Risk Factors for Severe COVID-19 Outcomes Among Persons Aged ≥18 Years Who Completed a Primary COVID-19 Vaccination Series — 465 Health Care Facilities, United States, December 2020–October 2021

Vaccination against SARS-CoV-2, the virus that causes COVID-19, is highly effective at preventing COVID-19-associated hospitalization and death; however, some vaccinated persons might develop COVID-19 with severe outcomes† (1,2). Using data from 465 facilities in a large U.S. health care database, this study assessed the frequency of and risk factors for developing a severe COVID-19 outcome after completing a primary COVID-19 vaccination series (primary vaccination), defined as receipt of 2 doses of an mRNA vaccine (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) or a single dose of JNJ-78436735 [Janssen (Johnson & Johnson)] ≥14 days before illness onset. Severe COVID-19 outcomes were defined as hospitalization with a diagnosis of acute respiratory failure, need for noninvasive ventilation (NIV), admission to an intensive care unit (ICU) including all persons requiring invasive mechanical ventilation, or death (including discharge to hospice). Among 1,228,664 persons who completed primary vaccination during December 2020-October 2021, a total of 2,246 (18.0 per 10,000 vaccinated persons) developed COVID-19 and 189 (1.5 per 10,000) had a severe outcome, including 36 who died (0.3 deaths per 10,000). Risk for severe outcomes was higher among persons who were aged ≥65 years, were immunosuppressed, or had at least one of six other underlying conditions. All persons with severe outcomes had at least one of these risk factors, and 77.8% of those who died had four or more risk factors. Severe COVID-19 outcomes after primary vaccination are rare; however, vaccinated persons who are aged ≥65 years, are immunosuppressed, or have other underlying conditions might be at increased risk. These persons should receive targeted interventions including chronic disease management, precautions to reduce exposure, additional primary and booster vaccine doses, and effective pharmaceutical therapy as indicated to reduce risk for severe COVID-19 outcomes. Increasing COVID-19 vaccination coverage is a public health priority.

Vaccination against SARS-CoV-2, the virus that causes COVID-19, is highly effective at preventing COVID-19associated hospitalization and death; however, some vaccinated persons might develop COVID-19 with severe outcomes † (1,2). Using data from 465 facilities in a large U.S. health care database, this study assessed the frequency of and risk factors for developing a severe COVID-19 outcome after completing a primary COVID-19 vaccination series (primary vaccination), defined as receipt of 2 doses of an mRNA vaccine (BNT162b2 ≥14 days before illness onset. Severe COVID-19 outcomes were defined as hospitalization with a diagnosis of acute respiratory failure, need for noninvasive ventilation (NIV), admission to an intensive care unit (ICU) including all persons requiring invasive mechanical ventilation, or death (including discharge to hospice). Among 1,228,664 persons who completed primary vaccination during December 2020-October 2021, a total of 2,246 (18.0 per 10,000 vaccinated persons) developed COVID-19 and 189 (1.5 per 10,000) had a severe outcome, including 36 who died (0.3 deaths per 10,000). Risk for severe outcomes was higher among persons who were aged ≥65 years, were immunosuppressed, or had at least one of six other underlying conditions. All persons with severe outcomes had at least one of these risk factors, and 77.8% of those who died had four or more risk factors. Severe COVID-19 outcomes after primary vaccination are rare; however, vaccinated persons who are aged ≥65 years, are immunosuppressed, or have other underlying conditions might be at increased risk. These persons should receive targeted interventions including chronic disease management, precautions to reduce exposure, additional primary and booster vaccine doses, and effective pharmaceutical therapy as indicated to reduce risk for severe COVID-19 outcomes. Increasing COVID-19 vaccination coverage is a public health priority.
Data from 465 facilities in the Premier Healthcare Database Special COVID-19 Release (PHD-SR) were analyzed. § Persons who completed primary vaccination (including those who might have received additional doses as part of their primary * These authors contributed equally to this report. † https://www.medrxiv.org/content/10.1101/2021.07.08.21259776v1 vaccination series, and booster vaccine doses) were included in the analysis. ¶ Persons with partial vaccination recorded in PHD-SR were excluded. COVID-19 was identified by querying all encounters in PHD-SR during March 2020-October 2021.** Severe outcomes were defined as any one of the following: diagnosis of acute respiratory failure, need for NIV, ICU admission, or death. † † The risk for COVID-19 § PHD-SR, formerly known as the PHD COVID-19 Database, is a large U.S. health care all-payor administrative database that includes inpatient and hospital-based outpatient (e.g., emergency department or clinic) health care encounters from >900 geographically diverse, nonprofit, nongovernmental, community, and teaching hospitals and health systems from rural and urban areas. PHD-SR represents approximately 20% of U.S. inpatient admissions. Of all reporting centers, 465 reported vaccination data during December 2020-October 2021 and were included in the study. Updated PHD-SR data are released every 2 weeks; data for this report were obtained from PHD-SR release date November 8, 2021. https://offers. premierinc.com/rs/381-NBB-525/images/PHD_COVID-19_White_Paper.pdf ¶ Completion of a primary vaccination series was defined as receipt of the second of 2 doses of an mRNA vaccination series (Pfizer-BioNTech or Moderna]) or a single dose of Janssen ≥14 days before onset of illness. Only vaccines with Food and Drug Administration (FDA) full or emergency use authorization were considered in this definition. The definition of persons who completed primary vaccination included persons who might have received either or both of additional doses as part of their primary vaccination series or booster vaccine doses after primary vaccination (1.2% received additional vaccine doses). Vaccination was collected using current procedural terminology (CPT) codes (0001A and 002A for first and second Pfizer-BioNTech doses, respectively, 0011A and 0012A for first and second Moderna doses, respectively, 0031A for Janssen vaccine) and standard charge codes (510771000010000 and 510771000020000 for first and second Pfizer-BioNTech doses, respectively, 510771000110000 and 510771000120000 for first and second Moderna doses, respectively, and 510771000310000 for Janssen vaccine). ** Inpatient and outpatient encounters for COVID-19 were identified based on primary or secondary diagnosis coding for COVID-19 (legacy coding with  (Figure 1). Compared with persons who received the Janssen vaccine, Pfizer-BioNTech recipients had similar odds of severe outcomes (aOR = 0.70; 95% CI = 0.39-1.26), whereas recipients of the Moderna vaccine had lower odds (aOR = 0.56; 95% CI = 0.32-0.98). Odds of severe outcomes did not differ significantly by sex, race/ ethnicity, time since primary vaccination, or whether infection occurred during the period of Delta variant predominance. Previous COVID-19 illness was associated with reduced odds of severe outcomes (aOR = 0.27; 95% CI = 0.09-0.84).
All persons with severe COVID-19 outcomes after primary vaccination had at least one of the eight risk factors identified as significant in the model. The frequency of having four or more risk factors increased with disease severity, ranging from 18.8% (386) among persons who had nonsevere outcomes, 56.9% (87) among survivors who had respiratory failure or were admitted to an ICU, to 77.8% (28) among persons who died. Among 36 persons who died, 15 (41.7%) had do-notresuscitate orders at the time of hospital admission (Figure 2).

Discussion
In this analysis of data from 465 U.S. health care facilities, severe COVID-19 outcomes (i.e., respiratory failure, ICU admission, or death) were rare among adults aged ≥18 years after primary vaccination. These findings are consistent with studies that have shown that COVID-19 vaccination lowers the likelihood of COVID-19-associated hospitalization and death (1,2). Risk for a severe COVID-19 outcome after primary vaccination was higher among persons aged ≥65 years, were immunosuppressed, or had one of six other underlying conditions; all persons with severe COVID-19 outcomes after primary vaccination had at least one risk factor. This study provides insight into the frequency of and risk factors for severe outcomes among persons who acquired COVID-19 after primary vaccination during periods of pre-Delta and Delta variant predominance; findings might not be applicable to the risk from SARS-CoV-2 B.1.1.529 (Omicron) variant or future variants.
In this study, age ≥65 years, immunosuppression, diabetes, and chronic kidney, cardiac, pulmonary, neurologic, and liver disease were associated with higher odds for severe COVID-19 outcomes; § § § all persons with severe COVID-19 outcomes after primary vaccination had at least one of these risk factors. § § § CDC's National Center for Chronic Disease Prevention and Health Promotion collects data on chronic disease in the U.S. population using a set of 124 indicators. https://www.cdc.gov/mmwr/pdf/rr/rr6401.pdf (Accessed December 12, 2021).

Summary
What is already known about this topic?
What is added by this report?
Among 1,228,664 persons who completed primary vaccination during December 2020-October 2021, severe COVID-19-associated outcomes (0.015%) or death (0.0033%) were rare. Risk factors for severe outcomes included age ≥65 years, immunosuppressed, and six other underlying conditions. All persons with severe outcomes had at least one risk factor; 78% of persons who died had at least four.
What are the implications for public health practice?
Vaccinated persons who are older, immunosuppressed, or have other underlying conditions should receive targeted interventions including chronic disease management, precautions to reduce exposure, additional primary and booster vaccine doses, and effective pharmaceutical therapy to mitigate risk for severe outcomes. Increasing vaccination coverage is a critical public health priority.
These findings are consistent with those of previous studies of a largely prevaccination U.S. population (3) and a U.K. population predominantly vaccinated with ChAdOx1-SARS-COV-2 (AstraZeneca) vaccine (4). Approximately one half of U.S. adults have a major chronic disease that increases their risk for severe . Even after primary vaccination, a significant proportion of the population might remain at risk and require additional strategies to prevent severe COVID-19 outcomes.
Population-wide data have demonstrated that COVID-19 hospitalization and death are more frequent among Hispanic, non-Hispanic Black, and non-Hispanic American Indian or Alaska Native persons than among non-Hispanic White persons. ¶ ¶ ¶ This might be explained by higher levels of SARS-CoV-2 exposure, reduced access to care, and higher rates of uncontrolled underlying conditions experienced by these populations (6); however, this study did not find an association ¶ ¶ ¶ CDC collects data on risk for SARS-CoV-2 infection, hospitalization, and death by race/ethnicity from COVID-NET, a population-based surveillance system collecting data through a network of 250 acute-care hospitals across 14 states. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/ hospitalization-death-by-race-ethnicity.html (Accessed December 12, 2021). between race/ethnicity and severe COVID-19 outcomes after primary vaccination, suggesting that COVID-19 vaccines are important for helping to mitigate racial and ethnic disparities exacerbated by the COVID-19 pandemic. Several factors could contribute to severe outcomes in populations who are at risk, including suboptimal response to vaccination, waning immunity, and predisposition to severe disease. Persons who might not have mounted a protective immune response after initial vaccination might benefit from an additional primary dose (2). Booster vaccination after primary vaccination has been demonstrated to further reduce the risk for infection, particularly severe COVID-19 (7), and is recommended by CDC for all persons aged ≥18 years.**** Pharmaceutical therapies are also available for preventing and treating COVID-19 in at-risk populations. † † † † In addition, findings from this study complement data from clinical trials (8,9) suggesting that anti-SARS-CoV-2 monoclonal antibodies when appropriate might protect vaccinated persons with COVID-19 from experiencing severe outcomes.
The findings in this report are subject to at least five limitations. First, the reliance on procedure, diagnosis, and billing codes to define vaccination status, underlying conditions, and outcomes might have led to misclassification because of inaccurate or incomplete records. In addition, presence of underlying conditions might not be fully collected by administrative coding. Second, outcomes that occurred during COVID-19 encounters might have been related to other factors (e.g., diminished access to routine services for control of chronic diseases might have exacerbated severe outcomes in persons with comorbidities). Third, the components of the composite outcome are not necessarily of equal severity and results should be interpreted accordingly; the number of deaths alone was too small to allow analysis of risk factors in this subgroup. Fourth, persons with underlying conditions might be more likely to access health care, thereby disproportionately increasing COVID-19 risk estimates in this group compared with persons without underlying conditions. Finally, PHD-SR represents a convenience sample of health care facilities, limiting generalizability to the U.S. population.
With the emergence of novel variants of concern and development of additional therapeutic strategies, studies in vaccinated populations are vital to guide targeted guidelines and interventions for persons at risk for severe outcomes. COVID-19associated outcomes occurred in a small proportion of persons (0.015%) who had completed primary vaccination, all of whom were aged ≥65 years, immunosuppressed, or had other underlying conditions. Even when vaccinated, persons with identifiable risk factors should receive interventions including chronic disease management, precautions to reduce exposure, additional primary and booster vaccine doses, and effective pharmaceutical therapy as indicated to reduce risk for severe COVID-19-associated outcomes. Increasing COVID-19 vaccination coverage is a public health priority.