Fluenz Tetra Passive Enhanced Safety Surveillance
Research type
Research Study
Full title
Passive Enhanced Safety Surveillance (ESS) of Quadrivalent Live Attenuated Influenza Vaccine (QLAIV) Fluenz Tetra in Children and Adolescents during the Early Influenza Season in England
IRAS ID
318705
Contact name
Sandeep Dhanda
Contact email
Sponsor organisation
DSRU Education and Research Ltd
Clinicaltrials.gov Identifier
D2560R00008, AstraZeneca study code
Duration of Study in the UK
0 years, 6 months, 31 days
Research summary
Research Summary
The purpose of this survey is to collect information on the safety of the nasal seasonal flu vaccine (Fluenz Tetra) in children and teenagers. Although some side effects may be expected after any vaccination, it is important to check whether the pattern of side effects for a vaccine changes each year. The UK Health Security Agency (UKHSA) detail yearly plans for the national flu vaccination programme, outlining age groups eligible for vaccination. Whilst eligible cohorts may vary from year to year, flu vaccination is recommended for children aged 2-3 years, all primary school-aged children and children at risk aged 2-17 years. Additionally, there may be seasonal variation regarding guidance for eligible cohorts, e.g., inclusion of secondary school year groups during COVID-19. For the current season, those eligible for flu vaccination includes secondary school children focusing on Years 7-9, with remaining vaccines offered to Years 10-11, if supply available.
The study will be carried out in GP surgeries and schools. Immunisation staff provide an information sheet and Safety Report Card (SRC) to the child/parent (or guardian) only after the vaccination has been administered (according to normal clinical practice). Administration of the vaccine is wholly independent of potential participation in this survey.
Study documentation strongly emphasises that taking part is entirely optional and provides reassurances that their medical care will not be affected by this decision. Consent is collected on the SRC, which asks simple questions about medical history and symptoms experienced by the child following vaccination. The parent/guardian of the child (<16 years) completes the SRC on behalf of the child. Children >16 years can complete this themselves. Completion of the SRC is voluntary and only required if the child experiences any side effects following vaccination. The completed SRC is returned directly to AstraZeneca (marketing authorisation holder).
Summary of Results
Rationale and background In April 2014, the European Medicines Agency (EMA) issued interim guidance on enhanced safety surveillance (ESS) for seasonal influenza vaccines in the EU. In response, DSRU and AstraZeneca have collaborated in the development of active and passive surveillance methods since 2014. The purpose of ESS is to rapidly detect any increase in the frequency or severity of local and systemic adverse events and to identify unexpected suspected adverse drug reactions (sADRs) following vaccination with Fluenz Tetra. Based on experience and lessons learnt from active and passive ESS methods used in previous seasons, AstraZeneca in collaboration with the DSRU conducted a passive ESS programme for the 2022-2023 influenza season in England. This is the ninth consecutive seasonal safety surveillance of Fluenz Tetra in England, part of an annual programme which started in 2014.
Objectives:
1. To quantify, describe and classify reported sADRs by age group, lot identifier and geographical region.
2. To describe characteristics of vaccinees experiencing sADRs.
3. To compare the reported sADR patterns between the current season and previous seasons.
4. To perform routine monitoring of data for safety signals at least once weekly throughout the early influenza season.
Design
The Passive ESS was implemented in General Practitioner (GP) practices and schools within England. The expanded UKHSA (formally Public Health England) influenza vaccination continued in 2022/2023 as both influenza and severe acute respiratory syndrome coronavirus 2 were in circulation. Similar to the 2021-2022 season, the programme was extended to include all secondary school aged children (prioritising years 7, 8 and 9, following the completion of primary school vaccination visits, with any remaining vaccine being offered to years 10 and 11, as per UKHSA recommendation). The two different types of sites reached two different study populations; younger children (aged 2-4 years) who had not started school were offered vaccinations at GP practices whereas primary school children (4-11 years old; school years Reception-6) and secondary school children (11-16 years old; school years 7-11) were offered vaccination at their respective schools. Reporting of sADRs was enhanced by providing vaccinees with appropriate reporting materials. Immunisation staff were instructed to hand out a Safety Report Card (SRC) to children and adolescents (aged between 2-17 years, inclusive), or their parents/guardians, following routine vaccination with Fluenz Tetra as part of the mass vaccination programme in England. Although recipients were encouraged to report sADRs experienced in the 14 days after vaccination, no time limit was imposed. A Participant Information Sheet explained the purpose of the surveillance and asked recipients to return the SRC by Freepost to AstraZeneca if the child experienced sADRs or report the sADR via an online portal to AstraZeneca UK. A Children’s Information Sheet was also included with the materials this season. In parallel, participating GP practices and school immunisation teams provided aggregate denominator data, detailing the number of children vaccinated during the surveillance period (‘safety population’) and the number of vaccinees given an SRC (‘evaluable population’), by age group and lot (batch) identifier. AstraZeneca’s safety surveillance team met weekly to review safety data from accumulating ESS and other spontaneous reports received by AstraZeneca outside of the ESS project.
Setting
This project was set within 40 GP practices and 50 schools geographically dispersed throughout England.
Participants
Children and adolescents between the ages of 2 years and 17 years (inclusive) vaccinated with the intranasal LAIV, Fluenz Tetra, during the early 2022-2023 national vaccination programme (30th September 2022 - 20th January 2023).
Variables and data sources
Participating sites provided the number of children vaccinated and the number of these vaccinees who received an SRC, by lot identifier and age group. Reporters (vaccine recipients or their parents/guardians) were asked to provide the following variables on SRCs: • Date of vaccination, lot identifier and site number (prepopulated by immunisation site);
• Demographic characteristics (age, gender);
• Details of other vaccinations within the last month, at the same time or since having Fluenz Tetra;
• Information on co-morbidities and concomitant medication;
• Suspected ADRs following vaccination;
• Date of onset of sADRs, if known;
• Date of resolution of sADRs, if available;
• Whether symptoms led to GP visit or hospital admission.
GPs completed follow-up questionnaires, where possible and appropriate, to validate and amplify information on reported sADRs.
Results
Participating sites (n=90) reported a total of 20,124 children vaccinated with Fluenz Tetra during the 2022-2023 surveillance period (from 30th September 2022 to 20th January 2023). Of these, 17,922 vaccinees (89.1%) were handed a SRC. The proportion of vaccinees who received an SRC varied by age group: 88.9% (5258/5916) in the 2-4 year age group, 85.6% (7833/9154) in 5-10 years, 95.8% in 11-15 years (4695/4902) and 89.5% (136/152) in 1617 years. A higher proportion of SRCs (70.0%) were issued at school sites as compared to GP sites (30.0%). In total, 89 (0.5%) SRCs were returned of which 12 were completed online.
Twenty-six SRCs were not eligible for the analyses as they did not describe an sADR (n=16 SRCs), did not provide consent (n=1 SRC) or the SRCs were returned completely blank (n=9). This report refers to 63 eligible SRCs returned to AstraZeneca from 30th September 2022 to 3rd February 2023.
The 63 eligible SRCs returned represent 0.4% of all 17,922 SRCs issued by sites during the surveillance period. At region level, at least one SRC was returned from all eight of the participating regional areas in England. Four of the 63 eligible SRCs returned did not specify their Clinical Research Network (CRN) region. As a proportion of eligible SRCs returned relative to the number of SRCs issued, the proportion was highest in the Eastern and North West Coast regions (0.9%) and lowest in the Kent, Surrey & Sussex region (0.1%). Despite the highest number of SRCs being issued on the East Midlands, only 0.2% returned an eligible SRC the majority of which were issued in schools. Whilst more regions were recruited from in 2021-2022 (n=13), the overall proportion of eligible SRCs returned this season (2022-23) and last season (2021-22) is comparable; 0.4% and 0.5% respectively. At individual site level, of the 90 sites participating in the ESS programme (40 GP sites and 50 school sites), 37 sites (41%) returned an eligible SRC. The proportion of SRCs returned per site ranged from 0.3% to 2.9% (median 0.8%; IQR 0.5% to 1.5%). According to site type, the proportion of SRCs returned was 0.4% (19 SRCs returned/5,381 SRCs issued) from GP sites and 0.1% (18 SRCs returned/12,541 SRCs issued) from school sites.
To reflect the expansion of the influenza immunisation programme in 2022-2023 to include children at secondary schools (11-16 years old, school years 7-11), the study population was stratified by age group as follows; 2-4 years, 5-10 years, 11-15 years and 16-17 years. Among the eligible SRCs returned and for whom age was specified (n=58), 29 (50.0%) were for 2-4 year olds, 22 (37.9%) were for 5-10 year olds, 7 (12.1%) were for 11-15 year olds and 0 (0.0%) were for 16-17 year olds. Of the 63 eligible SRCs returned in the current 2022-2023 season, 27 were for boys (42.9%) and 36 SRCs (57.1%) were for girls. Thirteen different vaccine lots were used at participating sites within the evaluable population. SRCs were returned with at least one sADR for 12 vaccine lots. Of the 63 eligible SRCs, 20.6% reported lot PF3032, 17.5% reported lot PK2464, 14.3% reported lot PH2004.
A range of co-morbidities and concomitant medications were reported for the vaccinees included in the evaluable cohort. The most frequently reported past medical history was food allergy (n=3, 4.8% of SRCs returned); the severity of food allergy was not reported. The reported comorbidities did not include contraindications for use of Fluenz Tetra. Cetirizine was the most frequent reported concomitant medication. For four vaccinees, it was reported that they had ticked yes to the question on whether the child received other vaccinations at the same time, since or in the month prior to receiving Fluenz Tetra, on the SRC.
Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PT) were used to aggregate and analyse sADRs. A total of 155 sADRs were reported on SRCs returned during the surveillance period; three cases were classified as serious. Time-to-onset was provided for 130 of the 155 reported sADRs. Event/symptoms started within less than 24 hours after vaccination up to a maximum of 55 days; median time to onset was one day (IQR 0, 2). Of the 155 reported sADRs, 111 (71.6%) occurred within two days of vaccination.
Almost half of the 63 eligible SRCs reported at least one sADR within the General disorders and administration site conditions (n=29, 46.0%) and respiratory (n=28, 44.4%) System
Organ Class (SOC). The three most frequently reported sADRs were rhinorrhoea (n=17; 0.1% of the 17922 SRCs issued), pyrexia (n=14; 0.1% of the 17922 SRCs issued) and fatigue (n=12, 0.1% of the 17922 SRCs issued). Rhinorrhoea was the most frequently reported sADR in the 2-4 year age group, rhinorrhoea and pyrexia were most frequent for the 5-10 year age group, and headache was most frequent for the 11-15 year age group. There were no reports of anaphylaxis or the event term hypersensitivity. However, other potential hypersensitivityrelated symptoms were dermatological (e.g. rash, urticaria). The reporting of serious sADRs during the 2022-2023 ESS season remained rare (<0.1% of SRCs issued, 4.8% of the 63 eligible SRCs returned). All serious sADRs were reported to the MHRA, by AstraZeneca within seven days of receipt of the SRC. In four cases (6.4%), the vaccinee visited their GP as a result of the sADR; two of which required hospital admission (PTs pyrexia and lethargy in one case; PTs nasopharyngitis, cough, sneezing and rhinorrhoea in the second case). In 37 cases (58.7%), the vaccinee had recovered from at least one sADR(s) at the time of completing the SRC and/or data lock (3rd February 2023). For 15 cases (23.8%), the vaccinee had not recovered from at least one sADR(s). For the remaining 11 cases the outcome of the sADR(s) was unknown (17.5%).
The reporting proportions for most sADRs were comparable with those reported in the previous three seasons. Newly reported PTs in the current season (n=9), which were not reported in any of the three previous seasons, were reported at a reporting proportion of ≤0.01%, all were classed as non-serious.
Strengths and Limitations
The ESS method is a useful extension to routine pharmacovigilance activities by facilitating collection of near real-time vaccinee reported outcomes following vaccination, along with corresponding denominator data. It also has utility in understanding variation in reporting of frequently occurring safety events from season to season. Limitations of the ESS approach include potential under-reporting and limited power to detect signals of infrequent, rare or latent events or to identify differences between lots.
Conclusion
Reporting of sADRs for Fluenz Tetra in the 2022-2023 ESS was low (<1.0% of SRCs issued were returned). The majority of sADRs were non-serious. The most frequently reported sADRs in the 2022-2023 ESS were predominantly non-serious events that are expected from existing safety knowledge on Fluenz Tetra. Potential hypersensitivity-related symptoms were rarely reported. There were newly reported events in this season which have not been reported in the previous three seasons, however, these were classified as non-serious. As with previous seasons, the 2022-2023 ESS programme has facilitated the rapid collection and analysis of data on sADRs experienced by vaccinees administered Fluenz Tetra. The 2022-2023 will be the last season of ESS following Pharmacovigilance Risk Assessment Committee (PRAC) recommendation.REC name
HSC REC A
REC reference
22/NI/0152
Date of REC Opinion
20 Sep 2022
REC opinion
Further Information Favourable Opinion