Association between COVID-19 mRNA vaccination and COVID-19 illness and severity during Omicron BA.4 and BA.5 sublineage periods

Importance Recent 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. Objective To 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 Participants Test-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. Exposure mRNA COVID-19 vaccination. Main Outcomes and Measures Emergency 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. Results Between 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). Conclusion VE 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. Question What 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? Findings This 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). Meaning First-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. ### Competing Interest Statement Conflict of Interest Disclosures: During the conduct of the study, all Westat- and Kaiser Permanente Northern California Division of Research-affiliated authors reported receiving contractual support from the CDC during the conduct of the study via payments made to respective institutions. Additionally, all authors affiliated with Baylor Scott & White Health, Children's Minnesota Columbia University Irving Medical Center, HealthPartners Institute, Intermountain Healthcare, Kaiser Permanente Northwest, Paso del Norte Health Information Exchange, Regenstrief Institute, and University of Colorado receiving contractual support from the CDC during the conduct of the study, via a subcontract from Westat, Inc. to their institution. Outside the submitted work in the past 36 months, the following disclosures were reported: Dr Naleway reported receiving grants from Pfizer and Vir Biotechnology; Dr Klein reported receiving grants from Pfizer, Merck, GlaxoSmithKline, and Sanofi Pasteur; Dr Gaglani reported receiving grants directly from CDC and from CDC via subcontracts from Abt Associates and Vanderbilt University Medical Center to her institution; Dr Irving reported receiving grants from the CDC to her institution; Dr Dixon reported receiving grants from CDC, NIH, AHRQ, and the U.S. Department of Veterans Affairs, personal fees from Elsevier and Springer Nature, consulting fees from Merck and Co; Dr. McEvoy reported receiving grants AztraZeneca; Dr Rao reported receiving grants from GSK; and Dr Uhlemann reported receiving grants from Merck. Dr Uhlemann and Dr Annavajhala also reported receiving grants from NIH/NIDA during the conduct of the study. No other disclosures were reported ### Funding Statement Funding: This study was funded by the Centers for Disease Control and Prevention though contract 75D30120C07986 to Westat, Inc. and contract 75D30120C07765 to Kaiser Foundation Hospitals. Study sponsors placed no limitations on publication nor required confidentiality in reporting of results ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Westat, Inc gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Dissemination to participants and related patient and public communities: The individual level dataset from this study is held securely in limited deidentified form at the US Centers for Disease Control and Prevention. Data sharing agreements between CDC and data providers prohibit CDC from making this dataset publicly available. CDC will share aggregate study data once study objectives are complete, consistent with data use agreements with partner institutions.