Study design, population and setting
Between October 9, 2020 and November 30, 2020, an EPSS was conducted to examine ADRs associated with IIV4 vaccination within seven participating sites (private clinics) in Finland. This EPSS included individuals aged 6 months and older who had received IIV4 from their HCP within 4 to 6 weeks following the start of seasonal influenza vaccination. Vaccines were administered as per routine clinical practice in accordance with the product labelling (indication).
The study was conducted in accordance with the Declaration of Helsinki, Good Epidemiological Practice, and the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. Informed consent was not required because the EPSS relied on routine pharmacovigilance and voluntary spontaneous reporting.
Vaccine formulation
The IIV4 vaccine contained 15 μg haemagglutinin per strain of A/Guangdong Maonan/SWL1536/2019 (H1N1) pdm09-like strain (A/Guangdong-Maonan/SWL1536/2019, CNIC-1909), A/Hong Kong/2671/2019 (H3N2)-like strain (A/Hong Kong/2671/2019, IVR-208), B/Washington/02/2019-like strain (B/Washington/02/2019, wild type) and B/Phuket/3073/2013-like strain (B/Phuket/3073/2013, wild type) within a 0.5 mL dose. All strains were propagated in fertilised hens' eggs from healthy chicken flocks [13].
Endpoints
The primary endpoint was the occurrence of suspected ADRs within 7 days following routine vaccination with IIV4 during the NH influenza season 2020/21. Secondary endpoints included the occurrence of suspected ADRs occurring within 7 days following routine vaccination with IIV4 according to pre-defined age groups (≥ 6 months to < 6 years, ≥ 6 to < 13 years, ≥ 13 to < 18 years, ≥ 18 to ≤ 65 years and > 65 years); the occurrence of serious suspected ADRs after vaccination with IIV4 at any time following vaccination; and vaccinee reporting rates of suspected ADRs observed during the NH influenza season 2020/21 compared with vaccinee reporting rates of suspected ADRs observed during the NH influenza season 2019/20, or compared with the frequencies documented in the SmPC. Serious suspected ADRs were defined as ADRs that result in death or are life threatening, or that require inpatient hospitalization or the prolongation of existing hospitalization, or result in the persistence of significant disability or incapacity.
Study conduct and data collection
Following vaccination with IIV4, the HCPs informed each vaccinee or vaccinee’s parents/legal guardians on the importance of reporting suspected ADRs, especially those occurring within the first 7 days, and instructed them on how to use the EDC system (Viedoc 4.60), which was set up using vaccinee-specific accounts, to report any ADRs directly in ‘real-time’. Alternatively, vaccinees or vaccinee’s parents/legal guardians could report ADRs by phone to the Finnish Sanofi Medical Information & Pharmacovigilance Call Centre and the ADRs reported to this centre were integrated into the pharmacovigilance database. The ADRs recognized as being of particular interest by the PRAC were analysed separately and classified as PRAC ADRs of interest. The following were defined by the PRAC as ADRs of interest: systemic reactions (fever [≥ 38 °C], nausea, vomiting, malaise, headache, decreased appetite, myalgia and/or arthralgia, irritability/prolonged crying [for children under 5 years of age]), injection-site reactions (pain, erythema and swelling) and events indicative of allergic and hypersensitivity reactions, including rash and ocular symptoms.
Vaccination cards (VC) were provided to the vaccinee or vaccinee’s parents/legal guardians to facilitate data collection. A copy of the VC was retained at the site so that the details could be transcribed into the EDC (including the unique patient identifier automatically generated using the EDC, batch number of vaccine, vaccination date and vaccinee age group). All data were extracted from the PV (pharmacovigilance) database for the statistical analyses of the safety data.
Statistical analysis
Descriptive statistics were used to summarise the data, including the vaccinee reporting rate and ADR reporting rate, with associated two-sided 95% confidence intervals (CI). The vaccinee reporting rate was calculated using the number of vaccinees who reported at least one suspected ADR divided by the total number of VCs distributed; and the ADR reporting rate was calculated using the number of suspected ADRs divided by the total number of VCs distributed. The ADR reporting rate 95% CIs were calculated using the Clopper-Pearson exact CI while the vaccinee reporting rate 95% CIs were calculated using the normal approximation method of binomial CI (Wald asymptotic CI) or using the Clopper-Pearson exact CI where applicable.
The EPSS current interim guidance [6] for seasonal influenza vaccines in the EU (EMA/PRAC/222346/2014) requires the system to be able to detect ADRs considered to be common, i.e. expected to occur with a reporting rate of ≥ 1%. To meet this requirement, 1000 individuals were targeted to be vaccinated within 4 to 6 weeks following the start of the influenza vaccination season across the participating sites. This population size provides a > 99% probability of collecting ≥ 1 report of a common AE. Data were summarised cumulatively by pre-defined age group, by ADRs occurring ≤ 7 or > 7 days after vaccination or missing, by seriousness and by severity.
The previous reporting rates obtained in the EPSS NH influenza season 2019/20 were used as a comparator for the reporting rates observed in the current EPSS NH influenza season 2020/21 in addition to SmPC, in order to evaluate any potential increase in reactogenicity. Any reports received outside the EPSS period were handled as routine spontaneous reports but were not included in the analysis.