Effectiveness of a Third Dose of Pfizer-BioNTech and Moderna Vaccines in Preventing COVID-19 Hospitalization Among Immunocompetent and Immunocompromised Adults — United States, August–December 2021

COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) provide protection against infection with SARS-CoV-2, the virus that causes COVID-19, and are highly effective against COVID-19-associated hospitalization among eligible persons who receive 2 doses (1,2). However, vaccine effectiveness (VE) among persons with immunocompromising conditions* is lower than that among immunocompetent persons (2), and VE declines after several months among all persons (3). On August 12, 2021, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for a third mRNA vaccine dose as part of a primary series ≥28 days after dose 2 for persons aged ≥12 years with immunocompromising conditions, and, on November 19, 2021, as a booster dose for all adults aged ≥18 years at least 6 months after dose 2, changed to ≥5 months after dose 2 on January 3, 2022 (4,5,6). Among 2,952 adults (including 1,385 COVID-19 case-patients and 1,567 COVID-19-negative controls) hospitalized at 21 U.S. hospitals during August 19-December 15, 2021, effectiveness of mRNA vaccines against COVID-19-associated hospitalization was compared between adults eligible for but who had not received a third vaccine dose (1,251) and vaccine-eligible adults who received a third dose ≥7 days before illness onset (312). Among 1,875 adults without immunocompromising conditions (including 1,065 [57%] unvaccinated, 679 [36%] 2-dose recipients, and 131 [7%] 3-dose [booster] recipients), VE against COVID-19 hospitalization was higher among those who received a booster dose (97%; 95% CI = 95%-99%) compared with that among 2-dose recipients (82%; 95% CI = 77%-86%) (p <0.001). Among 1,077 adults with immunocompromising conditions (including 324 [30%] unvaccinated, 572 [53%] 2-dose recipients, and 181 [17%] 3-dose recipients), VE was higher among those who received a third dose to complete a primary series (88%; 95% CI = 81%-93%) compared with 2-dose recipients (69%; 95% CI = 57%-78%) (p <0.001). Administration of a third COVID-19 mRNA vaccine dose as part of a primary series among immunocompromised adults, or as a booster dose among immunocompetent adults, provides improved protection against COVID-19-associated hospitalization.

COVID-19 mRNA vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) provide protection against infection with SARS-CoV-2, the virus that causes COVID-19, and are highly effective against COVID-19-associated hospitalization among eligible persons who receive 2 doses (1,2). However, vaccine effectiveness (VE) among persons with immunocompromising conditions* is lower than that among immunocompetent persons (2), and VE declines after several months among all persons (3). On August 12, 2021, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for a third mRNA vaccine dose as part of a primary series ≥28 days after dose 2 for persons aged ≥12 years with immunocompromising conditions, and, on November 19, 2021, as a booster dose for all adults aged ≥18 years at least 6 months after dose 2, changed to ≥5 months after dose 2 on January 3, 2022 (4,5,6). Among 2,952 adults (including 1,385 COVID-19 case-patients and 1,567 COVID-19-negative controls) hospitalized at 21 U.S. hospitals during August 19-December 15, 2021, effectiveness of mRNA vaccines against COVID-19-associated hospitalization was compared between adults eligible for but who had not received a third vaccine dose (1,251) and vaccine-eligible adults who received a third dose ≥7 days before illness onset (312 who received testing for SARS-CoV-2 were included in a VE analysis. The analysis start date of August 19, 2021, was one week after the EUA of a third dose for persons with immunocompromising conditions. VE against COVID-19 hospitalization was compared between two groups: 1) adults who had completed a 2-dose mRNA vaccination series and were eligible for but had not received a third dose † ; and 2) adults who were eligible for and had received a third dose ≥7 days before illness onset. VE was calculated for 2-dose and 3-dose recipients by comparing odds of antecedent vaccination between COVID-19 case-patients and control patients who † During the surveillance period, third doses were recommended ≥28 days after dose 2 if the patient had an immunocompromising condition to complete a primary series or at least 6 months after dose 2 as a booster dose if the patient did not have an immunocompromising condition. The booster dose for Moderna (0.25 mL) is one half the dose used for the primary series (0.5 mL). The third dose to complete a primary series in persons with immunocompromising conditions is the same as the first 2 doses (0.5 mL).
did not have COVID-19. Case-patients had COVID-19-like illness § and received positive SARS-CoV-2 test results by a nucleic acid amplification test (NAAT) or antigen test within 10 days of illness onset. Control patients were hospitalized with or without COVID-19-like illness and received negative SARS-CoV-2 test results by NAAT. Patients or their proxies were interviewed regarding patient demographic and clinical characteristics, and medical record searches were completed to collect information about chronic medical conditions. Information about receipt of prior COVID-19 vaccination doses, including dates, locations, and vaccine product received, was obtained through self-report and review of source documentation (including state vaccination registries, medical records, and vaccination cards). A patient was considered to be vaccinated if vaccination could be verified through source documentation or by self-report, including dates and location. Three vaccination groups were considered: 1) unvaccinated patients, who had received no COVID-19 vaccine doses before illness onset; 2) 2-dose mRNA vaccine recipients, who were eligible for but had not received a third vaccine dose or had received a third dose <7 days before illness onset; and 3) 3-dose mRNA vaccine recipients, who received a third dose ≥7 days before illness onset. Patients were excluded if they were admitted to the hospital ≤7 days after EUA authorization of a third dose, received one or more vaccine doses but did not qualify for inclusion in the 2-dose or 3-dose vaccine group, ¶ received a non-mRNA vaccine (e.g., Ad26.COV2.S [Janssen (Johnson & Johnson)]), or if verification of vaccination was pending.
VE against COVID-19-associated hospitalization was estimated using logistic regression, comparing the odds of being vaccinated versus being unvaccinated among case-patients and controls using the equation VE = 100 × (1 − adjusted odds ratio). The regression model included case-patient or control status as the outcome variable and an indicator vari¬able for vaccination group (unvaccinated, 2-dose recipient, or 3-dose recipient), and was adjusted for admission date, region of § COVID-19-like illness was defined as having one or more of the following: fever, cough, shortness of breath, loss of taste, loss of smell, use of respiratory support for the acute illness, or new pulmonary findings on chest imaging consistent with pneumonia. ¶ Patients were excluded if they received a third COVID-19 mRNA vaccine dose before the FDA EUA (before August 12, 2021 for patients with immunocompromising conditions or before September 22, 2021 for patients without immunocompromising conditions [when a single booster dose of the Pfizer-BioNTech vaccine was authorized]), were admitted to the hospital before ≤7 days had elapsed since EUA authorization (before August 19, 2021 for patients with immunocompromising conditions or before September 29, 2021 for patients without immunocompromising conditions) or received a third dose before recommended during the surveillance period (<28 days after dose 2 for patients with immunocompromising conditions or <180 days after dose 2 for patients without immunocompromising conditions). hospital (U.S. Department of Health and Human Services or U.S. Census Bureau), age group (18-49, 50-64, or ≥65 years), sex, and self-reported race and ethnicity. Separate models were generated for immunocompetent adults and adults with immunocompromising conditions. To compare VE among 2-dose versus 3-dose mRNA vaccine recipients, post hoc comparisons were performed with the pwcompare function in Stata with a two-sided significance threshold of p<0.05. Analyses were conducted using Stata software (version 16.0; StataCorp). This activity was determined to be public health surveillance by each participating site and CDC and was conducted consistent with applicable federal law and CDC policy.** During August 19-December 15, 2021, the IVY Network enrolled 4,094 adults aged ≥18 years. After excluding 1,142 patients (619 because they did not belong to an included vaccination group, 386 because the patients had received a non-mRNA vaccine or vaccination verification was incomplete, and 137 because they met other exclusion criteria), 2,952 hospitalized patients were included (1,385 case-patients and 1,567 non-COVID-19 controls). Among all participants, median age was 62 years, 49% of patients were female, 58% were non-Hispanic White, and 36% had an immunocompromising condition. Among the 1,385 case-patients, 931 (67%), 408 (29%), and 46 (3%) had received 0, 2, and 3 mRNA vaccine doses, respectively. Among 1,567 non-COVID-19 controls, 458 (29%), 843 (54%), and 266 (17%) had received 0, 2, and 3 mRNA vaccine doses, respectively. Among patients without immunocompromising conditions (Table 1), 2-and 3-dose recipients were similar in terms of age (median = 69 and 72 years, respectively) but differed in self-reported race/ ethnicity distribution (a higher percentage of non-Hispanic White persons were among 3-dose recipients; p = 0.008) and U.S. Census Bureau region of the admitting hospital (p = 0.030). Two-dose recipients were less likely to report working in health care settings (5%) than were 3-dose recipients (10%) (p = 0.023) and were more likely to be enrolled as a COVID-19 case-patient (31%) than were 3-dose recipients (8%) (p<0.001). Among patients with immunocompromising conditions (Table 2), 2-dose recipients were more likely to be enrolled as a case-patient (34%) than were 3-dose recipients (20%) (p<0.001). VE against COVID-19 hospitalization among adults without immunocompromising conditions was 82% (95% CI = 77%-86%) for 2 doses and 97% (95% CI = 95%-99%) for 3 doses (p<0.001) ( Table 3). VE against COVID-19 hospitalization among adults with immunocompromising conditions was 69% (95% CI = 57%-78%) for 2 doses and 88% (95% CI = 81%-93%) for 3 doses

No. of chronic medical condition types (IQR) 3 (2-4) 3 (2-4) 3 (3-4) 0.88 Self-reported previous laboratory-confirmed SARS-CoV-2 infection
33/324 (10) 38/572 (7) 12/181 (7) 1.00  Washington). § Three vaccination groups were included; unvaccinated patients received no COVID-19 vaccine doses before the date of current illness onset; 2-dose recipients received 2 doses of an mRNA COVID-19 vaccine with the second dose received ≥28 days before the date of illness onset; 3-dose recipients received 3 doses of vaccine to complete a primary vaccine series with ≥28 days between the second and third dose and ≥7 days between the date of dose 3 receipt and illness onset. ¶ Dose 3 received ≥28 days after dose 2. ** Comparisons were made between 2-dose and 3-dose recipient groups using Pearson's chi-square testing for categorical variables and the nonparametric Wilcoxon rank-sum test for continuous variables. † † Race and ethnic groups self-reported. § § LTCFs included residence in a nursing home, assisted living home, or rehab hospital or other subacute or chronic facility before the hospital admission.

Discussion
In a multistate network, adults vaccinated with 2 or 3 doses of a COVID-19 mRNA vaccine were protected against COVID-19-associated hospitalization. Significantly higher VE was observed in adults who received a third mRNA vaccine dose either as part of a primary vaccine series (immunocompromised persons) or as a booster dose (immunocompetent persons) compared with those who had received 2 doses. These findings underscore the importance of immunocompromised adults obtaining a third mRNA vaccine dose ≥28 days after the second vaccine dose and of immunocompetent adults receiving a third (booster) dose currently recommended ≥5 months after the second dose. § § † † The definition adapted from CDC definitions of moderately to severely immunocompromising conditions included having one or more of the following: active solid organ cancer (active cancer defined as treatment for the cancer or newly diagnosed cancer in the past 6 months), active hematologic cancer (such as leukemia, lymphoma, or myeloma), AIDS, congenital immunodeficiency syndrome, previous solid organ, stem cell, or bone marrow transplant, or active immunosuppressive medication use. § § https: //www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19vaccines-us.html This study was conducted during a period of SARS-CoV-2 Delta variant predominance (8). VE against the B.1.1.529 (Omicron) variant of SARS-CoV-2 might be lower than for other variants that have circulated widely, possibly because of immune evasion. Early evidence suggests that a third mRNA vaccine dose elicits markedly stronger neutralizing antibody responses to the Omicron variant compared with responses to 2 vaccine doses (9), and increases VE against severe disease following infection with the Omicron variant (10). The effectiveness of 3 doses of COVID-19 mRNA vaccines against a range of disease severity associated with the Omicron variant needs to be carefully evaluated in different populations.
The findings in this report are subject to at least six limitations. First, 2-dose and 3-dose vaccine recipients were similar in terms of most demographic and clinical characteristics but might have differed with respect to exposure risk for SARS-CoV-2 infection or risk factors for severe COVID-19. Therefore, residual or unmeasured confounding was possible. Second, VE associated with newly emergent variants, including Omicron, was not assessed. Third, VE was not assessed against SARS-CoV-2 infection or mild illness. Fourth, most 3-dose mRNA vaccine recipients were vaccinated within several weeks of enrollment and durability of protection will require future analysis. Fifth, VE associated with a fourth mRNA vaccine dose, recommended as a booster dose in immunocompromised individuals ≥5 months after dose 3, was not assessed. Finally, although medical centers in 18 states were included in the

Summary
What is already known about this topic?
For adults aged ≥18 years who received 2 doses of an mRNA COVID-19 vaccine, third doses are recommended. However, the associated benefits in preventing COVID-19 hospitalization are incompletely understood.
What is added by this report?
In a study of hospitalized adults, compared with receipt of 2 mRNA COVID-19 vaccine doses, receipt of a third dose increased vaccine effectiveness against hospitalization among adults without and with immunocompromising conditions, from 82% to 97% and from 69% to 88%, respectively.
What are the implications for public health practice?
Administration of a third COVID-19 mRNA vaccine dose as part of a primary series among immunocompromised adults, or as a booster dose among immunocompetent adults, provides improved protection against COVID-19-associated hospitalization.
analysis, patients might not be representative of the general U.S. population. Among adults with and without immunocompromising conditions who were eligible to receive a third dose of COVID-19 mRNA vaccine, third doses were found to increase protection beyond that of a 2-dose vaccination series for the prevention of COVID-19 hospitalization. Administration of a third COVID-19 mRNA vaccine dose as part of a primary series among immunocompromised adults, or as a booster dose among immunocompetent adults, provides improved protection against COVID-19 hospitalization.