Durability of protection from original monovalent and bivalent COVID-19 vaccines against COVID-19-associated hospitalization and severe in-hospital outcomes among adults in the United States — September 2022–August 2023

Objective: To evaluate the durability of protection provided by original monovalent and bivalent COVID-19 vaccination against COVID-19-associated hospitalization and severe in-hospital outcomes Design: Multicenter case-control design with prospective enrollment Setting: 26 hospitals in 20 US states Participants: Adults aged ≥18 years admitted to hospital with COVID-19-like illness from 8 September 2022 to 31 August 2023 Main outcome measures: The main outcomes were absolute and relative vaccine effectiveness of original monovalent and bivalent COVID-19 vaccines against COVID-19-associated hospitalization and severe in-hospital outcomes, including advanced respiratory support (defined as receipt of high-flow nasal cannula, non-invasive ventilation, or invasive mechanical ventilation [IMV]) and IMV or death. Vaccine effectiveness was estimated using multivariable logistic regression, in which the odds of vaccination (versus being unvaccinated or receiving original monovalent vaccination only) were compared between COVID-19 case patients and control-patients. Bivalent vaccine effectiveness analyses were stratified by time since dose receipt. Results: Among 7028 adults without immunocompromising conditions, 2924 (41.6%) were COVID-19 case patients and 4104 (58.4%) were control patients. Compared to unvaccinated patients, absolute vaccine effectiveness against COVID-19-associated hospitalization was 6% (-7% to 17%) for original monovalent doses only (median time since last dose [IQR] = 421 days [304-571]), 52% (39% to 61%) for a bivalent dose received 7-89 days earlier, and 13% (-10% to 31%) for a bivalent dose received 90-179 days earlier. Absolute vaccine effectiveness against COVID-19-associated advanced respiratory support was 31% (15% to 45%) for original monovalent doses only, 66% (47% to 78%) for a bivalent dose received 7-89 days earlier, and 33% (-1% to 55%) for a bivalent dose received 90-179 days earlier. Absolute vaccine effectiveness against COVID-19-associated IMV or death was 51% (34% to 63%) for original monovalent doses only, 61% (35% to 77%) for a bivalent dose received 7-89 days earlier, and 50% (11% to 71%) for a bivalent dose received 90-179 days earlier. Conclusion: When compared to original monovalent vaccination only, bivalent COVID-19 vaccination provided additional protection against COVID-19-associated hospitalization and certain severe in-hospital outcomes within 3 months of dose receipt. By 3-6 months, protection from a bivalent dose declined to a level similar to that remaining from original monovalent vaccination only. Although no protection remained from original monovalent vaccination against COVID-19-associated hospitalization, it provided durable protection against severe in-hospital outcomes >1 year after receipt of the last dose, particularly against IMV or death. ### Competing Interest Statement All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel Brown reports that ReddyPort pays royalties for a patent, outside the submitted work. Steven Chang reports consulting fees from PureTech Health and Kiniksa Pharmaceuticals, outside the submitted work. Abhijit Duggal reports participating on an advisory board for ALung Technologies, outside the submitted work. Manjusha Gaglani reports grants from CDC, CDC-Abt Associates, CDC-Westat, and served as co-chair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society (TPS) and received an honorarium serving as a TPS Project Firstline webinar speaker panelist for "Respiratory Virus Review: Clinical Considerations and IPC Guidance", outside the submitted work. Michelle N. Gong reports a grant from NHLBI and CDC, fees for serving on Scientific Advisory Panel for Philips Healthcare, travel to ATS conference as board member, outside the submitted work. Carlos Grijalva reports grants from NIH, CDC, AHRQ, FDA, and Syneos Health; receipt of compensation for participation in an advisory board for Merck, outside the submitted work. Natasha Halasa reports receiving grants from Sanofi, Merck, and Quidel, outside the submitted work. Adam Lauring reports receiving grants from CDC, FluLab, NIH/National Institute of Allergy and Infectious Diseases, and Burroughs Wellcome Fund, and MDHHS, and consulting fees from Roche related to baloxavir, outside the submitted work. Christopher Mallow reports Medical Legal Consulting, outside the submitted work. Ithan D. Peltan reports grants from NIH, and Janssen Pharmaceuticals and institutional support Regeneron, outside the submitted work. Mayur Ramesh reports participating in a non-branded Speaker Program supported by AstraZeneca and MD Briefcase, and participating on an advisory board for Moderna, Pfizer, and Ferring, outside the submitted work. No other potential conflicts of interest were disclosed. ### Funding Statement Primary funding for this work was provided by the United States Centers Disease Control and Prevention (contract 75D30122C14944 to Dr. Wesley Self). Scientists from the funding source, the United States Centers for Disease Control and Prevention, participated in all aspects of this study, including its design, analysis, interpretation of data, writing the report, and the decision to submit the article for publication. Scientists from the United States Centers for Disease Control and Prevention are included as authors on this manuscript. ### 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: These activities were determined to be public health surveillance with waiver of informed consent by institutional review boards at CDC and each enrolling site, and were conducted in accordance with applicable federal law and CDC policy (45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq). 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors