A late sharp increase in influenza detections and low interim vaccine effectiveness against the circulating A(H3N2) strain, Denmark, 2021/22 influenza season up to 25 March 2022

We estimated interim influenza A vaccine effectiveness (VE) following a late sharp rise in cases during an influenza A(H3N2)-dominated 2021/22 season, after lifting COVID-19 restrictions. In children aged 2–6 years offered a live attenuated influenza vaccine, adjusted VE was 62.7% (95% CI: 10.9–84.4) in hospitalised and 64.2% (95% CI: 50.5–74.1) in non-hospitalised children. In non-hospitalised patients aged 7–44 years, VE was 24.8% (95% CI: 12.8–35.2); VE was non-significant in remaining age groups and hospital/non-hospital settings.

In week 12 2020, a range of interventions and restrictions to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were introduced in Denmark, which led to a sharp decline in the influenza occurrence [1]. Since then, only sporadic laboratory-confirmed influenza cases have been detected. Here we present interim vaccine effectiveness (VE) estimates of seasonal influenza vaccines following the sharp increase in the influenza occurrence late in the season after the lifting of the COVID-19 restrictions in Denmark.

Influenza detections in Denmark up to week 12 2022
From mid-February 2022, upon the relaxing of restrictions, the weekly number of cases doubled from 65 in week 6 to 3,178 in week 12 and, despite a high testing activity, the percentage of positive tests continued to increase (Figure). The circulating strain for the 2021/22 season is influenza A(H3N2) and mainly clade 3C.2a1b.2a.2, which differs from the vaccine strain (clade 3C.2a1b.2a.1).

National monitoring of laboratoryconfirmed influenza cases and seasonal vaccination
For the 2021/22 season, influenza vaccination was -in accordance with previous seasons -offered free of charge to all individuals aged 65 years and above, and to individuals with a risk of severe influenza. In addition, vaccination was also recommended and offered free of charge to healthcare workers and children aged 2-6 years. Children between 2-6 years of age were offered a live attenuated influenza vaccine (LAIV). The rest of the population was offered quadrivalent inactivated influenza (QIV) vaccines. Individuals were considered vaccinated if they had received one dose of the 2021/22 influenza vaccine at least 14 days before being tested for influenza, except children under 9 years of age; they should either receive two doses in the current season or one dose in the previous season and one in the current season at least 14 days before being tested for influenza. All administered influenza vaccines are registered in the Danish Vaccination Register (DVR) [2]. By the end of October 2021, 67% of the 2021/22 influenza vaccine doses were administered.
During the influenza season, national guidelines in Denmark recommend that patients belonging to risk groups, including elderly people who present with influenza-like illness (ILI) at a general practitioner (GP) or with ILI and/or lower respiratory symptoms at hospitals, are swabbed and tested for influenza virus (http://www.infmed.dk/guidelines). In the Danish Microbiology Database (MiBa), data on all patients swabbed at the GP or at hospitals and tested for influenza A and B viruses by PCR are registered in realtime [3]. Each sample result provides information on the date of sampling and if the sample was positive or negative for influenza virus. A random subsample of the positive influenza tests was subtyped and genetically characterised at the National Influenza Center at Statens Serum Institut.
Information on hospital admission and underlying disease(s) were available from the National Patient Registry (NPR) [4]. Patients swabbed by the GP were counted as non-hospitalised, patients swabbed within 4 days of or during an admission lasting less than 12 h in duration were also considered as non-hospitalised, while patients admitted for 12 h or more were considered as hospitalised. An increase in patients admitted to the hospital following infection with influenza A was observed, from nine patients in week 6 to 549 in week 12.

Estimating vaccine effectiveness against the circulating influenza A strain in Denmark
To examine vaccine effectiveness (VE) we initially identified all individuals tested for influenza from week 40 in 2021 and onwards. Data from MiBa, DVR and NPR were linked using the unique person-identifier that all Danish citizens receive at birth or immigration.
We excluded individuals vaccinated less than 14 days before the date of swabbing, all children aged 0-1 year and swabs taken in October and November 2021, when

Discussion
In Denmark, almost all COVID-19 interventions and restrictions were lifted by the end of January 2022 (end of week 4), which might explain the sharp increase in the influenza transmission from week 6 in 2022 and onwards. The low to no effect of the administered vaccines in both hospitalised and non-hospitalised patients aged 7 years and above against the circulating influenza A stain is similar to findings in a study from the United States where the overall VE against medically attended outpatients with influenza A(H3N2) virus was estimated to 16% (95% CI: −16 to 39) [5]. In Denmark, the majority of the influenza vaccines were administered during October 2021, which was almost 5 months before the influenza A(H3N2)-dominated increase was observed. In particular, the VE against influenza A(H3N2) declines with an increase in time since vaccination [6], which could be one explanation for the generally low VE we observed in the age groups from 7 years and above. The difference between the circulating strain and the vaccine strain is another contributing factor as the circulating influenza A(H3N2) strain belonged mainly to clade 3C.2a1b.2a.2, which has changes in the antigenic sites compared with the vaccine strain.
The higher VE in children 2-6 years might be attributed to the use of a LAIV, which can result in a better immune response in the mucosal epithelia [7]. The majority of children aged 2-6 years received the influenza vaccination for the first time this season, thus two doses were administered compared with the single dose administration of the QIV in the older age groups. In addition, the LAIV is only offered to healthy children, which might also explain the higher VE compared with the risk groups with an expected weakened immune response.
This study also has limitations. Symptom onset is not registered in the national registers, this might imply that some patients testing negative for influenza might previously have been positive.

Conclusion
In conclusion, this study showed a very late increase in the seasonal influenza transmission and no observable VE against the circulating influenza A(H3N2) strain following vaccination with the QIV in adults above 45 years, which may be due to a combination of waning immunity and antigenic drift. The study highlights that 2 years of varying COVID-19 restrictions may have affected the transmission dynamics of influenza virus. Thus, it is important to have an all-year surveillance to capture out-of-season influenza and circulation of other respiratory viruses.

Statements
Ethical statement: No ethical approval was required for this register-based study based on routine surveillance data.
Funding statement: Neither Statens Serum Institut nor any authors received funding for this study. Data availability: The individual level data used in this study are sensitive and cannot be publicly shared. Any data requests should be sent to Forskerservice at the Danish Health and Medicine Authority.