further doses had been received. 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 or COVID-19 diagnosis was after the most recent vaccine dose. In addition, if patients had more than one hospitalization-associated NAAT, they were considered a case-patient if their NAAT was positive at any point and were excluded from being a controlpatient, (i.e., cases-patients could not also serve as control-patients).

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 controlpatients. 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 § § Vaccination information for each patient was collected from four sources: 1) vaccine doses administered within the health system, 2) electronic health records, 3) vaccination information obtained from other health systems using a shared data platform, and 4) vaccination information obtained directly from a state or other vaccine registry. ¶ ¶ Characteristics were classified on the date of the NAAT associated with the hospital admission. 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%). § § § Among 25,641 patients with a positive NAAT >90 days after an initial positive SARS-CoV-2 NAAT or diagnosis of COVID-19 during June 20-December 31, 2021, 2,378 (9.3%) were admitted to a hospital with COVID-19-like illness between 10 days after and 3 days before the subsequent positive NAAT result, indicating reinfection with COVID-19-associated hospitalization. 

Among persons with previous SARS-CoV-2 infection or COVID-19 diagnosis, receipt of a COVID-19 mRNA vaccine provided protection against subsequent COVID-19 hospitalization. The highest level of protection was conferred by a booster vaccine dose, with similar VE during the Delta-and Omicron-predominant periods (approximately 60%-70%). In contrast, VE of 1 or 2 doses declined from 50%-60% during the Delta-predominant to approximately 35% during the Omicron-predominant period. Receiving a booster dose conferred protection even if the previous infection occurred after receipt of the second vaccine dose. Findings from this report indicate that SARS-CoV-2 reinfections leading to COVID-19-associated hospitalizations are preventable by COVID-19 vaccination.

Benefit of vaccination after previous SARS-CoV-2 infection was also indicated by an analysis of surveillance data from New York City that estimated approximately 50%-70% protection against hospitalization from reinfection (5). A case-control analysis using surveillance data from Brazil estimated 90% protection by 2 doses of Pfizer-BioNTech vaccine against hospitalization or death after reinfection (6); the high estimated VE might partly reflect recent vaccination in the context of potential decreased infection-induced immunity. The similar estimated benefit from 1 or 2 vaccine doses in preventing reinfection leading to hospitalization in the current study is consistent with evidence that vaccination elicits a more rapid immunologic response if preceded by a SARS-CoV-2 infection ¶ ¶ ¶ (7) . In the current analysis, a booster dose offered superior protection against reinfection leading to hospitalization. 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 ( Immunity from previous SARS-CoV-2 infection wanes over time (1, 8) and was lower against the Omicron variant compared with immunity against other virus variants (2). However, protection is estimated to have remained stable against SARS-CoV-2 reinfection leading to hospitalization or death (2) . Previous studies have indicated that, in general, protection by a hybrid of infectioninduced and vaccination-induced immunity is superior to that from either alone and is less likely to wane over time (1, 8) . Compared with unvaccinated persons without previous infection, persons with a booster dose of mRNA vaccine have been estimated to have 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. The findings in this report are subject to at least five limitations. First, underascertainment of vaccination status from available information would likely lead to an underestimation of VE, particularly if vaccinated control-patients were misclassified as unvaccinated; this might have led to lower estimated VE 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.

compared with similar analyses (5, 6, 9) . Second, generalizability might be limited by incomplete data or by missing data from persons who do not seek health care; however, Cosmos data are broadly representative of the U.S. population (4) . Third, several VE estimates were imprecise, with broad CIs; estimates should be interpreted with caution. Fourth, underascertainment of previous infection might have occurred because of dependence on EHR data; however, findings were similar when restricting analyses to case-patients with positive initial NAAT results, and the test-negative design for an endpoint of severe illness mitigates the risk for selection bias. Finally, there might be residual or unmeasured confounding by characteristics associated with exposure, vaccination, or hospitalization that were not recorded in the data set. An increasing proportion of the U.S. population has had SARS-CoV-2 infection † † † † and might be at risk for SARS-CoV-2 reinfection leading to hospitalization. In the current analysis, approximately 50% of these reinfections occurred during the Omicron-predominant period. Vaccination remains the safest strategy for preventing complications of SARS-CoV-2 infection. COVID-19 vaccination offers additional protection against reinfection leading to hospitalization, with a booster

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-19associated 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.

dose offering the highest level of protection. To prevent COVID-19-associated hospitalization, all eligible persons should stay up to date with vaccination, including those with previous SARS-CoV-2 infection.

SIREN Study Group. Protection against SARS-CoV-2 after Covid-19 vaccination and previous infection

Protection against the Omicron variant from previous SARS-CoV-2 infection

Science brief: SARS-CoV-2 infection-induced and vaccine-induced immunity

The Cosmos Collaborative: a vendor-facilitated electronic health record data aggregation platform

Reduced odds of SARS-CoV-2 reinfection after vaccination among New York City adults

Effectiveness of CoronaVac, ChAdOx1 nCoV-19, BNT162b2, and Ad26.COV2.S among individuals with previous SARS-CoV-2 infection in Brazil: a test-negative, case-control study

Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals following mRNA vaccination

Protection and waning of natural and hybrid COVID-19 immunity. medRxiv

The effect of misclassification on evaluating the effectiveness of influenza vaccines