Interim 2022/23 influenza vaccine effectiveness: six European studies, October 2022 to January 2023

Background Between October 2022 and January 2023, influenza A(H1N1)pdm09, A(H3N2) and B/Victoria viruses circulated in Europe with different influenza (sub)types dominating in different areas. Aim To provide interim 2022/23 influenza vaccine effectiveness (VE) estimates from six European studies, covering 16 countries in primary care, emergency care and hospital inpatient settings. Methods All studies used the test-negative design, but with differences in other study characteristics, such as data sources, patient selection, case definitions and included age groups. Overall and influenza (sub)type-specific VE was estimated for each study using logistic regression adjusted for potential confounders. Results There were 20,477 influenza cases recruited across the six studies, of which 16,589 (81%) were influenza A. Among all ages and settings, VE against influenza A ranged from 27 to 44%. Against A(H1N1)pdm09 (all ages and settings), VE point estimates ranged from 28% to 46%, higher among children (< 18 years) at 49–77%. Against A(H3N2), overall VE ranged from 2% to 44%, also higher among children (62–70%). Against influenza B/Victoria, overall and age-specific VE were ≥ 50% (87–95% among children < 18 years). Conclusions Interim results from six European studies during the 2022/23 influenza season indicate a ≥ 27% and ≥ 50% reduction in disease occurrence among all-age influenza vaccine recipients for influenza A and B, respectively, with higher reductions among children. Genetic virus characterisation results and end-of-season VE estimates will contribute to greater understanding of differences in influenza (sub)type-specific results across studies.


Introduction
In European Union (EU) countries and the United Kingdom (UK), seasonal influenza vaccine is recommended for older adults (mainly considered as those aged ≥ 60 years or ≥ 65 years, depending on the country) and those at increased risk of influenza complications and severe disease (e.g. those with chronic conditions) [1]. Moreover, routine childhood influenza vaccination programmes have been introduced in some World Health Organization (WHO) European Region countries, including in the UK since 2013/14, in Ireland since 2020/21, and in Denmark in 2-6-year-olds only, since 2021/22 [2,3].  [4].
The influenza season for 2022/23 started early in most of the 53 WHO European Region countries, with activity crossing the epidemic threshold of 10% sentinel specimen positivity in week 45 2022 and high seasonal influenza virus circulation reported from 29 of the 37 influenza-reporting countries by the first week in January 2023 [5]. In primary care sentinel specimens, during the period covered by this study, which goes up to the end of January (week 4) 2023, influenza A(H3N2) subtypes were initially dominant, with influenza A(H1N1)pdm09 subtypes subsequently dominating from week 2 2023, although there was substantial heterogeneity in influenza A subtype distribution by country [6]. Influenza B virus was also reported. For hospitalised patients, (mostly untyped) influenza A viruses were detected in urgent care wards, while specimens from patients with severe acute respiratory illness (SARI) were predominantly influenza A(H1N1)pdm09 [7]. Other respiratory viruses, particularly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) were also co-circulating during the 2022/23 influenza season, the latter at high levels [7]. We report interim influenza VE estimates for the 2022/23 season from six studies (four single-and two multi-country), including out-patient (primary care), in-patient (hospital) and emergency care settings, in order to inform measures of influenza prevention and control for the remaining season.

Study setting
The two primary care studies were conducted in Denmark (Danish primary care study; DK-PC) and in several EU countries (EU primary care study; EU-PC) through the ECDC VEBIS multi-country network ( Table 1). All 10 participating countries in this network had available data for interim analysis; one country, Spain, includes two study sites: Navarra region as one, and 11 other regions combined as the other. The single study at hospital emergency care department level was conducted in England (English emergency care study; EN-EC), with 76% (9,867/13,058) of patients subsequently admitted to hospital. The three studies in the hospital setting were in Denmark (DK-H), Scotland (SC-H) and across several EU countries through the ECDC VEBIS multi-country network (EU-H; Table 1). Seven of 14 participating countries in this network provided data for interim analysis; one country, Spain, has two study sites: one being Navarra and the second comprising 12 other regions combined (Figure 1). A total of 16 European countries (with England and Scotland counted as two countries) contributed data to these interim influenza VE results.
What did you want to address in this study? Different types (A or B) or subtypes (e.g. A(H3N2), A(H1N1)pdm09)) of influenza viruses exist. In Europe several virus (sub)types have been co-circulating in the 2022/23 influenza season. We wanted to understand how well the influenza vaccine for this season has protected people so far. Because people's settings, the virus (sub)types they encounter and their age might all influence vaccine effectiveness, these potential factors were considered.

What have we learnt from this study?
In primary care, emergency and hospital settings, interim influenza vaccine effectiveness estimations for 2022/23 indicated some protection by the vaccine. Regardless of setting, all-age vaccine effectiveness against influenza A(H3N2) and A(H1N1)pdm09 virus subtypes ranged from 2 to 46%; this was higher for influenza B (≥ 50%). Vaccine effectiveness point estimates in <18-year-old children were higher (49-95%) than adults across all (sub)types.
What are the implications of your findings for public health? While this report presents interim results, the findings support that influenza vaccination should be continued according to national guidelines as the influenza season unfolds. Further characterisations of circulating influenza viruses and updated vaccine effectiveness estimates at the end of the season will enhance the understanding of the protection conferred by the vaccine in a European context, supporting preparation for future seasons. The EU-ARI definition is sudden onset of symptoms AND ≥ 1 of cough, sore throat, shortness of breath or coryza AND a clinician's judgement that the illness is due to an infection.

KEY PUBLIC HEALTH MESSAGE
f Varies according to SARS-CoV-2/influenza testing practices by Health Board.
g Vaccines were prepared from egg-propagated vaccine viruses, non-adjuvanted and administered intramuscularly unless otherwise specified.
h Where indicated, vaccine coverage among controls were used as representative of the source population from which the cases arose.
i For all studies 'sex' is used in the statistical model for estimating VE as a binary variable: male/female. j The QCOVID risk groups are defined as the number of generic comorbidity conditions of a patient, and are used as a measure of comorbidity. The list of conditions is found in the study of Clift et al [26].

Study design
The methods for all six studies have been described elsewhere [8][9][10][11][12]. All studies used the test-negative design [13], although some differed in how they recruited patients and/or in their data collection (Table 1)   date of vaccination, were excluded. In EN-EC children vaccinated within 20 days were excluded from the analysis to avoid live attenuated influenza vaccine (LAIV)related infections.
Many study countries (eight from EU-PC; three from EU-H; and Denmark) selected all or a random sample of influenza virus-positive specimens for haemagglutinin genome segment and/or whole genome sequencing, where technically feasible. In SC-H, the selection was based on other criteria (including vaccination status, antiviral use and being from an area with other cases) and cannot be considered a random sample. Sequencing was followed by phylogenetic analysis to determine clade distribution for potential impact on VE. Sequencing results were provided for both studies in Denmark together (DK-PC and DK-H).

Statistical analysis
We computed VE in each study as one minus the adjusted ratio of the odds of vaccination in cases and controls, as a percentage: VE = (1 − ORa) × 100. We applied logistic regression to adjust for measured potential confounding variables (Table 1). We estimated study-specific VE overall and, where possible, by age group and target population (as defined locally in the various studies and study sites) against influenza A and B combined (not in DK-PC or DK-H, as this country decided to only present A and B types separately due to the heterogeneity across influenza typespecific estimates), influenza A overall, A(H1N1)pdm09, A(H3N2), and influenza B. We defined small sample size analyses as those having fewer than 10 cases or controls per parameter. For these, a sensitivity analysis was performed using Firth's method of penalised logistic regression (PLR) to assess small sample bias [14,15]. We considered a difference of > 10% between the original estimate and that obtained using PLR to be an indication of small sample bias; none of these estimates are shown.

All influenza (A and B)
The overall VE estimates for influenza types A and B together were not presented for DK-PC and DK-H due to difference in VE across influenza types.   Table 1. c All influenza (A and B) estimates were not presented for DK-PC and DK-H due to difference in VE across influenza types. d Groups targeted by seasonal influenza vaccination as defined locally in the studies and study sites. e Three study sites with < 10 A(H1N1)pdm09 cases were excluded from A(H1N1)pdm09 VE analysis (11 cases); two study sites with < 10 A(H3N2) cases were dropped from A(H3N2) VE analysis (8 cases); five study sites with < 10 B cases were not included in B VE analysis (8 cases).
f Two study sites with < 10 influenza A(H3N2) cases were dropped from A(H3N2) VE analysis (10 cases).

Virological results
Of the 570 influenza A (H3N2)

Virological results
Of the 82 influenza B/Victoria viruses sequenced, all belonged to the V1A.3a.2 clade, represented by B/ Austria/1359417/2021, which is also the vaccine virus (Table 3).

Sensitivity analyses
Results with small sample sizes were subject to sensitivity analyses, most of which gave similar results (absolute difference < 10%). Results from the three estimates with absolute difference ≥ 10% (evidence of small sample bias) were not presented.

Discussion
In six well-established influenza studies across Europe during the 2022/23 influenza season, interim VE against influenza A (all subtypes) (all ages; primary care, emergency care and hospital settings) ranged from 27% to 44%. All interim VE against influenza B was ≥ 50%, among overall and age-stratified estimates. The proportions of influenza A and B and influenza A subtypes circulating differed by country and setting.
The proportion of subtyped influenza A viruses varied by study site (between 17% and 95%). While the lack of subtyping may have affected the precision of subtypespecific estimates, descriptive analyses at study site level indicated that those subtyped are likely to belong to a representative sample of all viruses.
In the EN-EC and EU-PC studies, for which the end-ofseason 2021/22 influenza A(H1N1)pmd09 VE are available, the 2022/23 interim season estimates were lower: 26% (among ≥ 18-year-olds) vs 76% (among ≥ 50-yearolds) in EN-EC and 28% vs 75% (among all ages) EU-PC [16,17]. The influenza vaccine component remained the same between these two seasons; however, circulating strains differed. While post-infection ferret antisera raised against the vaccine strain A/Victoria/2570/2019 had good recognition to circulating viruses, postvaccination human sera showed lower reactivity [18]. The 2022/23 end-of-season overall results, as well as clade/genetic variant-specific results and birth cohortspecific VE, may help unravel the differences between these two seasons. Additionally, around 25% of all sequenced influenza A(H1N1)pdm09 viruses in DK-PC/ DK-H and in EU-PC, and all 20 sequenced viruses in SC-H belonged to the A/Norway/25089/2022-like viruses.
The VE point estimates against influenza A(H3N2) among the three primary care and emergency care studies (DK-PC, EU-PC and EN-EC) over adult ages, at 36-42%, were slightly lower than the VE point estimates from Canada (58-59%) [19]. Among children, the primary care and emergency care study results presented here were higher at 62-70% compared with those in the Canadian study (47%). Authors in Canada noted a high proportion of T135K substitutions among those ≤ 25 years of age. Position 135 is a haemagglutinin (HA) glycosylation site associated with potential antigenic change [20]. Information on substitutions at this position is not available from all studies, but only two of the 444 sequenced EU-PC viruses and only one of 93 from the DK-H/PC studies, also in an individual aged < 25 years, harboured the T135K substitution. In EU-PC, 11% (51/444) of sequenced samples had a T135A substitution, which also involves the loss of the HA glycosylation site. All A(H3N2) viruses with available genetic information from the studies presented here belonged to the 3C.2a1b.2a.2 clade, but with varying genetic diversity within this clade.
In the DK-PC, DK-H, EN-EC and EU-PC studies, for which end-of-season 2021/22 influenza A(H3N2) VE estimates were available, the overall 2022/23 interim results against influenza A(H3N2) were higher for EN-EC and EU-PC studies (37% vs 28% and 44% vs 29%, for EN-EC and EU-PC, respectively, noting a difference in the reported age cohort for EN-EC) [16,17]. For DK-PC and DK-H, 2021/22 influenza A(H3N2) varied considerably by age group, particularly above and below 45 years of age, and cannot be directly compared with the interim 2022/23 A(H3N2) VE results in these studies [3]. However, VE was generally low (23% and 2% for DK-PC and DK-H, respectively), although sample size was also low.  [21][22][23]. All sequenced viruses belonged to the V1A.3a.2 clade and, as expected, no influenza B/Yamagata was detected among sequenced viruses. Recent B/Victoria viruses harbour substitutions at positions resulting in a phenotypic 'reversion' to viruses with similar antigenic properties to viruses circulating ≥ 50 years before [24]. Potential imprinting effects may explain differing VE by birth cohort and could be explored further if endof-season sample size allows.
In general, across influenza (sub)types, particularly for influenza A(H3N2) and B, VE point estimates were high in children. While some confidence intervals overlapped between children's and adults' estimates, the point estimates were consistently higher among children across all influenza (sub)types in each study. LAIV is part of the routine childhood immunisation schedule in the UK and has been introduced in Ireland and Denmark in recent years. The use of LAIV could contribute to the age-specific differences in VE and these results indicate good performance of LAIV in this season. A further contribution to age-specific differences in VE is that routine childhood immunisation is targeted towards all children, including healthy children. In contrast, in young adults, immunisation is indicated mainly for those with underlying medical conditions, who may be at greater risk of influenza infection/ hospitalisation.
The early start of the season in most European countries included in these six studies [5][6][7] resulted in higher incidence and greater precision for interim VE estimates than in other interim season estimates. However, due to the different circulation of influenza viruses across Europe, some studies had lower sample size for some subgroups in this interim analysis and results should be interpreted with caution. Each study used their own specific criteria to define whether a sample size was too small to attempt VE estimation. Sensitivity analyses were used to address potential small sample bias where appropriate. These studies are all observational in nature and residual confounding and bias may potentially be present.

Conclusion
Vaccination remains a successful means of influenza prevention. Interim results from six European studies during the 2022/23 influenza season indicate a ≥ 27% and ≥ 50% reduction in disease occurrence among allage influenza vaccine recipients for influenza A and B, respectively. Influenza VE point estimates were ≥ 50% against all influenza (sub)types in children, indicating a successful LAIV campaign. Influenza vaccination should continue to be promoted according to national guidelines in all European countries with ongoing influenza virus circulation.
Findings of the current study were presented as part of the Global Influenza Vaccine Effectiveness (GIVE) report to the WHO Vaccine Strain Selection Committee, held on 20-23 February 2023. In this meeting, the WHO recommendations for the 2023/24 Northern Hemisphere influenza vaccine viruses did not change for influenza B/Victoria, B/Yamagata or A(H3N2) [25]. For influenza A(H1N1)pdm09, the recommendation for the 2023-24 influenza vaccines changed to A/Victoria/4897/2022 (H1N1)pdm09-like virus for egg-based vaccines and A/ Wisconsin/67/2022 (H1N1)pdm09-like viruses for cellbased vaccines.
End-of-season influenza VE and genetic analyses may help understand observed differences in age as well as study-specific VE.

Ethical statement
The planning, conduct and reporting of the studies was in line with the Declaration of Helsinki [27]. Some countries/studies did not require official ethical approval or patient consent as they are part of routine care/surveillance: DK-H, DK-PC, EN-EC, EU-H (Ireland, Malta and Spain), EU-PC (Ireland, Spain), SC-H. In EU-PC (the Netherlands), as the data are initially collected through surveillance, no formal ethical approval was necessary. Verbal informed consent from patients for participation in the national respiratory surveillance, however, is required. In addition, patients have the option to object against participation in any further research (including VE studies). In SC-H, the EAVE-II study in Scotland was granted ethical approval by the National Research Ethics Service Committee (Southeast Scotland 02; reference number 12/SS/0201), and the approval for data linkage was granted by the Public Benefit and Privacy Panel for Health and Social Care (reference number 1920-0279). Other study sites received local ethical approval from a national or regional review board: EU-H (

Funding statement
ECDC funded the study sites and coordination of the EU-PC and EU-H VEBIS multi-country studies.