Association between COVID-19 mRNA vaccination and COVID-19 illness and severity during Omicron BA.4 and BA.5 sublineage periods
Authors: Link-Gelles Ruth , Levy Matthew E. , Natarajan Karthik , Reese Sarah E. , Naleway Allison L. , Grannis Shaun J. , Klein Nicola P. , DeSilva Malini B. , Ong Toan C. , Gaglani Manjusha , Hartmann Emily , Dickerson Monica , Stenehjem Edward , Kharbanda Anupam B. , Han Jungmi , Spark Talia L. , Irving Stephanie A. , Dixon Brian E. , Zerbo Ousseny , McEvoy Charlene E. , Rao Suchitra , Raiyani Chandni , Sloan-Aagard Chantel , Patel Palak , Dascomb Kristin , Uhlemann Anne-Catrin , Dunne Margaret M. , Fadel William F. , Lewis Ned , Barron Michelle A. , Murthy Kempapura , Nanez Juan , Griggs Eric P. , Grisel Nancy , Annavajhala Medini K. , Akinseye Akintunde , Valvi Nimish R. , Goddard Kristin , Mamawala Mufaddal , Arndorfer Julie , Yang Duck-Hye , Embí Peter J. , Fireman Bruce , Ball Sarah W. , Tenforde Mark W. 
Published: October 2022

ABSTRACTImportanceRecent sublineages of the SARS-CoV-2 Omicron variant, including BA.4 and BA.5, may be associated with greater immune evasion and less protection against COVID-19 following vaccination.ObjectiveTo evaluate the association between COVID-19 mRNA vaccination with 2, 3, or 4 doses among immunocompetent adults and the risk of medically attended COVID-19 illness during a period of BA.4/BA.5 predominant circulation; to evaluate the relative severity of COVID-19 in hospitalized cases across Omicron BA.1, BA.2/BA.2.12.1, and BA.4/BA.5 sublineage periods.Setting, Design and ParticipantsTest-negative study of adults with COVID-19-like illness (CLI) and molecular testing for SARS-CoV-2 conducted in 10 states from December 16, 2021, to August 20, 2022.ExposuremRNA COVID-19 vaccination.Main Outcomes and MeasuresEmergency department/urgent care encounters, hospitalizations, and admission to the intensive care unit (ICU) or in-hospital death. The adjusted odds ratio (OR) for the association between prior vaccination and medically attended COVID-19 was used to estimate VE, stratified by care setting and vaccine doses (2, 3, or 4 doses vs 0 doses as reference group). Among hospitalized case-patients, demographic and clinical characteristics and in-hospital outcomes including ICU admission and death were compared across sublineage periods.ResultsBetween June 19 – August 20, 2022, 82,229 ED/UC and 21,007 hospital encounters were included for the BA.4/BA.5 vaccine effectiveness analysis. Among adults hospitalized with CLI, the adjusted odds ratio (OR) was 0.75 (95% CI: 0.68-0.83) for receipt of 2 vaccine doses at ≥150 days after receipt, 0.32 (95% CI: 0.20-0.50) for a third dose 7-119 days after receipt, and 0.64 (95% CI: 0.58-0.71) for a third dose ≥120 days (median 235 days) after receipt for cases vs controls. For COVID-19-associated hospitalization, among patients ages ≥65 years 7-59 and ≥60 days (median 88 days) after a fourth dose, ORs were 0.34 (95% CI: 0.25-0.47) and 0.43 (95% CI: 0.34-0.56), respectively. Among hospitalized cases, ICU admission and/or in-hospital death occurred in 21.4% during the BA.1 vs 14.7% during the BA.4/BA.5 period (standardized mean difference: 0.17).ConclusionVE against medically attended COVID-19 illness decreased over time since last dose; receipt of one or two booster doses increased effectiveness over a primary series alone.KEY POINTSQuestionWhat is the association between receipt of first-generation COVID-19 mRNA vaccines and medically attended COVID-19 during Omicron BA.4/BA.5 sublineage predominance?FindingsThis test-negative analysis included 82,229 emergency department or urgent care encounters and 21,007 hospitalizations for COVID-19-like illness. Among hospitalized patients, the likelihood of recent vaccination (7-119 days) with 3 mRNA vaccine doses (vs unvaccinated) was significantly lower (odds ratio, 0.32) in cases than SARS-CoV-2-negative controls, but with lower associated protection ≥120 days post-vaccination (odds ratio, 0.64).MeaningFirst-generation COVID-19 vaccines were associated with protection against COVID-19 during the Omicron BA.4/BA.5 sublineage-predominant periods but this declined over time.