Rationale and background: The coronavirus disease 2019 (COVID-19) HIPRA vaccine BIMERVAX® is a recombinant protein-based bivalent variant vaccine intended for use as a booster in individuals 16 years of age and older who have previously received a messenger RNA (mRNA) COVID-19 vaccine. In March 2023, the European Commission granted marketing authorisation of BIMERVAX® vaccine for use in the European Union [1].This study will evaluate the effectiveness of BIMERVAX® as a booster vaccine compared with non-BIMERVAX® booster vaccines using real-world data from European countries.
Research question and objectives:
Overall research question: What is the relative effectiveness of receiving BIMERVAX® as a booster vaccine on COVID-19–related outcomes compared with receipt of another authorised COVID-19 vaccine as a booster?
Objectives:
• The primary objective is to estimate the effect of BIMERVAX® on the following COVID-19–related outcome compared with other COVID-19 vaccines authorised for the booster indication:
• Primary outcome: COVID-19–requiring a hospitalisation or emergency department (ED) visit
• The secondary objective is to estimate the effect of BIMERVAX® on the following COVID-19–related outcome compared with other COVID-19 vaccines authorised for the booster indication:
• Secondary outcome: COVID-19 diagnosis in any setting
Study design: A cohort design will be used to estimate the effectiveness of BIMERVAX® on COVID-19–related outcomes compared with other COVID-19 booster vaccines.
Population: The eligible population will be all individuals who have received a booster dose of BIMERVAX® or a comparator COVID-19 vaccine and are actively enrolled in one of the selected European health data sources for at least 12 months before receipt of the booster vaccination. The study period will be from the date of availability of BIMERVAX® vaccine in each participant country to 2 to 3 years past that date, pending the timing and potential seasonality of booster administration campaigns.
Variables:
• Exposures will be based on recorded prescription, dispensing, or administration of COVID-19 vaccines as booster during the study period.
• The outcomes will be based on the recorded diagnoses of COVID-19, which will be identified as COVID-19 requiring a hospitalisation or ED visit or COVID-19 diagnosis in any medical care setting.
• Key confounders will include demographics, COVID-19 history, vaccinations, personal lifestyle characteristics, comorbidities, comedications, immunocompromising conditions, and others.• Subgroups will be defined by baseline variables such as comorbidities, immunocompromised status, vaccinations, and others.
Data sources: The planned data sources for this study, pending vaccine rollout confirmation, are EpiChron (Spain), Information System for Research in Primary Care (SIDIAP) (Spain), Valencia Health System Integrated Database (VID) (Spain), Clinical Practice Research Datalink (CPRD) (United Kingdom [UK]), and French Administrative Healthcare Database (SNDS) (France). Rollout in other European countries will be monitored to evaluate other potential data sources
Study size: The study size for the effectiveness study will be determined by the uptake of BIMERVAX® as a booster vaccine in the participating data sources.
Data analysis: The cohort study will estimate the risk of COVID-19 related outcomes in individuals receiving BIMERVAX® compared with individuals receiving a contemporary COVID-19 vaccine also authorised for booster indication. The data analysis will be characterised by the following:
• Baseline will be defined as the date on which eligible individuals receive the booster vaccine (BIMERVAX® or a comparator vaccine). Follow-up starts and eligibility criteria are applied at baseline.
• Eligible vaccinated individuals will be followed from baseline until the occurrence of a COVID-19–related outcome, death, disenrolment from the data source, or end of the study period, whichever occurs first.
• The study will estimate the effect of receiving 1 dose of BIMERVAX® as a booster vaccine versus the effect of receiving 1 booster dose of other COVID-19 vaccines. Standard epidemiological methods will be used to achieve baseline exchangeability conditional on the measured confounders.
• Outcomes will be treated as time-to-event variables and will be analysed accordingly. Effect estimates will be provided in both relative (e.g., risk ratio) and absolute (e.g., risk differences) scales. Relative vaccine effectiveness will be estimated as 1 minus the risk ratio.
Milestones: Key milestones are
• Protocol submission: 19 September 2023
• Regulatory endorsement: estimated Q4 2023 to Q1 2024 (fourth quarter of 2023 to first quarter of 2024)
• Progress report: 3 months after protocol endorsement, estimated Q1 2024 to Q2 2024
• Final study report: 24 to 36 months after rollout of BIMERVAX® in first participating country