Research question and objectives:
Research question: Is there a difference in the risk of selected adverse events of special interest (AESIs) after vaccination with BIMERVAX® compared with vaccination by other vaccines for the same indication?
Primary objectives:
?? To characterise recipients of BIMERVAX® in relation to demographics and clinical characteristics at the time of vaccination, including the following: pregnancy status, age of childbearing potential, immunocompromised status, comorbidities, presence of
autoimmune and inflammatory disorders, and interaction with other vaccines (influenza).
?? To estimate the risk ratio and risk difference of prespecified AESIs comparing recipients of BIMERVAX® with recipients of other COVID-19 vaccines with the same indication, using a cohort design.
?? To estimate the incidence rate ratio of selected AESIs comparing a prespecified risk interval following BIMERVAX® vaccination with a later post-risk interval, using a selfcontrolled risk interval (SCRI) design.
Secondary objectives (study size allowing):
?? To estimate the risk ratio and risk difference of prespecified AESIs comparing recipients of BIMERVAX® with recipients of other COVID-19 vaccines with the same indication, using a cohort design in subgroups defined by the following baseline variables:
pregnancy status, immunocompromised status, frailty due to comorbidities, presence of autoimmune or inflammatory disorders, prior use of influenza vaccine and calendar time.
?? To estimate the incidence rate ratio of selected AESIs comparing a prespecified risk interval following BIMERVAX® vaccination with a later post-risk interval, using an SCRI design in subgroups defined by the following baseline variables: immunocompromised status, frailty due to comorbidities, presence of autoimmune or inflammatory disorders, prior use of influenza vaccine and calendar time.Study design:
The study will comprise:
?? A vaccine utilisation study component, which will use a descriptive study design to characterise individuals at the time of vaccination
?? A component on comparative safety studies, including:
– A cohort design to estimate the incidence of AESIs after receiving a BIMERVAX® vaccine dose compared with the incidence in a comparator group vaccinated by other COVID-19 vaccines.
– A self-controlled risk interval design to evaluate the risk of AESIs in a time interval following the receipt of a BIMERVAX® vaccine (the risk interval) compared with the risk of the same AESI during a subsequent post-risk time interval (the control
interval).
Population: The eligible population for the vaccine utilisation study will be all individuals actively enrolled in each of the selected European health data sources for at least 12 months before receiving a dose of the BIMERVAX® vaccine within the study period. For the comparative safety studies, the main eligibility criterion will be receiving BIMERVAX® or other COVID-19 vaccine at baseline (matched cohort design) or receiving BIMERVAX® and have experienced an AESI during the risk or control interval (self-controlled risk interval design). The study period will begin from the date of first availability of the BIMERVAX® original vaccine in each participating data source/country and will end 36 months (48 months for pregnancy outcomes) after the start of data collection. The start of data collection will be anchored on the threshold of a total of 4,000 BIMERVAX® doses administered across the participating data sources.
Variables:
?? In the vaccine utilisation study, the following variables will be measured at the time of vaccination: demographics; pregnancy status and trimester of pregnancy, as feasible; immunocompromised status; comorbidities that may determine frailty; autoimmunity,
and inflammatory conditions; prior COVID-19 vaccination (brand, doses); prior use of other vaccines (influenza); comedications; and COVID-19 history.
?? In the comparative safety studies, exposures will be based on recorded prescription, dispensing, or administration of COVID-19 vaccines during the study period. The outcomes will be based on the BIMERVAX® risk management plan that included AESIs
proposed by the ACCESS project for a cohort and an SCRI study design. 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 immunocompromised status, vaccinations, and others.
Data sources: The planned data sources for this study, pending confirmation of vaccine rollout, are EpiChron (Spain), Information System for Research in Primary Care (SIDIAP) (Spain), and Valencia Health System Integrated Database (VID) (Spain). Rollout in other European countries will be monitored to evaluate other potential data sources.
Study size: The study size for both the vaccine utilisation study and the comparative safety studies will be determined by the uptake of BIMERVAX® in the participating data sources during the study period.
Data analysis: The vaccine utilisation study will summarise the variables of interest at the time of vaccination using standard measures of central tendency and of dispersion for continuous variables as well as counts and percentages for categorical variables.
The comparative safety cohort study will use matching and inverse probability weighting to adjust for the measured baseline confounders. Outcomes will be treated as time-to-event variables and will be analysed accordingly. Effect estimates will be provided as risk ratios and as risk differences scales.
The SCRI study will compare the risk of each AESI during a prespecified period following the index date (the “risk interval” during which there is a hypothesised increased risk of the outcome) with that of a self-matched “control interval,” used to assess the baseline risk of the outcome.