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Item Effectiveness of 2, 3, and 4 COVID-19 mRNA Vaccine Doses Among Immunocompetent Adults During Periods when SARS-CoV-2 Omicron BA.1 and BA.2/BA.2.12.1 Sublineages Predominated — VISION Network, 10 States, December 2021–June 2022(Center for Disease Control, 2022-07-22) Link-Gelles, Ruth; Levy, Matthew E.; Gaglani, Manjusha; Irving, Stephanie A.; Stockwell, Melissa; Dascomb, Kristin; DeSilva, Malini B.; Reese, Sarah E.; Liao, I-Chia; Ong, Toan C.; Grannis, Shaun J.; McEvoy, Charlene; Patel, Palak; Klein, Nicola P.; Hartmann, Emily; Stenehjem, Edward; Natarajan, Karthik; Naleway, Allison L.; Murthy, Kempapura; Rao, Suchitra; Dixon, Brian E.; Kharbanda, Anupam B.; Akinseye, Akintunde; Dickerson, Monica; Lewis, Ned; Grisel, Nancy; Han, Jungmi; Barron, Michelle A.; Fadel, William F.; Dunne, Margaret M.; Goddard, Kristin; Arndorfer, Julie; Konatham, Deepika; Valvi, Nimish R.; Currey, J. C.; Fireman, Bruce; Raiyani, Chandni; Zerbo, Ousseny; Sloan-Aagard, Chantel; Ball, Sarah W.; Thompson, Mark G.; Tenforde, Mark W.; Epidemiology, Richard M. Fairbanks School of Public HealthThe Omicron variant (B.1.1.529) of SARS-CoV-2, the virus that causes COVID-19, was first identified in the United States in November 2021, with the BA.1 sublineage (including BA.1.1) causing the largest surge in COVID-19 cases to date. Omicron sublineages BA.2 and BA.2.12.1 emerged later and by late April 2022, accounted for most cases.* Estimates of COVID-19 vaccine effectiveness (VE) can be reduced by newly emerging variants or sublineages that evade vaccine-induced immunity (1), protection from previous SARS-CoV-2 infection in unvaccinated persons (2), or increasing time since vaccination (3). Real-world data comparing VE during the periods when the BA.1 and BA.2/BA.2.12.1 predominated (BA.1 period and BA.2/BA.2.12.1 period, respectively) are limited. The VISION network† examined 214,487 emergency department/urgent care (ED/UC) visits and 58,782 hospitalizations with a COVID-19-like illness§ diagnosis among 10 states during December 18, 2021-June 10, 2022, to evaluate VE of 2, 3, and 4 doses of mRNA COVID-19 vaccines (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) compared with no vaccination among adults without immunocompromising conditions. VE against COVID-19-associated hospitalization 7-119 days and ≥120 days after receipt of dose 3 was 92% (95% CI = 91%-93%) and 85% (95% CI = 81%-89%), respectively, during the BA.1 period, compared with 69% (95% CI = 58%-76%) and 52% (95% CI = 44%-59%), respectively, during the BA.2/BA.2.12.1 period. Patterns were similar for ED/UC encounters. Among adults aged ≥50 years, VE against COVID-19-associated hospitalization ≥120 days after receipt of dose 3 was 55% (95% CI = 46%-62%) and ≥7 days (median = 27 days) after a fourth dose was 80% (95% CI = 71%-85%) during BA.2/BA.2.12.1 predominance. Immunocompetent persons should receive recommended COVID-19 booster doses to prevent moderate to severe COVID-19, including a first booster dose for all eligible persons and second booster dose for adults aged ≥50 years at least 4 months after an initial booster dose. Booster doses should be obtained immediately when persons become eligible.Item Effectiveness of 2-Dose Vaccination with mRNA COVID-19 Vaccines Against COVID-19–Associated Hospitalizations Among Immunocompromised Adults — Nine States, January–September 2021(CDC, 2021-11) Embi, Peter J.; Levy, Matthew E.; Naleway, Allison L.; Patel, Palak; Gaglani, Manjusha; Natarajan, Karthik; Dascomb, Kristin; Ong, Toan C.; Klein, Nicola P.; Liao, I-Chia; Grannis, Shaun J.; Han, Jungmi; Stenehjem, Edward; Dunne, Margaret M.; Lewis, Ned; Irving, Stephanie A.; Rao, Suchitra; McEvoy, Charlene; Bozio, Catherine H.; Murthy, Kempapura; Dixon, Brian E.; Grisel, Nancy; Yang, Duck-Hye; Goddard, Kristin; Kharbanda, Anupam B.; Reynolds, Sue; Raiyani, Chandni; Fadel, William F.; Arndorfer, Julie; Rowley, Elizabeth A.; Fireman, Bruce; Ferdinands, Jill; Valvi, Nimish R.; Ball, Sarah W.; Zerbo, Ousseny; Griggs, Eric P.; Mitchell, Patrick K.; Porter, Rachael M.; Kiduko, Salome A.; Blanton, Lenee; Zhuang, Yan; Steffens, Andrea; Reese, Sarah E.; Olson, Natalie; Williams, Jeremiah; Dickerson, Monica; McMorrow, Meredith; Schrag, Stephanie J.; Verani, Jennifer R.; Fry, Alicia M.; Azziz-Baumgartner, Eduardo; Barron, Michelle A.; Thompson, Mark G.; DeSilva, Malini B.; Medicine, School of MedicineWhat is already known about this topic? Studies suggest that immunocompromised persons who receive COVID-19 vaccination might not develop high neutralizing antibody titers or be as protected against severe COVID-19 outcomes as are immunocompetent persons. What is added by this report? Effectiveness of mRNA vaccination against laboratory-confirmed COVID-19–associated hospitalization was lower (77%) among immunocompromised adults than among immunocompetent adults (90%). Vaccine effectiveness varied considerably among immunocompromised patient subgroups. What are the implications for public health practice? Immunocompromised persons benefit from COVID-19 mRNA vaccination but are less protected from severe COVID-19 outcomes than are immunocompetent persons. Immunocompromised persons receiving mRNA COVID-19 vaccines should receive 3 doses and a booster, consistent with CDC recommendations, practice nonpharmaceutical interventions, and, if infected, be monitored closely and considered early for proven therapies that can prevent severe outcomes.Item 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(U.S. Department of Health & Human Services, 2022-01-28) Thompson, Mark G.; Natarajan, Karthik; Irving, Stephanie A.; Rowley, Elizabeth A.; Griggs, Eric P.; Gaglani, Manjusha; Klein, Nicola P.; Grannis, Shaun J.; DeSilva, Malini B.; Stenehjem, Edward; Reese, Sarah E.; Dickerson, Monica; Naleway, Allison L.; Han, Jungmi; Konatham, Deepika; McEvoy, Charlene; Rao, Suchitra; Dixon, Brian E.; Dascomb, Kristin; Lewis, Ned; Levy, Matthew E.; Patel, Palak; Liao, I-Chia; Kharbanda, Anupam B.; Barron, Michelle A.; Fadel, William F.; Grisel, Nancy; Goddard, Kristin; Yang, Duck-Hye; Wondimu, Mehiret H.; Murthy, Kempapura; Valvi, Nimish R.; Arndorfer, Julie; Fireman, Bruce; Dunne, Margaret M.; Embi, Peter; Azziz-Baumgartner, Eduardo; Zerbo, Ousseny; Bozio, Catherine H.; Reynolds, Sue; Ferdinands, Jill; Williams, Jeremiah; Link-Gelles, Ruth; Schrag, Stephanie J.; Verani, Jennifer R.; Ball, Sarah; Ong, Toan C.; Family Medicine, School of MedicineItem Effectiveness of COVID-19 mRNA Vaccines Against COVID-19–Associated Hospitalizations Among Immunocompromised Adults During SARS-CoV-2 Omicron Predominance — VISION Network, 10 States, December 2021—August 2022(U.S. Department of Health & Human Services, 2022-10-21) Britton, Amadea; Embi, Peter J.; Levy, Matthew E.; Gaglani, Manjusha; DeSilva, Malini B.; Dixon, Brian E.; Dascomb, Kristin; Patel, Palak; Schrader, Kristin E.; Klein, Nicola P.; Ong, Toan C.; Natarajan, Karthik; Hartmann, Emily; Kharbanda, Anupam B.; Irving, Stephanie A.; Dickerson, Monica; Dunne, Margaret M.; Raiyani, Chandni; Grannis, Shaun J.; Stenehjem, Edward; Zerbo, Ousseny; Rao, Suchitra; Han, Jungmi; Sloan-Aagard, Chantel; Griggs, Eric P.; Weber, Zachary A.; Murthy, Kempapura; Fadel, William F.; Grisel, Nancy; McEvoy, Charlene; Lewis, Ned; Barron, Michelle A.; Nanez, Juan; Reese, Sarah E.; Mamawala, Mufaddal; Valvi, Nimish R.; Arndorfer, Julie; Goddard, Kristin; Yang, Duck-Hye; Fireman, Bruce; Ball, Sarah W.; Link-Gelles, Ruth; Naleway, Allison L.; Tenforde, Mark W.; Biomedical Engineering and Informatics, Luddy School of Informatics, Computing, and EngineeringItem Effectiveness of COVID-19 Pfizer-BioNTech BNT162b2 mRNA Vaccination in Preventing COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Nonimmunocompromised Children and Adolescents Aged 5–17 Years — VISION Network, 10 States, April 2021–January 2022(Centers for Disease Control and Prevention, 2022-03-04) Klein, Nicola P.; Stockwell, Melissa S.; Demarco, Maria; Gaglani, Manjusha; Kharbanda, Anupam B.; Irving, Stephanie A.; Rao, Suchitra; Grannis, Shaun J.; Dascomb, Kristin; Murthy, Kempapura; Rowley, Elizabeth A.; Dalton, Alexandra F.; DeSilva, Malini B.; Dixon, Brian E.; Natarajan, Karthik; Stenehjem, Edward; Naleway, Allison L.; Lewis, Ned; Ong, Toan C.; Patel, Palak; Konatham, Deepika; Embi, Peter J.; Reese, Sarah E.; Han, Jungmi; Grisel, Nancy; Goddard, Kristin; Barron, Michelle A.; Dickerson, Monica; Liao , I-Chia; Fadel, William F.; Yang, Duck-Hye; Arndorfer, Julie; Fireman, Bruce; Griggs, Eric P.; Valvi, Nimish R.; Hallowell, Carly; Zerbo, Ousseny; Reynolds, Sue; Ferdinands, Jill; Wondimu, Mehiret H.; Williams, Jeremiah; Bozio, Catherine H.; Link-Gelles, Ruth; Azziz-Baumgartner, Eduardo; Schrag, Stephanie J.; Thompson, Mark G.; Verani, Jennifer R.; Family Medicine, School of MedicineItem Effectiveness of COVID-19 vaccines at preventing emergency department or urgent care encounters and hospitalizations among immunocompromised adults: An observational study of real-world data across 10 US states from August-December 2021(Elsevier, 2023) Embi, Peter J.; Levy, Matthew E.; Patel, Palak; DeSilva, Malini B.; Gaglani, Manjusha; Dascomb, Kristin; Dunne, Margaret M.; Klein, Nicola P.; Ong, Toan C.; Grannis, Shaun J.; Natarajan, Karthik; Yang, Duck-Hye; Stenehjem, Edward; Zerbo, Ousseny; McEvoy, Charlene; Rao, Suchitra; Thompson, Mark G.; Konatham, Deepika; Irving, Stephanie A.; Dixon, Brian E.; Han, Jungmi; Schrader, Kristin E.; Grisel, Nancy; Lewis, Ned; Kharbanda, Anupam B.; Barron, Michelle A.; Reynolds, Sue; Liao, I-Chia; Fadel, William F.; Rowley, Elizabeth A.; Arndorfer, Julie; Goddard, Kristin; Murthy, Kempapura; Valvi, Nimish R.; Weber, Zachary A.; Fireman, Bruce; Reese, Sarah E.; Ball, Sarah W.; Naleway, Allison L.; Medicine, School of MedicineBackground: Immunocompromised (IC) persons are at increased risk for severe COVID-19 outcomes and are less protected by 1-2 COVID-19 vaccine doses than are immunocompetent (non-IC) persons. We compared vaccine effectiveness (VE) against medically attended COVID-19 of 2-3 mRNA and 1-2 viral-vector vaccine doses between IC and non-IC adults. Methods: Using a test-negative design among eight VISION Network sites, VE against laboratory-confirmed COVID-19-associated emergency department (ED) or urgent care (UC) events and hospitalizations from 26 August-25 December 2021 was estimated separately among IC and non-IC adults and among specific IC condition subgroups. Vaccination status was defined using number and timing of doses. VE for each status (versus unvaccinated) was adjusted for age, geography, time, prior positive test result, and local SARS-CoV-2 circulation. Results: We analyzed 8,848 ED/UC events and 18,843 hospitalizations among IC patients and 200,071 ED/UC events and 70,882 hospitalizations among non-IC patients. Among IC patients, 3-dose mRNA VE against ED/UC (73% [95% CI: 64-80]) and hospitalization (81% [95% CI: 76-86]) was lower than that among non-IC patients (ED/UC: 94% [95% CI: 93-94]; hospitalization: 96% [95% CI: 95-97]). Similar patterns were observed for viral-vector vaccines. Transplant recipients had lower VE than other IC subgroups. Conclusions: During B.1.617.2 (Delta) variant predominance, IC adults received moderate protection against COVID-19-associated medical events from three mRNA doses, or one viral-vector dose plus a second dose of any product. However, protection was lower in IC versus non-IC patients, especially among transplant recipients, underscoring the need for additional protection among IC adults.Item Estimation of COVID-19 mRNA Vaccine Effectiveness Against Medically Attended COVID-19 in Pregnancy During Periods of Delta and Omicron Variant Predominance in the United States(American Medical Association, 2022-09-01) Schrag, Stephanie J.; Verani, Jennifer R.; Dixon, Brian E.; Page, Jessica M.; Butterfield, Kristen A.; Gaglani, Manjusha; Vazquez-Benitez, Gabriela; Zerbo, Ousseny; Natarajan, Karthik; Ong, Toan C.; Lazariu, Victoria; Rao, Suchitra; Beaver, Ryan; Ellington, Sascha R.; Klein, Nicola P.; Irving, Stephanie A.; Grannis, Shaun J.; Kiduko, Salome; Barron, Michelle A.; Midturi, John; Dickerson, Monica; Lewis, Ned; Stockwell, Melissa S.; Stenehjem, Edward; Fadel, William F.; Link-Gelles, Ruth; Murthy, Kempapura; Goddard, Kristin; Grisel, Nancy; Valvi, Nimish R.; Fireman, Bruce; Arndorfer, Julie; Konatham, Deepika; Ball, Sarah; Thompson, Mark G.; Naleway, Allison L.; Epidemiology, School of Public HealthImportance: Pregnant people are at high risk for severe COVID-19 but were excluded from mRNA vaccine trials; data on COVID-19 vaccine effectiveness (VE) are needed. Objective: To evaluate the estimated effectiveness of mRNA vaccination against medically attended COVID-19 among pregnant people during Delta and Omicron predominance. Design, setting, and participants: This test-negative, case-control study was conducted from June 2021 to June 2022 in a network of 306 hospitals and 164 emergency department and urgent care (ED/UC) facilities across 10 US states, including 4517 ED/UC encounters and 975 hospitalizations among pregnant people with COVID-19-like illness (CLI) who underwent SARS-CoV-2 molecular testing. Exposures: Two doses (14-149 and ≥150 days prior) and 3 doses (7-119 and ≥120 days prior) of COVID-19 mRNA vaccine (≥1 dose received during pregnancy) vs unvaccinated. Main outcomes and measures: Estimated VE against laboratory-confirmed COVID-19-associated ED/UC encounter or hospitalization, based on the adjusted odds ratio (aOR) for prior vaccination; VE was calculated as (1 - aOR) × 100%. Results: Among 4517 eligible CLI-associated ED/UC encounters and 975 hospitalizations, 885 (19.6%) and 334 (34.3%) were SARS-CoV-2 positive, respectively; the median (IQR) patient age was 28 (24-32) years and 31 (26-35) years, 537 (12.0%) and 118 (12.0%) were non-Hispanic Black and 1189 (26.0%) and 240 (25.0%) were Hispanic. During Delta predominance, the estimated VE against COVID-19-associated ED/UC encounters was 84% (95% CI, 69% to 92%) for 2 doses within 14 to 149 days, 75% (95% CI, 5% to 93%) for 2 doses 150 or more days prior, and 81% (95% CI, 30% to 95%) for 3 doses 7 to 119 days prior; estimated VE against COVID-19-associated hospitalization was 99% (95% CI, 96% to 100%), 96% (95% CI, 86% to 99%), and 97% (95% CI, 79% to 100%), respectively. During Omicron predominance, for ED/UC encounters, the estimated VE of 2 doses within 14 to 149 days, 2 doses 150 or more days, 3 doses within 7 to 119 days, and 3 doses 120 or more days prior was 3% (95% CI, -49% to 37%), 42% (95% CI, -16% to 72%), 79% (95% CI, 59% to 89%), and -124% (95% CI, -414% to 2%), respectively; for hospitalization, estimated VE was 86% (95% CI, 41% to 97%), 64% (95% CI, -102% to 93%), 86% (95% CI, 28% to 97%), and -53% (95% CI, -1254% to 83%), respectively. Conclusions and relevance: In this study, maternal mRNA COVID-19 vaccination, including booster dose, was associated with protection against medically attended COVID-19. VE estimates were higher against COVID-19-associated hospitalization than ED/UC visits and lower against the Omicron variant than the Delta variant. Protection waned over time, particularly during Omicron predominance.Item 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(CDC, 2021-11) Bozio, Catherine H.; Grannis, Shaun J.; Naleway, Allison L.; Ong, Toan C.; Butterfield, Kristen A.; DeSilva, Malini B.; Natarajan, Karthik; Yang, Duck-Hye; Rao, Suchitra; Klein, Nicola P.; Irving, Stephanie A.; Dixon, Brian E.; Dascomb, Kristin; Liao, I.-Chia; Reynolds, Sue; McEvoy, Charlene; Han, Jungmi; Reese, Sarah E.; Lewis, Ned; Fadel, William F.; Grisel, Nancy; Murthy, Kempapura; Ferdinands, Jill; Kharbanda, Anupam B.; Mitchell, Patrick K.; Goddard, Kristin; Embi, Peter J.; Arndorfer, Julie; Raiyani, Chandni; Patel, Palak; Rowley, Elizabeth A.; Fireman, Bruce; Valvi, Nimish R.; Griggs, Eric P.; Levy, Matthew E.; Zerbo, Ousseny; Porter, Rachael M.; Birch, Rebecca J.; Blanton, Lenee; Ball, Sarah W.; Steffens, Andrea; Olson, Natalie; Williams, Jeremiah; Dickerson, Monica; McMorrow, Meredith; Schrag, Stephanie J.; Verani, Jennifer R.; Fry, Alicia M.; Azziz-Baumgartner, Eduardo; Barron, Michelle; Gaglani, Manjusha; Thompson, Mark G.; Stenehjem, Edward; Family Medicine, School of MedicineWhat is already known about this topic? Previous infection with SARS-CoV-2 or COVID-19 vaccination can provide immunity and protection against subsequent SARS-CoV-2 infection and illness. What is added by this report? Among COVID-19–like illness hospitalizations among adults aged ≥18 years whose previous infection or vaccination occurred 90–179 days earlier, the adjusted odds of laboratory-confirmed COVID-19 among unvaccinated adults with previous SARS-CoV-2 infection were 5.49-fold higher than the odds among fully vaccinated recipients of an mRNA COVID-19 vaccine who had no previous documented infection (95% confidence interval = 2.75–10.99). What are the implications for public health practice? All eligible persons should be vaccinated against COVID-19 as soon as possible, including unvaccinated persons previously infected with SARS-CoV-2.Item Waning 2-Dose and 3-Dose Effectiveness 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(Center for Disease Control, 2022-02-18) Ferdinands, Jill M.; Rao, Suchitra; Dixon, Brian E.; Mitchell, Patrick K.; DeSilva, Malini B.; Irving, Stephanie A.; Lewis, Ned; Natarajan, Karthik; Stenehjem, Edward; Grannis, Shaun J.; Han, Jungmi; McEvoy, Charlene; Ong, Toan C.; Naleway, Allison L.; Reese, Sarah E.; Embi, Peter J.; Dascomb, Kristin; Klein, Nicola P.; Griggs, Eric P.; Konatham, Deepika; Kharbanda, Anupam B.; Yang, Duck-Hye; Fadel, William F.; Grisel, Nancy; Goddard, Kristin; Patel, Palak; Liao, I-Chia; Birch, Rebecca; Valvi, Nimish R.; Reynolds, Sue; Arndorfer, Julie; Zerbo, Ousseny; Dickerson, Monica; Murthy, Kempapura; Williams, Jeremiah; Bozio, Catherine H.; Blanton, Lenee; Verani, Jennifer R.; Schrag, Stephanie J.; Dalton, Alexandra F.; Wondimu, Mehiret H.; Link-Gelles, Ruth; Azziz-Baumgartner, Eduardo; Barron, Michelle A.; Gaglani, Manjusha; Thompson, Mark G.; Fireman, Bruce; Community and Global Health, Richard M. Fairbanks School of Public HealthCDC recommends that all persons aged ≥12 years receive a booster dose of COVID-19 mRNA vaccine ≥5 months after completion of a primary mRNA vaccination series and that immunocompromised persons receive a third primary dose.* Waning of vaccine protection after 2 doses of mRNA vaccine has been observed during the period of the SARS-CoV-2 B.1.617.2 (Delta) variant predominance† (1-5), but little is known about durability of protection after 3 doses during periods of Delta or SARS-CoV-2 B.1.1.529 (Omicron) variant predominance. A test-negative case-control study design using data from eight VISION Network sites§ examined vaccine effectiveness (VE) against COVID-19 emergency department/urgent care (ED/UC) visits and hospitalizations among U.S. adults aged ≥18 years at various time points after receipt of a second or third vaccine dose during two periods: Delta variant predominance and Omicron variant predominance (i.e., periods when each variant accounted for ≥50% of sequenced isolates). Persons categorized as having received 3 doses included those who received a third dose in a primary series or a booster dose after a 2 dose primary series (including the reduced-dosage Moderna booster). The VISION Network analyzed 241,204 ED/UC encounters** and 93,408 hospitalizations across 10 states during August 26, 2021-January 22, 2022. VE after receipt of both 2 and 3 doses was lower during the Omicron-predominant than during the Delta-predominant period at all time points evaluated. During both periods, VE after receipt of a third dose was higher than that after a second dose; however, VE waned with increasing time since vaccination. During the Omicron period, VE against ED/UC visits was 87% during the first 2 months after a third dose and decreased to 66% among those vaccinated 4-5 months earlier; VE against hospitalizations was 91% during the first 2 months following a third dose and decreased to 78% ≥4 months after a third dose. For both Delta- and Omicron-predominant periods, VE was generally higher for protection against hospitalizations than against ED/UC visits. All eligible persons should remain up to date with recommended COVID-19 vaccinations to best protect against COVID-19-associated hospitalizations and ED/UC visits.Item Waning of vaccine effectiveness against moderate and severe covid-19 among adults in the US from the VISION network: test negative, case-control study(BMJ Publishing, 2022-10-03) Ferdinands, Jill M.; Rao, Suchitra; Dixon, Brian E.; Mitchell, Patrick K.; DeSilva, Malini B.; Irving, Stephanie A.; Lewis, Ned; Natarajan, Karthik; Stenehjem, Edward; Grannis, Shaun J.; Han, Jungmi; McEvoy, Charlene; Ong, Toan C.; Naleway, Allison L.; Reese, Sarah E.; Embi, Peter J.; Dascomb, Kristin; Klein, Nicola P.; Griggs, Eric P.; Liao, I-Chia; Yang, Duck-Hye; Fadel, William F.; Grisel, Nancy; Goddard, Kristin; Patel, Palak; Murthy, Kempapura; Birch, Rebecca; Valvi, Nimish R.; Arndorfer, Julie; Zerbo, Ousseny; Dickerson, Monica; Raiyani, Chandni; Williams, Jeremiah; Bozio, Catherine H.; Blanton, Lenee; Link-Gelles, Ruth; Barron, Michelle A.; Gaglani, Manjusha; Thompson, Mark G.; Fireman, Bruce; Epidemiology, School of Public HealthObjective: To estimate the effectiveness of mRNA vaccines against moderate and severe covid-19 in adults by time since second, third, or fourth doses, and by age and immunocompromised status. Design: Test negative case-control study. Setting: Hospitals, emergency departments, and urgent care clinics in 10 US states, 17 January 2021 to 12 July 2022. Participants: 893 461 adults (≥18 years) admitted to one of 261 hospitals or to one of 272 emergency department or 119 urgent care centers for covid-like illness tested for SARS-CoV-2. Main outcome measures: The main outcome was waning of vaccine effectiveness with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine during the omicron and delta periods, and the period before delta was dominant using logistic regression conditioned on calendar week and geographic area while adjusting for age, race, ethnicity, local virus circulation, immunocompromised status, and likelihood of being vaccinated. Results: 45 903 people admitted to hospital with covid-19 (cases) were compared with 213 103 people with covid-like illness who tested negative for SARS-CoV-2 (controls), and 103 287 people admitted to emergency department or urgent care with covid-19 (cases) were compared with 531 168 people with covid-like illness who tested negative for SARS-CoV-2. In the omicron period, vaccine effectiveness against covid-19 requiring admission to hospital was 89% (95% confidence interval 88% to 90%) within two months after dose 3 but waned to 66% (63% to 68%) by four to five months. Vaccine effectiveness of three doses against emergency department or urgent care visits was 83% (82% to 84%) initially but waned to 46% (44% to 49%) by four to five months. Waning was evident in all subgroups, including young adults and individuals who were not immunocompromised; although waning was morein people who were immunocompromised. Vaccine effectiveness increased among most groups after a fourth dose in whom this booster was recommended. Conclusions: Effectiveness of mRNA vaccines against moderate and severe covid-19 waned with time after vaccination. The findings support recommendations for a booster dose after a primary series and consideration of additional booster doses.