TABLE 3. Estimated vaccine effectiveness against hospitalization with COVID-19 after previous SARS-CoV-2 infection* among persons with initial infection occurring before the first vaccine dose, and by age group —United States, June 2021–February 2022.

Characteristic	No. of case-patients† (N = 3,761)	No. of control-patients† (N = 7,522)	VE (95% CI)§
			Unadjusted	Adjusted
Infection before dose 1
Unvaccinated (Ref)	2,304	3,581	—	—
Any mRNA vaccine, 1 dose¶,**	161	412	42.5 (30.2–52.7)	43.1 (30.7–53.2)
Any mRNA vaccine, 2 doses¶,**	960	2,356	39.1 (32.9–44.7)	41.7 (35.5–47.3)
Any mRNA vaccine, booster dose¶,**	183	777	67.6 (61.1–73.0)	70.3 (64.1–75.4)
Age ≥65 yrs
Unvaccinated (Ref)	823	1,196	—	—
Any mRNA vaccine, 1 dose	72	163	35.3 (11.6–52.6)	35.7 (11.9–53.1)
Any mRNA vaccine, 2 doses	520	1,167	33.5 (23.0–42.6)	33.4 (22.4–42.9)
Any mRNA vaccine, booster dose	169	659	64.9 (56.6–71.6)	64.5 (56.0–71.4)
Age <65 yrs
Unvaccinated (Ref)	1,480	2,375	—	—
Any mRNA vaccine, 1 dose	89	250	46.0 (29.6–58.6)	45.7 (28.9–58.5)
Any mRNA vaccine, 2 doses	518	1,329	40.3 (32.0–47.6)	41.9 (33.5–49.2)
Any mRNA vaccine, booster dose	90	383	66.1 (55.9–74.0)	67.7 (57.7–75.3)

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.