Influenza returns with a season dominated by clade 3C.2a1b.2a.2 A(H3N2) viruses, WHO European Region, 2021/22

In the WHO European Region, COVID-19 non-pharmaceutical interventions continued slowing influenza circulation in the 2021/22 season, with reduced characterisation data. A(H3) predominated and, in some countries, co-circulated with A(H1)pdm09 and B/Victoria viruses. No B/Yamagata virus detections were confirmed. Substantial proportions of characterised circulating virus subtypes or lineages differed antigenically from their respective northern hemisphere vaccine components. Appropriate levels of influenza virus characterisations should be maintained until the season end and in future seasons, when surveillance is adapted to integrate SARS-CoV-2.

In the WHO European Region, COVID-19 non-pharmaceutical interventions continued slowing influenza circulation in the 2021/22 season, with reduced characterisation data. A(H3) predominated and, in some countries, co-circulated with A(H1)pdm09 and B/ Victoria viruses. No B/Yamagata virus detections were confirmed. Substantial proportions of characterised circulating virus subtypes or lineages differed antigenically from their respective northern hemisphere vaccine components. Appropriate levels of influenza virus characterisations should be maintained until the season end and in future seasons, when surveillance is adapted to integrate SARS-CoV-2.
This study describes the 2021/22 influenza season in the World Health Organization (WHO) European Region through results of influenza virus detection and typing up to week 10 2022. Viral characterisations reported to The European Surveillance System (TESSy) up to week 4 2022 are also presented, taking into consideration continued implications of the coronavirus disease (COVID-19) pandemic. Based on the WHO Collaborating Centre (CC)'s assessments for the 2022 northern hemisphere (NH) vaccine composition meeting (VCM), similarity of circulating influenza viruses to the 2021/22 NH vaccine components are discussed.

Description of the 2021/22 influenza season up to week 10 2022
After scant influenza virus circulation in 2020/21, the 2021/22 influenza season started in week 49 2021 in the WHO European Region. In week 2 2022, positivity in sentinel primary care specimens dipped below the epidemic threshold of 10% but rose again above it in weeks 8 to 10 2022 ( Figure 1). From week 40 2021 to week 10 2022, 55,049 influenza virus detections from sentinel and non-sentinel sources were reported to TESSy by 50 countries and territories of the Region (Supplement 1). Based on sentinel detections, AH1pdm09 predominated in France [1]. In all the other countries, A(H3) was the major influenza A subtype [1], co-circulating with A(H1)pdm09 subtype and to a lesser extent type B viruses.
In the 2020 southern hemisphere (SH) and the 2020/21 NH influenza seasons, circulation of influenza viruses was shown to be very limited [2]. In 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-variant waves dominated by Delta (Phylogenetic Assignment of Named Global Outbreak (Pango) lineage designation: B.1.617.2) and Omicron (Pango: B.1.1.529) coincided with the course of the 2021/22 influenza season in the European Region [3]. Despite an overall increased testing for influenza viruses from sentinel and non-sentinel sources in the Region, which was probably related to enhanced testing for SARS-CoV-2, the total number of influenza virus detections appeared to remain lower than in seasons before the COVID-19 pandemic as shown in Supplement 1. Public health measures aimed at limiting circulation of SARS-CoV-2 likely could have contributed to this reduced positivity. Although sentinel sources continued reporting during the COVID-19 pandemic, data for the 2021/22 influenza season reflected increased testing in some of these sources, while others either did not test or reported on reduced numbers tested (Supplement 1).

Influenza virus characterisation
European influenza national reference laboratories in the Region collect virological influenza surveillance data, perform virus characterisations and report weekly aggregated and strain-based data to TESSy. The Francis Crick Institute, WHO Collaborating Centre (WHO CC) for Reference and Research on Influenza based in London, United Kingdom (UK), provides laboratories with post-infection ferret antisera for antigenic characterisation using haemagglutination inhibition assays. The Francis Crick Institute WHO CC also provides a list of reference sequences for the assignment of viruses to haemagglutinin (HA) gene clades/subclades following sequencing [4,5].
In addition to the Francis Crick Institute WHO CC, there are globally six designated WHO CCs. WHO CCs conduct research and analyses on influenza data or samples, provided by National Influenza Centers (NICs) [6]. Laboratories ship influenza specimens to WHO CCs for further in-depth analyses essential for the WHO Vaccine Composition Meeting (VCM) decisions [7].

Reporting of viral characterisations to The European Surveillance System in the beginning of the 2021/22 season
Compared with 2019/20 and 2018/19, seemingly lower amounts of antigenic and genetic characterisation data in 2021/22 were reported to TESSy ahead of the VCM on 25 February 2022 ( Figure 2). The WHO European Region Member States reporting characterisations also appeared to be fewer, with the most apparent decrease observed in numbers of countries providing antigenic data. The reason might have been that antigenic characterisation is more laborious. Combinations of reduced human or laboratory resources and biosafety concerns related to the possibility of SARS-CoV-2 coinfection might have also played a role [8].
Up to week 4 2022, 11 of 50 countries submitted virus genetic characterisation data to TESSy for the 2021/22 season (Table 1). Antigenic characterisation data were reported to TESSy by six countries. Of all viruses detected, < 1% (144/34,653) were characterised antigenically and 2% (843/34,653) genetically [9]. Ideally, all or at least 10% of the viruses originating from sentinel sources should be genetically characterised [10,11]. Reported antigenic data ( Figure 2) are presented in Table 2. In their vast majority (134/144, 93%), the antigenic data were not linked with genetic data this season.

Circulating influenza viruses at the beginning of the 2021/22 season in relation to northern hemisphere vaccine components
Because the antigenic data reported to TESSy were not linked to genetic data, they could not be used for assessing the apparent discrepancies of circulating clade proportions or the similarity of the circulating strains with the respective vaccine virus components. The WHO CC assessments for the 2022 NH VCM were used instead [7]. The characterisations further reported are until week 4 2022.

Discussion
Influenza is still circulating above the epidemic threshold in the WHO European Region as at week 10 2022 [9]. While we are in the third year of the COVID-19 pandemic, the public health emergency measures in place have continued to impact the circulation of influenza viruses in 2021/22, although less visibly than in the 2020/21 and 2019/20 seasons. With the lifting of public health measures, influenza detections rose again above the epidemic threshold in week 8 2022, and in the coming weeks influenza viruses may continue to co-circulate with SARS-CoV-2 and other respiratory viruses. Out-ofseason influenza outbreaks cannot be excluded either, particularly with increasing international travel.
The need to prioritise resources for SARS-CoV-2 surveillance during the pandemic likely affected the     proportion of influenza viruses that were characterised and their surveillance generally. As a result, the number of countries that reported influenza characterisation data were substantially fewer than in seasons before the COVID-19 pandemic. Our study has some limitations. Characterisation data up to week 4 2022 have been considered and therefore it cannot be excluded that the proportions of circulating influenza types and subtypes may change and that different clades and subclades spread throughout the remainder of the season. As only 22% (11/50) of the countries that report surveillance data to TESSy reported also genetic data, the proportion of different clades may not be generalisable to the WHO European Region as a whole.

Conclusion
NICs play a crucial role in surveillance of influenza being responsible for providing representative specimens to the WHO CC for making VCM recommendations. As influenza presently continues to circulate, NICs should keep up testing and characterising viruses throughout the remainder of current season, while staying vigilant to detect out of season influenza outbreaks as well. Characterisation data from the NH will inform the VCM decisions in the SH VCM that takes place in September─October 2022. The transition towards surveillance systems that integrate influenza, SARS-CoV-2 and other respiratory pathogens may pose challenges to the surveillance systems that need to collect, analyse and timely report data. During this transition period, laboratories will need to ensure that representative specimens for influenza virus detection continue to be collected, and subsequent virus characterisations are performed and reported [10,11].