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In a multicentre European hospital study we measured influenza vaccine effectiveness (IVE) against A(H3N2) in 2016/17. Adjusted IVE was 17% (95% confidence interval (CI): 1 to 31) overall; 25% (95% CI: 2 to 43) among 65–79-year-olds and 13% (95% CI: −15 to 30) amongthose ≥80 years. As the A(H3N2) vaccine component has not changed for 2017/18, physicians and public health experts should be aware that IVE could be low where A(H3N2) viruses predominate.
In 2016/17, the influenza season in Europe was characterised by an early start (week 46, 2016) and a predominance of A(H3N2) viruses. Overall, 89% of strains reported to the European Centre for Disease Prevention and Control (ECDC) were A(H3N2) viruses . High hospitalisation rates and case fatality ratios were reported among persons aged 65 years and above . The I-MOVE+(Integrated Monitoring of Vaccines in Europe plus) hospital network early estimates, suggested a low 2016/17 seasonal influenza vaccine effectiveness (IVE) against hospitalisation with influenza A(H3N2) among persons aged 65 years and above in the European Union (EU) .
Since the A(H3N2) vaccine component has not changed in 2017/18, we present the final 2016/17 season IVE against hospitalisation with influenza A(H3N2) among persons aged 65 years and above in Europe, to inform on the level of IVE that can be expected against A(H3N2) in the upcoming 2017/18 season.
We conducted a multicentre hospital-based test-negative design (TND) case-control study in 27 hospitals from 10 countries (Croatia, Finland, France, Hungary, Italy, Lithuania, the Netherlands, Portugal, Romania and Spain) according to a generic protocol adapted to each local setting . The detailed methods are described elsewhere . In brief, hospital teams identified and swabbed patients aged 65 years and above, hospitalised with signs compatible with a severe acute respiratory infection (SARI) defined as at least one systemic and one respiratory sign or symptom. Swabs were tested with reverse-transcriptase polymerase chain reaction (RT-PCR) for influenza A(H3N2), A(H1N1)pdm09 and B. We compared the odds of vaccination between patients positive for influenza A(H3N2) virus and those negative for any influenza virus. We calculated IVE as (1-odds ratio (OR)).
We measured IVE stratified by age group (65–79 year-olds and≥80 year-olds), presence of underlying conditions (diabetes mellitus, cancer, heart or lung disease, and presence of at least two underlying chronic diseases) and 2015/16 seasonal influenza vaccination status. In a one-stage approach, using logistic regression with the study site as a fixed effect, we adjusted IVE estimates for date of symptoms onset, age (as cubic splines) and individual underlying conditions. Using patients unvaccinated in both 2015/16 and 2016/17 seasons as a reference, we computed the effectiveness of being vaccinated in 2015/16 season only, in 2016/17 season only and in both seasons.
We included 1,073 influenza A(H3N2) cases, nine A(H1N1)pdm09 cases, 13 cases of influenza B and 1,541 controls between week 47, 2016 and week 14, 2017. Due to the small number of cases, we were not able to measure IVE against influenza A(H1N1)pdm09 and B. We excluded these 22 records from all analyses.
The median age of A(H3N2) cases was 81 years (range: 65−102 years) while that of controls was 80 (range: 65−102 years). Ninety-four percent of cases and 95% of controls had at least one underlying condition (p=0.14). Controls were more likely than cases to have underlying lung disease (44 vs 37%, p<0.05), rheumatologic disease (22 vs 15%, p<0.05) and cancer (24 vs 19%, p<0.05), to have been hospitalised in the past 12 months (44 vs 33%, p<0.05) and to be current smokers (26 vs 20%, p<0.05) (Table 1).
The one-stage pooled adjusted IVE was 17% (95% confidence interval (CI): 1 to 31) overall; 25% (95% CI: 2 to 43) among patients aged 65–79 years and 10% (95 %CI: −15 to 30) among those aged 80 years and above. Among patients with specific underlying conditions, IVE ranged between 19% (95% CI: −1 to 35) among patients with heart disease and 35% (95% CI: 14 to 51) among patients with lung disease (Table 2).
The 2016/17 seasonal IVE was −2% (95% CI: −44 to 28) among patients who had received 2015/16 seasonal influenza vaccine and 39% (95 %CI: −3 to 59) among patients not vaccinated in 2015/16 (Table 2). Taking as a reference patients unvaccinated in 2015/16 and 2016/17, IVE for those vaccinated in 2015/16 only was 19% (95% CI: −15 to 42) and IVE when vaccinated both in 2015/16 and 2016/17 was 15% (95 %CI: −3 to 30) (Table 3).
In the 2016/17 influenza season, A(H3N2) viruses largely predominated. IVE against hospitalisation with influenza A(H3N2) virus infection among persons aged 65 years and above was low at 17%. The IVE point estimate was even lower (10%) among patients aged 80 years and above. IVE was similar among patients with heart disease, diabetes mellitus and cancer. The IVE point estimate was higher among patients with lung disease. While 95% CIs were largely overlapping, the 2016/17 IVE point estimate was lower (IVE: −2%) among patients vaccinated also in 2015/16 than among those unvaccinated in 2015/16 (IVE:39%).
Low IVE against influenza A(H3N2) among persons aged 65 years and above has been previously observed in hospital settings [6-8]. A recent meta-analysis measured that the pooled IVE against hospitalisation with influenza A(H3N2) in seasons when circulating and vaccine strains were antigenically different was 14% (95% CI: −3 to 30) among persons aged 65 years and above . It was 43% (95% CI: 33 to 53) in seasons when circulating and vaccine A(H3N2) strains were antigenically similar; 48% (95% CI: 37 to 59) against influenza A(H1N1)pdm09 and 38% (95% CI: 25 to 53) against influenza B .
Based on specimens received from week 40/2016 to week 5/2017, available antigenic data from the World Health Organization (WHO) European Region indicated that most circulating viruses that could be analysed were considered as antigenically similar to the 2016/17 vaccine component . Consequently, European data supported the WHO recommendation to maintain the same vaccine component A/Hong Kong/4801/2014 (clade 3C.2a) for influenza A(H3N2) in the 2017/18 season vaccine for the northern hemisphere . However, one third of viruses isolated during the above-mentioned period could not be assigned to an antigenic reporting category, reflecting technical challenges or antigenic changes in circulating viruses. Genetic data from Europe centralised at the ECDC suggested that circulating A(H3N2) viruses had undergone considerable genetic diversification during the above-mentioned period, with the emergence of subclusters within clade 3C.2a and subclade 3C.2a1 .
In September 2017, WHO updated the A(H3N2) component to A/Singapore/INFIMH-16-0019/2016 (subclade 3C.2a1) in the 2018 seasonal vaccine for the southern hemisphere . The latest WHO update on 2 October 2017, reported that influenza A(H3N2) viruses were still predominating worldwide in September 2017. Further genetic information was not provided at this stage .
Our results taking patients unvaccinated in both 2015/16 and 2016/17 seasons as a reference suggested that influenza vaccination in 2015/16 and/or 2016/17 reduced the risk of influenza-associated hospitalisation among vaccinated patients. Our stratified results suggested that 2015/16 vaccination modified the 2016/17 IVE. Although too imprecise to be conclusive, our results could suggest that patients vaccinated in both seasons benefited from a residual protection from the 2015/16 vaccine, with no additional effect of the 2016/17 vaccine uptake.
Our results suggest a low IVE against hospitalised influenza A(H3N2) among persons aged 65 years and above, particularly among patients aged 80 years and above. They also suggest a modifying effect of 2015/16 influenza vaccination on 2016/17 IVE. The A(H3N2) virus component included in the 2017/18 vaccine will remain the same as in the 2016/17 season. The latest WHO influenza surveillance report suggests that influenza A(H3N2) viruses were predominating worldwide in August 2017. Low IVE may be expected during the 2017/18 season in case of predominant circulation of A(H3N2) viruses. However, IVE against influenza A(H1N1)pdm09 and B are usually reported to be higher. Close monitoring of virological surveillance data will be required to prompt early promotion of complementary measures such as the use of antivirals or non-pharmaceutical interventions.
Funding: The I-MOVE+ project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 634446. The Lithuanian I-MOVE+ study sites were supported by a grant from the Research Council of Lithuania (SEN-03/2015). We are grateful to all patients, medical staff, study nurses and epidemiologists from the 12 study sites who actively participated in the study.
Poland: Iwona Paradowska-Stankiewicz, Monika Korczyńska, Lidia Brydak, Katarzyna Cieślak, Dorota Kowalczyk, Karol Szymański, NIPH, NIH Poland. All participating GPs, Epidemiologists and Virologists from SES in Poland
Finland: Jukka Jokinen, Outi Lyytikäinen and Arto Palmu (study design, protocol writing), Päivi Sirén (clinical data collection), Esa Ruokokoski (data management), The laboratory staff in Viral Infections Unit of THL, Tampere University Hospital, Hatanpää Hospital (collaboration with the clinical work and data collection).
France: Hôpital Cochin, Paris: J. Charpentier, N. Marin, B. Doumenc, C. Le jeunne, A. Krivine, D. Dusser, S. Momcilovic, F. Terrier. CHU de Rennes: N. Belhomme, S. Simon, S. Cochennec, A. Reilhac, F. Erhel, C. Doudnikoff, J. Fouchard, B. Lefeuvre. Hôpital Edouard Herriot, Lyon: T. Benet, S. Amour, L. Henaff. Hôpital Saint-Eloi, Montpellier: P. Géraud, M. Berthelot, V. Driss, A. le Quellec, A. Bourdin, L. Landreau, A. Konaté, P. Corne, M. Sebbane, K. Klouche, M.S. Léglise, H. Goin.
Members of the I-Move+hospital working group: EpiConcept: Marta Valenciano
Spain: F. Pozo (National Centre for Microbiology, National Influenza Reference Laboratory, WHO-National Influenza Centre, Institute of Health Carlos III), M. García, M. Latorre (Dirección General de Salud Pública, Aragón), M. Omeñaca (H.U. Miguel Servet, Aragón), M. Oribe Amores, N. Muñoz (Subdirección de Salud Pública Gipuzkoa, País Vasco), G. Cilla (H. U. Donostia, Pais Vasco)
Navarre: L Fernandino, I Martínez-Baz (Instituto de Salud Pública de Navarra, Pamplona), A Navascués, A Pérez-García, A Aguinaga, C Ezpeleta (Complejo Hospitalario de Navarra, IdiSNA, Pamplona, Spain)
Italy: A. Bella, Eva Charlotte Appelgren, M.R. Castrucci, S. Puzelli (Istituto Superiore di Sanità, Rome), M.Chironna, C. Germinario (Policlicnico Hospital, University of Bari); F. Ansaldi, A. Manini, E. Montomoli (Department of Molecular and Developmental Medicine, University of Siena)
Romania: E. Lupulescu, M. Lazar, M.E. Mihai, C.M Cherciu, S. Dinu, C. Tecu (National Institute for Research Cantacuzino), M. Nitescu, R. Bacruban, D. Azamfire, A. Dumitrescu, E. Ianosik. (INBI Prof Dr Matei Bals, Bucuresti), E. Ceausu, C. P. Popescu, SA. Florescu, G. Târdei (Spitalul Clinic de Boli Infectioase si Tropicale Victor Babes, Bucuresti), C. Bejan, A. Teodor, G. Juganariu, C. Plesca, E. Duca (Spitalul Clinic de Boli Infectioase Sf. Parascheva, Iasi)
France: N. Lenzi, Z. Lesieur [Inserm, F-CRIN, Innovative clinical research network in vaccinology (I-REIVAC)], P. Loulergue (CIC De Vaccinologie, Cochin-Pasteur Paris, I-REIVAC), F. Galtier (Hôpital Saint-Eloi, CHU de Montpellier, I-REIVAC), C. Agostini, M. Ray, C. Merle, V. Foulongne (CHU de Montpellier), B. Lina (Université Lyon 1, CNR Virus Influenza France Sud, Lyon), F. Lainé (Hôpital Pontchaillou, CHU de Rennes, I-REIVAC), S. De Guibert, G. Lagathu, P. Tattevin, S. Jouneau, A. Esvant, T. le Gallou (Hôpital Pontchaillou, CHU de Rennes), F. Carrat (UPMC Univ Paris 06, IPLESP UMRS 1136, Public health department, Hôpital Saint-Antoine, Paris), G. Mawuvi, F. CHAU (UMRS 1136, Paris).
Finland: H. Nohynek, A. Haveri (National Institute for Health and Welfare)
Lithuania: G. Gefenaite, D. Velyvyte (Department of Infectious Diseases of Lithuanian University of Health Sciences, Kaunas, Lithuania) L. Jancoriene, B. Zablockiene, A. Ambrozaitis (Clinic of Infectious, Chest Diseases, Dermatovenerology and Allergology, Vilnius University Faculty of Medicine, Vilnius, Lithuania; Centre of Infectious Diseases, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania), R. Grimalauskaite, G. Damuleviciene, V. Lesauskaite (Department of Geriatrics, Lithuanian University of Health Sciences, Kaunas, Lithuania), A. Bagdonas (Department of Internal Medicine, Lithuanian University of Health Sciences)
Portugal: B. Nunes, I. Kislaya, A.P. Rodrigues (National Health Institute Doutor Ricardo Jorge, Lisbon), V. Gomes, R. Côrte-Real (Centro Hospitalar de Lisboa Central, Lisbon), J. Poças, M.J. Peres (Centro Hospitalar de Setúbal, Setúbal)
Croatia: Bernard K., S. Kurecic-Filipovic, V. Visekruna Vucina (Croatian Institute of Public Health), A. Topic, N. Papic, J. Budimir (University Hospital for Infectious Diseases “Dr.Fran Mihaljevic”)
Hungary: B. Oroszi (Office of the Chief Medical Officer, Budapest)
The Netherlands: A. Meijer, W. van der Hoek (National Institute for Public Health and the Environment (RIVM), Bilthoven), P.M. Schneeberger (Jeroen Bosch Hospital, 's Hertogenbosch)
Conflict of interest: None declared.
Authors’ contributions: Marc Rondy was involved in the original methodological design of the study (generic protocol). He coordinated the European hospital IVE network, undertook the statistical analysis on which the research article is based and led the writing of the research article.Alain Moren initiated the original methodological design of the study. He coordinated the European hospital IVE network and contributed to the writing of the research article.
Alin Gherasim, Itziar Casado, Odile Launay, Caterina Rizzo, Daniela Pitigoi, Aukse Mickiene, Sierk D. Marbus, Ausenda Machado, Ritva S. Syrjänen, Iva Pem-Novosel, Judith Krisztina Horváth, Amparo Larrauri, Jesús Castilla, Philippe Vanhems, Valeria Alfonsi, Alina E. Ivanciuc, Monika Kuliese, AB van Gageldonk-Lafeber, Veronica Gomez, Niina Ikonen, Zvjezdana Lovric and Annamária Ferenczi were responsible for the coordination of the study at the local level. They were in charge of the data collection and management. They read, contributed to and approved the final version of the manuscript.
The I-MOVE+ hospital working group contributors contributed to developing the study site specific protocol. They were in charge of supervising the study at the hospital level and collect the data published in this research article. They read, contributed to and approved the final version of the manuscript.