Laboratory-Confirmed COVID-19 Among Adults Hospitalized with COVID-19–Like Illness with Infection-Induced or mRNA Vaccine-Induced SARS-CoV-2 Immunity — Nine States, January–September 2021

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Previous infection with SARS-CoV-2 (the virus that causes COVID-19) or COVID-19 vaccination can provide immunity and protection from subsequent SARS-CoV-2 infection and illness. CDC used data from the VISION Network* to examine hospitalizations in adults with COVID-19–like illness and compared the odds of receiving a positive SARS-CoV-2 test result, and thus having laboratory-confirmed COVID-19, between unvaccinated patients with a previous SARS-CoV-2 infection occurring 90–179 days before COVID-19–like illness hospitalization, and patients who were fully vaccinated with an mRNA COVID-19 vaccine 90–179 days before hospitalization with no previous documented SARS-CoV-2 infection. Hospitalized adults aged ≥18 years with COVID-19–like illness were included if they had received testing at least twice: once associated with a COVID-19–like illness hospitalization during January–September 2021 and at least once earlier (since February 1, 2020, and ≥14 days before that hospitalization). Among COVID-19–like illness hospitalizations in persons whose previous infection or vaccination occurred 90–179 days earlier, the odds of laboratory-confirmed COVID-19 (adjusted for sociodemographic and health characteristics) among unvaccinated, previously infected adults were higher than the odds among fully vaccinated recipients of an mRNA COVID-19 vaccine with no previous documented infection (adjusted odds ratio [aOR] = 5.49; 95% confidence interval [CI] = 2.75–10.99). These findings suggest that among hospitalized adults with COVID-19–like illness whose previous infection or vaccination occurred 90–179 days earlier, vaccine-induced immunity was more protective than infection-induced immunity against laboratory-confirmed COVID-19. All eligible persons should be vaccinated against COVID-19 as soon as possible, including unvaccinated persons previously infected with SARS-CoV-2.

To compare the early protection against COVID-19 conferred by SARS-CoV-2 infection and by receipt of mRNA COVID-19 vaccines (i.e., 90–179 days after infection or vaccination), the VISION Network collected data from 187 hospitals across nine states during January–September 2021 (1). Eligible hospitalizations were defined as those among adults aged ≥18 years who had received SARS-CoV-2 molecular testing (from 14 days before to 72 hours after admission) and had a COVID-19–like illness discharge diagnosis^† during January–September 2021. Eligible patients had also been tested at least once since February 1, 2020. To limit the analysis to patients with access to SARS-CoV-2 testing before hospitalization, patients who did not receive SARS-CoV-2 testing ≥14 days before hospitalization were excluded.

Two exposure groups were defined based on COVID-19 vaccination status and previous SARS-CoV-2 infection. Vaccination status was documented in electronic health records and immunization registries. Previous infection was ascertained based on SARS-CoV-2 testing from rapid antigen tests or molecular assays (e.g., real-time reverse transcription–polymerase chain reaction) performed before mRNA vaccination and ≥14 days before admission; testing performed after February 2020 was primarily within network partners’ medical facilities. Adults were considered unvaccinated with a previous SARS-CoV-2 infection if no COVID-19 vaccine doses were received and if the most recent positive SARS-CoV-2 test result occurred ≥90 days before hospitalization. Adults were considered fully vaccinated with an mRNA COVID-19 vaccine with no previous documented infection if the second dose of Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) mRNA vaccine was received ≥14 days before the index test date^§ and if they had been tested since February 1, 2020, and had no positive test results ≥14 days before hospitalization. Patients were excluded if they had received 1 mRNA vaccine dose only, received the second dose <14 days before index test date, or received the Janssen (Johnson & Johnson [Ad26.COV2]) vaccine (because of sparse data). To reduce the chance that the hospitalization was related to an ongoing SARS-CoV-2 infection, patients were also excluded from the previous infection group if their most recent previous positive test result occurred 14–89 days before hospitalization.^¶

The outcome of laboratory-confirmed COVID-19 was defined as COVID-19–like illness and a positive SARS-CoV-2 result from molecular testing. Among patients hospitalized with COVID-19–like illness whose previous infection or completion of vaccination occurred 90–179 days earlier, the odds of laboratory-confirmed COVID-19 were compared between previously infected persons and fully vaccinated mRNA COVID-19 vaccine recipients. aORs and 95% CIs were calculated using multivariable logistic regression, adjusted for age, geographic region, calendar time (days from January 1 to hospitalization), and local virus circulation, and weighted based on propensity to be in the vaccinated category (1,2). Established methods were used to calculate weights to account for differences in sociodemographic and health characteristics between groups (3). Separate weights were calculated for each model. aORs were stratified by mRNA vaccine product and age group.

Three secondary analyses were also conducted. First, the impact of whether and how the time interval since previous infection or full vaccination was adjusted was examined. Specifically, any time since either previous infection or completion of vaccination was considered. Then, previously infected patients were limited to those with more recent infections (i.e., 90–225 days before hospitalization [the lowest two tertiles of number of days since infection]), and fully vaccinated patients were limited to those with the longest interval since completion of vaccination (i.e., receipt of second mRNA vaccine dose 45–213 days before hospitalization [the highest two tertiles of number of days since vaccination]). Then, number of days since previous infection or completion of vaccination, rather than calendar time, was adjusted in the model. For the next secondary analysis, aORs for hospitalizations that occurred before and during SARS-CoV-2 B.1.617.2 (Delta) variant predominance (June–September 2021) were compared, beginning on the date the Delta variant accounted for >50% of sequenced isolates in each medical facility’s state (2). Finally, effect modification was assessed by mRNA vaccine product or by age group; p-values <0.2 were considered indicative of a statistically significant difference in aOR by product or age, similar to previous modeling studies of effect modification (4). All analyses were conducted using SAS (version 9.4; SAS Institute) and R (version 4.0.2; R Foundation). This study was reviewed and approved by Westat, Inc. institutional review board.**

During January 1–September 2, 2021, a total of 201,269 hospitalizations for COVID-19–like illness were identified; 139,655 (69.4%) patients were hospitalized after COVID-19 vaccines were generally available to persons in their age group within their geographic region. Molecular testing for SARS-CoV-2 was performed for 94,264 (67.5%) patients with COVID-19–like illness hospitalizations. Among these patients, 7,348 (7.8%) had at least one other SARS-CoV-2 test result ≥14 days before hospitalization and met criteria for either of the two exposure categories: 1,020 hospitalizations were among previously infected and unvaccinated persons, and 6,328 were among fully vaccinated and previously uninfected patients (Table 1).

Laboratory-confirmed SARS-CoV-2 infection was identified among 324 (5.1%) of 6,328 fully vaccinated persons and among 89 of 1,020 (8.7%) unvaccinated, previously infected persons. A higher proportion of previously infected than vaccinated patients were aged 18–49 years (31% versus 9%), Black (10% versus 7%), and Hispanic (19% versus 12%).

Among COVID-19–like illness hospitalizations in persons whose previous infection or vaccination occurred 90–179 days earlier, the odds of laboratory-confirmed COVID-19 were higher among previously infected, unvaccinated patients than among fully vaccinated patients (aOR = 5.49; 95% CI = 2.75–10.99) (Table 2). In secondary analyses, the aORs that examined the impact of whether and how time since infection or vaccination was adjusted and that stratified hospitalizations before and during Delta variant predominance were all similar to the primary aOR estimate. For product- and age group–specific estimates, sparse data limited the precision of these aORs. However, an assessment of effect modification indicated the aOR of laboratory-confirmed COVID-19 was higher for previously infected patients compared with patients vaccinated with Moderna (aOR = 7.30) than compared with patients vaccinated with Pfizer-BioNTech (aOR = 5.11) during January–September (p = 0.02). Similarly, the interaction term for exposure group by age indicated that the aOR was higher for patients aged ≥65 years (aOR = 19.57) than for those aged 18–64 years (aOR = 2.57) (interaction term, p = 0.05).

Acknowledgments

Jefferson Jones, Claire Midgley, Ruth Link-Gelles, Sharon Saydah, Jerome Tokars, Adi Gundlapalli, Natalie Thornburg, Abigail Shefer, John Kools, Erin Tromble, Melissa Carter, Cory Kokko, Stephanie Weaver, Kuzhali Muthumalaiappan, Bao-Ping Zhu, Roumiana Boneva, CDC.

Corresponding author: Catherine H. Bozio, [email protected].

¹CDC COVID-19 Response Team; ²Center for Biomedical Informatics, Regenstrief Institute, Indianapolis, Indiana; ³Indiana University School of Medicine, Indianapolis, Indiana; ⁴Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon; ⁵Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado; ⁶Westat, Rockville, Maryland; ⁷HealthPartners Institute, Minneapolis, Minnesota; ⁸Department of Biomedical Informatics, Columbia University, New York, New York; ⁹New York Presbyterian Hospital, New York City, New York; ¹⁰Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California, Oakland, California; ¹¹Fairbanks School of Public Health, Indiana University, Indianapolis, Indiana; ¹²Division of Infectious Diseases and Clinical Epidemiology, Intermountain Healthcare, Salt Lake City, Utah; ¹³Baylor Scott & White Health, Texas A&M University College of Medicine, Temple, Texas; ¹⁴Children’s Minnesota, Minneapolis, Minnesota; ¹⁵Regenstrief Institute, Indianapolis, Indiana.

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Abbreviation: NA = not applicable.
* Medical events with a discharge code consistent with COVID-19–like illness were included. 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, Ninth Revision and International Classification of Diseases, Tenth Revision. Clinician-ordered molecular assays (e.g., real-time reverse transcription–polymerase chain reaction) for SARS-CoV-2 occurring ≤14 days before to <72 hours after hospital admission were included.
^† Index test date was defined as the date of respiratory specimen collection associated with the most recent positive or negative SARS-CoV-2 test result before the hospitalization or the hospitalization date if testing only occurred after the admission.
^§ Full vaccination was defined as receipt of the second dose of Pfizer-BioNTech or Moderna mRNA vaccine ≥14 days before the index test date.
^¶ Partners contributing hospitalizations were in California, Colorado, Indiana, Minnesota and Wisconsin, Oregon and Washington, Utah, and New York.
** In comparing characteristics between unvaccinated adults with a previous infection and fully vaccinated adults without a previous documented infection, a standardized mean or proportion difference >0.2 was considered noteworthy. After balancing characteristics that differed between the two comparison groups, the standardized mean or proportion differences were ≤0.06.
^†† Other race includes Asian, Hawaiian or Other Pacific islander, American Indian or Alaskan Native, Other not listed, and multiple races.

Abbreviations: CI = confidence interval; ref = referent group.
* Odds ratios were adjusted for age, geographic region, calendar time (days since January 1, 2021), and local virus circulation (percentage of SARS-CoV-2 positive results from testing within the counties surrounding the facility on the date of the hospitalization) and balanced using inverse weights on characteristics that differed between the two groups (calculated separately for each odds ratio model) using facility characteristics, sociodemographic characteristics, and underlying medical conditions. Cardiovascular disease was also adjusted in the main model and in the model for Pfizer-BioNTech. Any likely immunosuppression was also included in the model for Moderna. Neuromuscular and respiratory conditions were also adjusted in the model for adults aged ≥65 years. Number of days since previous infection or completion of vaccination, instead of calendar time, was adjusted in the model within the stated secondary analysis.
^† Full vaccination was defined as receipt of the second dose of Pfizer-BioNTech or Moderna mRNA vaccine ≥14 days before the index test date.
^§ P-value from assessment of effect modification by mRNA product was 0.02.
^¶ P-value for interaction term for exposure group by age group was 0.05.
** SARS-CoV-2 B.1.617.2 (Delta) variant predominance began on the date the Delta variant accounted for >50% of sequenced isolates in each medical facility’s state. https://doi.org/10.15585/mmwr.mm7037e2