Modelling approaches for estimating vaccine effectiveness of consecutive SARS-CoV-2 variant sublineages in the absence of study-specific genetic sequencing data, VEBIS hospital network, Europe, 2023/24

Introduction Genetic changes in COVID-19 variants/sublineages (VSLs) can reduce vaccine effectiveness (VE). Timely VSL-specific VE estimates are essential, but study-specific VSL identification by whole genome sequencing (the “gold standard”) is expensive and time-consuming. Alternatively, VSL-specific VE has been estimated from external sequencing data (VSL predominance period by proxy: PP). We propose two novel approaches for use in test-negative design (TND) studies to estimate VSL-specific VE when study-specific VSL identification is not possible.

We demonstrate the variant category model (VCM) and the variant proportion model (VPM) approaches. Using data from a hospital-based TND study among adults ≥65 years, during the period of sequential predominance of XBB and BA.2.86 in 2023/24, we estimated the VE as (1-OR) x 100%. For the VCM, we used a binary variable categorising “most likely underlying sublineage” based on publicly available sequencing data. For the VPM, we used a continuous variable with values from 0 to 1 representing the weekly proportion of BA.2.86. We validated results using study-specific VSL identification from sequenced study data (SD) and the standard PP approach.

Overall, at 14–59 days post vaccination, VE point estimates against XBB were within ±3% absolute for the VE estimated using both models, with an equivalent standard PP validation. We could not validate using SD, as there were no vaccinated XBB cases. Against BA.2.86, VE was lower than against XBB, and the VCM and VPM results were within ±7% absolute of each other, with lowest validation results from SD but equivalent results from the PP.

Both proposed approaches produced similar VE estimates to those from well-known methods. The VPM could also provide VE estimates when the validation techniques were limited by low sample size. Competing Interest Statement Ligita Jančorienė has received honoraria fees for lectures from Pfizer, Viatris, Swixx Biopharma. All other authors have declared no conflicts of interest. Funding Statement The Vaccine Effectiveness, Burden and Impact Studies (VEBIS) is a project of the European Centre for Disease Prevention and Control (ECDC) run under the framework contract No. ECDC/2021/016. 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 planning, conduct and reporting of the studies was in line with the Declaration of Helsinki. Official ethical approval was not required if studies were classified as being part of routine care/surveillance (Spain, Ireland, Malta); In Belgium and Germany, VE estimation is included in SARI surveillance. For Belgium, the study protocol was approved by the central Ethical Committee (CHU Saint-Pierre (AK/12-02-11/4111) initially in 2011, and UZ VUB (B.U.N. 143201215671) from 2014 on) and each participating hospital's local ethical committees. The most recent amendment was approved on 27/9/2023 (reference 2012/310 Am6). The German SARI surveillance was approved by the Charité-Universitätsmedizin Berlin Ethical Board (Reference EA2/218/19). Other study sites obtained local ethical approval from a national review board (Croatia: 3 July 2023 by the Ethics committee of the Croatian Institute of Public Health, Class 030-02/23-01/3; Hungary: approved in March 2021 by the National Scientific and Ethical Committee for the period 01 September 2021-01 September 2024 (IV/1885-5/2021/EKU); Lithuania: approved 03 July 2020 by the Lithuanian Biomedical Research Ethics Committee No.: L-20-3/1-2; and later permission extended for the study period for seasons 2020-2024; Navarra: PI2020/45; Portugal: approved 19 January 2021 by the Ethics Committee of Instituto Nacional de Saúde Doutor Ricardo Jorge, no registration number given; Romania: approved by the Ethics Committee of the Ministerul Apararii Naionale Institutul Naional de Cercetare pentru Dezvoltare Medico-Militara, "Cantacuzino" for the period 2022-2023, No. CE199/2022 and by the Ethics Committee of the National Institute of Public Health Romania No. 23468/2023). No personal identifiers were collected. 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 Data Availability All data produced in the present study are available upon reasonable request to the authors.