Relative vaccine effectiveness (rVE) of mRNA COVID-19 boosters in people aged at least 75 years in the UK vaccination programme, during the Spring-Summer (monovalent vaccine) and Autumn-Winter 2022 (bivalent vaccine) booster campaigns: a prospective test negative case-control study

Background Understanding the relative vaccine effectiveness (rVE) of new COVID-19 vaccine formulations against SARS-CoV-2 infection is an urgent public health priority. A precise analysis of the rVE of monovalent and bivalent boosters given during the 2022 Spring-Summer and Autumn-Winter campaigns, respectively, in a defined population has not been reported. Aim We therefore assessed rVE against hospitalisation for the Spring-Summer (fourth vs third monovalent mRNA vaccine doses) and Autumn-Winter (fifth BA.1/ancestral bivalent vs fourth monovalent mRNA vaccine dose) boosters. Methods A prospective single-centre test-negative design case-control study of ≥75 year-olds hospitalised with COVID-19 or other acute respiratory disease. We conducted regression analyses controlling for age, sex, socioeconomic status, patient comorbidities, community SARS-CoV-2 prevalence, vaccine brand and time between baseline dose and hospitalisation. Results 682 controls and 182 cases were included in the Spring-Summer booster analysis; 572 controls and 152 cases for the Autumn-Winter booster analysis. A monovalent mRNA COVID-19 vaccine as fourth dose showed rVE 46·6% (95% confidence interval [CI] 13·9-67·1) versus those not fully boosted. A bivalent mRNA COVID-19 vaccine as fifth dose had rVE 46·7% (95%CI 18-65·1), compared to a fourth monovalent mRNA COVID-19 vaccine dose. Conclusions Both fourth monovalent and fifth BA.1/ancestral mRNA bivalent COVID-19 vaccine doses demonstrated benefit as a booster in older adults. Bivalent mRNA boosters offer similar protection against hospitalisation with Omicron infection to monovalent mRNA boosters given earlier in the year. These findings support immunisation programmes in several European countries that advised the use of BA.1/ancestral bivalent booster doses. ### Competing Interest Statement CH is Principal Investigator of the AvonCAP study which is an investigator-led University of Bristol study funded by Pfizer and has previously received support from the NIHR in an Academic Clinical Fellowship. JO and LD are Co-Investigators on the AvonCAP Study. AF is a member of the Joint Committee on Vaccination and Immunization (JCVI) and, until December 2022 was chair of the World Health Organization European Technical Advisory Group of Experts on Immunization (ETAGE) committee. In addition to receiving funding from Pfizer as Chief Investigator of this study, he leads another project investigating transmission of respiratory bacteria in families jointly funded by Pfizer and the Gates Foundation. The other authors have no relevant conflicts of interest to declare. ### Funding Statement This study was conducted as a collaboration between The University of Bristol (study sponsor) and Pfizer (study funder). The study funder did not undertake any data collection, data analysis or manuscript preparation. ### 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: The Health Research Authority Research Ethics Committee (East of England, Essex), REC20/EE/0157 approved this study, including using Section 251 of the 2006 NHS Act under Confidentiality Advisory Group authorisation. 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 The data used in this study are sensitive and cannot be made publicly available without breaching patient confidentiality rules. The data dictionary is therefore unavailable. The data used in this study are sensitive and cannot be made publicly available without breaching patient confidentiality rules. The data dictionary is therefore unavailable.