Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance — VISION Network, 10 States, August 2021–January 2022

Estimates of COVID-19 mRNA vaccine effectiveness (VE) have declined in recent months (1,2) because of waning vaccine induced immunity over time,* possible increased immune evasion by SARS-CoV-2 variants (3), or a combination of these and other factors. CDC recommends that all persons aged ≥12 years receive a third dose (booster) of an mRNA vaccine ≥5 months after receipt of the second mRNA vaccine dose and that immunocompromised individuals receive a third primary dose.† A third dose of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine increases neutralizing antibody levels (4), and three recent studies from Israel have shown improved effectiveness of a third dose in preventing COVID-19 associated with infections with the SARS-CoV-2 B.1.617.2 (Delta) variant (5-7). Yet, data are limited on the real-world effectiveness of third doses of COVID-19 mRNA vaccine in the United States, especially since the SARS-CoV-2 B.1.1.529 (Omicron) variant became predominant in mid-December 2021. The VISION Network§ examined VE by analyzing 222,772 encounters from 383 emergency departments (EDs) and urgent care (UC) clinics and 87,904 hospitalizations from 259 hospitals among adults aged ≥18 years across 10 states from August 26, 2021¶ to January 5, 2022. Analyses were stratified by the period before and after the Omicron variant became the predominant strain (>50% of sequenced viruses) at each study site. During the period of Delta predominance across study sites in the United States (August-mid-December 2021), VE against laboratory-confirmed COVID-19-associated ED and UC encounters was 86% 14-179 days after dose 2, 76% ≥180 days after dose 2, and 94% ≥14 days after dose 3. Estimates of VE for the same intervals after vaccination during Omicron variant predominance were 52%, 38%, and 82%, respectively. During the period of Delta variant predominance, VE against laboratory-confirmed COVID-19-associated hospitalizations was 90% 14-179 days after dose 2, 81% ≥180 days after dose 2, and 94% ≥14 days after dose 3. During Omicron variant predominance, VE estimates for the same intervals after vaccination were 81%, 57%, and 90%, respectively. The highest estimates of VE against COVID-19-associated ED and UC encounters or hospitalizations during both Delta- and Omicron-predominant periods were among adults who received a third dose of mRNA vaccine. All unvaccinated persons should get vaccinated as soon as possible. All adults who have received mRNA vaccines during their primary COVID-19 vaccination series should receive a third dose when eligible, and eligible persons should stay up to date with COVID-19 vaccinations.

On January 21, 2022, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr).
Estimates of COVID-19 mRNA vaccine effectiveness (VE) have declined in recent months (1,2) because of waning vaccine induced immunity over time,* possible increased immune evasion by SARS-CoV-2 variants (3), or a combination of these and other factors. CDC recommends that all persons aged ≥12 years receive a third dose (booster) of an mRNA vaccine ≥5 months after receipt of the second mRNA vaccine dose and that immunocompromised individuals receive a third primary dose. † A third dose of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine increases neutralizing antibody levels (4), and three recent studies from Israel have shown improved effectiveness of a third dose in preventing COVID-19 associated with infections with the SARS-CoV-2 B.1.617.2 (Delta) variant (5)(6)(7). Yet, data are limited on the real-world effectiveness of third doses of COVID-19 mRNA vaccine in the United States, especially since the SARS-CoV-2 B.1.1.529 (Omicron) variant became predominant in mid-December 2021. The VISION Network § examined VE by analyzing 222,772 encounters from 383 emergency departments (EDs) and urgent care (UC) clinics and 87,904 hospitalizations from * https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3961378 † CDC initially recommended a third dose of mRNA vaccine for all adults 6 months after receipt of the second mRNA COVID-19 vaccine dose. On January 4, 2022, CDC amended the interval to 5 months after receipt of the second dose for recipients of the BNT162b2 (Pfizer-BioNTech) vaccine. On January 7, 2022, CDC amended the interval to 5 months for recipients of the mRNA-1273 (Moderna) vaccine. CDC recommends the Pfizer-BioNTech booster at 5 months, and an additional primary dose for certain immunocompromised persons aged ≥5 years (https://www.cdc.gov/coronavirus/2019-ncov/vaccines/ recommendations/immuno.html). CDC  259 hospitals among adults aged ≥18 years across 10 states from August 26, 2021 ¶ to January 5, 2022. Analyses were stratified by the period before and after the Omicron variant became the predominant strain (>50% of sequenced viruses) at each study site. During the period of Delta predominance across study sites in the United States (August-mid-December 2021), VE against laboratory-confirmed COVID-19-associated ED and UC encounters was 86% 14-179 days after dose 2, 76% ≥180 days after dose 2, and 94% ≥14 days after dose 3. Estimates of VE for the same intervals after vaccination during Omicron variant predominance were 52%, 38%, and 82%, respectively. During the period of Delta variant predominance, VE against laboratory-confirmed COVID-19-associated hospitalizations was 90% 14-179 days after dose 2, 81% ≥180 days after dose 2, and 94% ≥14 days after dose 3. During Omicron variant predominance, VE estimates for the same intervals after vaccination were 81%, 57%, and 90%, respectively. The highest estimates of VE against COVID-19-associated ED and UC encounters or hospitalizations during both Delta-and Omicron-predominant periods were among adults who received a third dose of mRNA vaccine. All unvaccinated persons should get vaccinated as soon as possible. All adults who have received mRNA vaccines during their primary COVID-19 vaccination series should receive a third dose when eligible, and eligible persons should stay up to date with COVID-19 vaccinations.
VISION Network methods have been previously published (1,8,9). In brief, eligible medical encounters were defined as those among adults aged ≥18 years with a COVID-19-like illness diagnosis** who had received molecular testing (primarily reverse transcription-polymerase chain reaction assay) for ¶ The study period at Baylor Scott & White Health began on September 11, 2021. ** 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  (9). VE was estimated using a test-negative design, comparing the odds of a positive SARS-CoV-2 test result between vaccinated and unvaccinated patients using multivariable logistic regression models, as previously described ¶ ¶ (1,8,9). Vaccination status was categorized based on the number of vaccine doses received and number of days from vaccination to the index medical encounter date.*** Potential effect modification by vaccine product, age group (aged 18-64 years versus ≥65 years), and immunocompromised status (for whom a third dose is the last dose in their primary series) was assessed by adding interaction terms for vaccination by these covariates to the regression model. Effect modification was only examined for medical encounters during the Delta period of predominance, given relatively sparse data during the Omicron period. A statistically significant difference was indicated by a p-value <0.01 for an interaction term, 95% CI that did not overlap, or standardized mean or proportion differences ≥0.2 indicating nonnegligible difference in distributions of vaccination or infection status (9). This study was reviewed and approved by the institutional review boards at participating sites or under a reliance agreement with the Westat, Inc. institutional review board. † † † † † h t t p s : / / w w w. f d a . g o v / n e w s -e v e n t s / p r e s s -a n n o u n c e m e n t s / coronavirus-covid-19-update-fda-authorizes-additional-vaccine-dosecertain-immunocompromised § § Immunocompromising conditions were derived from lists used in previous studies of large hospital-based or administrative databases and included the following conditions: 1) solid malignancies, 2) hematologic malignancies, 3) rheumatologic or inflammatory disorders, 4) other intrinsic immune conditions or immunodeficiencies, and 5) organ or stem cell transplants. ¶ ¶ With a test-negative design, vaccine performance is assessed by comparing the odds of antecedent vaccination among case-patients with acute laboratory-confirmed COVID-19 and control-patients without acute COVID-19. This odds ratio was adjusted for age, geographic region, calendar time (days from August 26, 2021), and local virus circulation in the community and weighted for inverse propensity to be vaccinated or unvaccinated (calculated separately for each vaccine exposure group). *** 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 admission. † † † 45 C.F.R. part 46; 21 C.F.R. part 56.
Among 222,772 eligible ED or UC encounters, 204,745 (92%) and 18,027 (8%) occurred during the Delta-and Omicron-predominant periods, respectively (Table 1). A higher percentage of Hispanic, non-Hispanic Black, persons of unknown race/ethnicity, and adults aged <65 years were unvaccinated or had not received a third COVID-19 vaccine dose; adults aged <65 years were more likely to have received a positive SARS-CoV-2 test result. Among persons with COVID-19-like illness seeking care at ED or UC facilities who had received the second dose <180 days earlier and ≥180 days earlier, the median interval since receipt of the second dose was 137 days and 223 days, respectively. Among those who had received the third dose ≥14 days earlier, the median interval since receipt of that dose was 44 days. During the Delta-predominant period, VE against laboratoryconfirmed COVID-19-associated ED and UC encounters was significantly lower among patients who had received the second vaccine dose ≥180 days earlier (76%) than it was among those who had received the dose 14-179 days earlier (86%); VE among those who had received the third mRNA COVID-19 vaccine dose was 94% (Table 2). VE after receipt of the third dose was lower among the 4% of patients with immunocompromised status (74%; 95% CI = 65%-80%) versus those without (95%; 95% CI = 94%-95%) (p<0.001) (CDC, unpublished data, 2022). During the period of Omicron predominance, the pattern was similar, although all VE estimates were significantly lower. VE against COVID-19associated ED and UC encounters 14-179 days after receipt of dose 2 was 52%, and at ≥180 days after dose 2 was 38%. VE after receipt of 3 vaccine doses among all adults was 82%.
Among 87,904 eligible hospitalizations, 86,327 (98%) and 1,577 (2%) occurred during the Delta-and Omicronpredominant periods, respectively (Table 3). Hospitalized adults aged <65 years or who were Hispanic, non-Hispanic Black, unknown race/ethnicity, or who did not have chronic nonrespiratory medical conditions were more likely to be unvaccinated or, if vaccinated, less likely to have received a third vaccine dose. In addition, adults aged <65 years and those without chronic nonrespiratory conditions were more likely to have received a positive SARS-CoV-2 test result. Among persons hospitalized with COVID-19-like illness who had received the second mRNA COVID-19 vaccine dose <180 days earlier and ≥180 days earlier, the median interval since receipt of the second dose was 144 days and 222 days, respectively. Among those who had received the third dose ≥14 days earlier, the median interval since receipt of that dose was 41 days. During Delta predominance, VE against laboratory-confirmed COVID-19-associated hospitalization was 90% among persons who had received the second dose 14-179 days earlier, 81% among those who had received it ≥180 days earlier, and 94% among persons who had received a third dose ≥14 days earlier (Table 2). VE after receipt of the third dose was lower among the 21% of patients with immunocompromised status (83%; 95% CI = 78%-87%) versus among those without (96%; 95% CI = 95%-97%) (p = 0.001) (CDC, unpublished data, 2022). During Omicron predominance, VE against COVID-19-associated hospitalization was 81% among 2-dose recipients who had received the second dose 14-179 days earlier, 57% among those who had received it ≥180 days earlier, and 90% at ≥14 days after receipt of a third dose. VE estimates for patients who received dose 2 ≥180 days earlier significantly declined during Omicron predominance compared with estimates during Delta predominance.

Discussion
In a multistate analysis of 222,772 ED and UC encounters and 87,904 hospitalizations among adults with COVID-19-like illness during August 26, 2021-January 5, 2022, estimates of VE against laboratory-confirmed COVID-19 declined during the Omicron-predominant period compared with VE during the Delta-predominant period. During both periods, VE was significantly lower among patients who received their second mRNA COVID-19 vaccine dose ≥180 days before the medical
* 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 the encounter date were included. Recipients of Janssen, 1 or >3 doses of an mRNA vaccine, and those for whom 1-13 days had elapsed since receipt of any dose were excluded. † Vaccination was defined as having received the listed number of doses of an mRNA-based COVID-19 vaccine ≥14 days before the medical event index date, which was the date of respiratory specimen collection associated with the most recent positive or negative SARS-CoV-2 test result before the medical event or the admission date if testing only occurred after the admission.  encounters compared with those vaccinated more recently. VE increased following a third dose and was highly effective during both the Delta-and Omicron-predominant periods at preventing COVID-19-associated ED and UC encounters (94% and 82%, respectively) and preventing COVID-19-associated hospitalizations (94% and 90%, respectively). Estimates of VE for 2 doses of an mRNA vaccine were higher against COVID-19-associated hospitalizations than against COVID-19-associated ED or UC encounters, especially during the Omicron period, which is consistent with possible vaccine attenuation of severity of COVID-19 disease but was not observed in this network previously (1,8). This study also found that immunocompromised adults had lower third dose VE against COVID-19-associated ED and UC encounters and hospitalization, which is consistent with trends observed for VE following a second dose (9) and is consistent with recommendations for a booster dose for this group 5 months after the additional primary dose. § § § The findings in this report are subject to at least seven limitations. First, VE estimates from this study do not include COVID-19-associated outpatient visits or non-medically attended COVID-19. Second, the median interval from receipt of dose 3 to medical encounters was 41-44 days; thus, the observed performance of dose 3 is limited to a relatively short period after vaccination. Third, the reasons for the decline in § § § CDC recommends that all immunocompromised persons receive a booster dose of either  and weighted for inverse propensity to be vaccinated or unvaccinated (calculated separately for each VE estimate). Generalized boosted regression trees were used to estimate the propensity to be vaccinated based on sociodemographic characteristics, underlying medical conditions, and facility characteristics. † 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 admission were included. Recipients of Janssen, 1 or >3 doses of an mRNA vaccine, and those for whom 1-13 days had elapsed since receipt of any dose were excluded. § Vaccination status was documented in electronic health records and immunization registries and was defined as having received the listed number of doses of an mRNA-based COVID-19 vaccine ≥14 days before the medical event index date. Index 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 medical event or the admission date if testing only occurred after the admission. Threedose recipients include persons who received a third dose in their primary series or received an additional (booster) dose after their 2-dose primary series; this includes the reduced-dosage Moderna booster.