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Home Eurosurveillance Edition  2017: Volume 22/ Issue 7 Article 2
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Eurosurveillance, Volume 22, Issue 7, 16 February 2017
Rapid communication
Castilla, Navascués, Casado, Díaz-González, Pérez-García, Fernandino, Martínez-Baz, Aguinaga, Pozo, Ezpeleta, Primary Health Care Sentinel Network, and Network for Influenza Surveillance in Hospitals of Navarre: Combined effectiveness of prior and current season influenza vaccination in northern Spain: 2016/17 mid-season analysis

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Citation style for this article: Castilla J, Navascués A, Casado I, Díaz-González J, Pérez-García A, Fernandino L, Martínez-Baz I, Aguinaga A, Pozo F, Ezpeleta C, Primary Health Care Sentinel Network, Network for Influenza Surveillance in Hospitals of Navarre. Combined effectiveness of prior and current season influenza vaccination in northern Spain: 2016/17 mid-season analysis. Euro Surveill. 2017;22(7):pii=30465. DOI: http://dx.doi.org/10.2807/1560-7917.ES.2017.22.7.30465

Received:07 February 2017; Accepted:16 February 2017


During the early 2016/17 influenza season, influenza A(H3N2) was the main circulating virus in Europe [1]. Although most of the A(H3N2) viruses characterised genetically matched the vaccine component, a high incidence of severe cases was detected [1,2]. We present the 2016/17 mid-season vaccine effectiveness (VE) estimates in preventing laboratory-confirmed influenza A(H3N2), relative to different combinations of current and prior seasonal influenza vaccinations.

Setting and information sources

In the 2016/17 season the A(H3N2) component recommended for the influenza vaccine in the northern hemisphere was A/HongKong/4801/2014-like virus (group 3C.2a) [3], in the 2015/16 season A/Switzerland/9715293/2013-like (group 3C.3a) [4], and in seasons 2012/13 to 2014/15 it was A/Texas/50/2012-like or A/Victoria/361/2011-like (group 3C.1) [5].

The Influenza Surveillance System in Spain reported that as of 9 February 2017, 99% of the sentinel detections of influenza virus were A(H3N2), and sequence analysis of the HA1 fragment of the haemagglutinin gene found 74% of strains as A/Bolzano/7/2016 (group 3C.2a1) and 21% as A/HongKong/4801/2014, both of which matched the vaccine component [2].

A test-negative case–control study was conducted, based on epidemiological and virological surveillance of influenza in primary healthcare and hospitals in Navarre, northern Spain. The influenza vaccination campaign took place in October and November 2016. The trivalent inactivated non-adjuvanted vaccine was offered free of charge to a target group for vaccination, including people aged 60 years or over and those with major chronic conditions (body mass index ≥40 kg/m2, cancer, liver cirrhosis, dementia, diabetes mellitus, immunodeficiency, heart disease, renal disease, respiratory disease, rheumatic disease, and stroke).

Influenza vaccine status in seasons 2012/13 to 2016/17 was obtained from the online regional vaccination register [6]. These five seasons were considered because for all of them the A(H3N2) component included in the vaccine belonged to clade 3C [3-5].

Patients were considered to be protected from influenza 14 days after vaccine administration in the current season.

Influenza surveillance was based on automatic reporting of cases of influenza-like illness (ILI) from all primary healthcare physicians and hospitals [7]. A sentinel network of primary healthcare physicians was requested to take nasopharyngeal and pharyngeal swabs from their patients diagnosed with ILI, whose symptoms had begun less than five days previously. In hospitals, the protocol specified early detection and swabbing of all hospitalised patients with ILI. Samples were processed by reverse transcription-polymerase chain reaction assay.

Statistical analysis

The study population included persons covered by the Navarre Health Service since 2012 (96% of the population). All patients who were swabbed between 1 December 2016 (beginning of continued detection of influenza virus) and 31 January 2017 were initially considered. Healthcare workers, persons living in nursing homes, children less than 9 years-old and patients hospitalised before ILI symptom onset were excluded. We compared seasonal vaccination status in patients for whom A(H3N2) influenza virus was detected (cases) and in those who were negative for influenza (controls). Crude and adjusted odds ratios (OR) with their 95% confidence intervals (CI) were calculated using logistic regression models. Adjusted models included sex, age group (9–24, 25–44, 45–64, 65–84 and ≥ 85 years), major chronic conditions, month of swabbing, and healthcare setting (primary healthcare and hospital). Six categories combining current vaccination status with vaccination in the four prior seasons and thus distinguishing between frequent and infrequent vaccinees were considered [8,9]: current-season vaccination and > 2 prior doses, current-season vaccination and 1–2 prior doses, current-season vaccination and no prior doses, no current-season vaccination and > 2 prior doses, no current-season vaccination and 1–2 prior doses, and no current-season vaccination and no prior doses (reference group). To compare VE among categories, the model was repeated using the category with current season vaccination and > 2 prior doses as the reference. VE was estimated as a percentage: (1–OR) × 100.

Early estimation of influenza vaccine effectiveness

Of 1,243 ILI initial patients, one case of non-subtyped influenza A and two influenza B cases were not further considered. The remaining 1,240 ILI patients were included in the study and consisted of 783 (63%) hospitalised patients and 457 primary healthcare patients. A total of 591 (48%) were confirmed cases for influenza A(H3N2) and were compared with 649 controls negative for any influenza virus.

Compared with test-negative controls, A(H3N2) influenza cases had a lower proportion of persons over 65 years-old (53% (315/591) in cases vs 62% (401/649) in controls; p = 0.003), with major chronic conditions (59% vs 71%; p < 0.001; Table 1) and who were treated in hospital (51% (300/591) vs 74% (483/649; p < 0.001)). Among the cases, 41% had received the 2016/17 seasonal vaccine, vs 50% of the controls (p = 0.001) (Table 1).

Table 1

Characteristics, according to the healthcare setting and test result, of patients with medically-attended influenza-like illness included in the test-negative case–control analysis, Navarre, Spain, 1 December 2016–31 January 2017 (n = 1,240 patients)

Characteristics All patients Hospitalised patients Primary healthcare patients
Controls Cases Controls Cases Controls Cases
N % N % N % N % N % N %
Age groups in years
9–24 37 6 56 9 14 3 1 0 23 14 55 19
25–44 76 12 99 17 22 5 7 2 54 33 92 32
45–64 135 21 121 20 80 17 33 11 55 33 88 30
65–84 269 41 197 33 236 49 143 48 33 20 54 19
≥ 85 132 20 118 20 131 27 116 39 1 1 2 1
Sex
Male 331 51 274 46 269 56 151 50 62 37 123 42
Female 318 49 317 54 214 44 149 50 104 63 168 58
Residence
Rural 237 37 213 36 213 44 154 51 24 15 59 20
Urban 412 63 378 64 270 56 146 49 142 86 232 80
Major chronic conditions
No 189 29 242 41 78 16 43 14 111 67 199 68
Yes 460 71 349 59 405 84 257 86 55 33 92 32
Month of swabbing
December 159 24 139 24 106 22 58 19 53 32 81 28
January 490 76 452 76 377 78 242 81 113 68 210 72
Target group for vaccinationa
No 124 19 182 31 36 7 11 4 88 53 171 59
Yes 525 81 409 69 447 93 289 96 78 47 120 41
2016/17 season vaccine
No 327 50 351 59 205 42 113 38 122 73 238 82
Yes 322 50 240 41 278 58 187 62 44 27 53 18
Total 649 100 591 100 483 100 300 100 166 100 291 100

a Target group for vaccination includes people ≥ 60 years old and people with major chronic conditions (body mass index ≥40 kg/m2, cancer, liver cirrhosis, dementia, diabetes mellitus, immunodeficiency, heart disease, renal disease, respiratory disease, rheumatic disease and stroke).

The overall adjusted estimate of influenza VE was 15% (95%CI: –11 to 35). The estimates were similar in the analysis of the target group for vaccination (16%), and were somewhat better in persons younger than 65 years (24%) than in the older age group (≥ 65 years; 11%). The point estimates suggested higher VE in outpatients (48%; 95%CI: –1 to 65) than in inpatients (0%; 95%CI: –38 to 27) (Table 2).

Table 2

Influenza vaccine effectiveness in preventing laboratory-confirmed influenza A(H3N2) among individuals ≥ 9 years-old in Navarre, Spain, 1 December 2016–31 January 2017 (n = 1,240 patients)

Characteristics Controls
Vaccinated/unvaccinated
Cases
Vaccinated/unvaccinated
   Crude VE   
% (95% CI)
   Adjusted VE   
% (95% CI)a
Both healthcare settings
All swabbed patients 322/327 240/351 31 (13 to 45) 15 (−11 to 35)
Target group for vaccinationb 307/218 225/184 13 (−13 to 33) 16 (−12 to 37)
Age group in years
9−64 56/192 37/239 47 (16 to 66) 24 (−26 to 55)
≥ 65 266/135 203/112 8 (−25 to 33) 11 (−23 to 35)
Hospitalised patients
All swabbed patients 278/205 187/113 −22 (−64 to 9) 0 (−38 to 27)
Target group for vaccinationb 272/175 185/104 −14 (−55 to 16) 2 (−36 to 29)
Age group in years
9−64 33/83 14/27 −30 (−179 to 39) −27 (−188 to 44)
≥ 65 245/122 173/86 0 (−40 to 29) 5 (−34 to 33)
Primary healthcare patients
All swabbed patients 44/122 53/238 38 (3 to 61) 48 (−1 to 65)
Target group for vaccinationb 35/43 40/80 39 (−10 to 66) 54 (10 to 77)
Age group in years
9−64 23/109 23/212 49 (4 to 72) 43 (−8 to 70)
≥ 65 21/13 30/26 29 (−70 to 70) 44 (−41 to 78)

CI: confidence interval; VE: vaccine effectiveness.

a Logistic regression model adjusted for sex, age group (9–24, 25–44, 45–64, 65–85 and ≥ 85 years), major chronic conditions, month of swabbing and healthcare setting (primary healthcare and hospital).

b Target group for vaccination includes people ≥ 60 years old and people with major chronic conditions (body mass index ≥40 kg/m2, cancer, liver cirrhosis, dementia, diabetes mellitus, immunodeficiency, heart disease, renal disease, respiratory disease, rheumatic disease and stroke).

In the pooled analysis of all patients, as compared with individuals unvaccinated in the current and four prior seasons, the preventive effect was 61% (95%CI: 30 to 78) in those vaccinated in the current season who had also received 1–2 doses of vaccine in the prior seasons, 24% (95% CI: –6 to 46) in those vaccinated in the current season after 3–4 doses, 42% (95% CI: –5 to 68) in those vaccinated only in the current season, 58% (95%CI: 26 to 78) in individuals without current vaccination but with > 2 prior doses, and 44% (95% CI: 3 to 68) in those unvaccinated in the current season but with 1–2 prior doses. Current and 1–2 dose prior season vaccination, or current season non-vaccination in people with > 2 prior doses showed statistically significant higher protection than current and > 2 prior season vaccinations (Figure).

Figure

Effectiveness of current season influenza vaccination and of vaccination in the four prior seasons in preventing laboratory confirmed influenza A(H3N2) cases among people ≥ 9 years-old in Navarre, Spain, 1 December 2016–31 January 2017 (n = 1,240 patients)

/images/dynamic/articles/22719/17-00095-f1

CI: confidence interval.

a Vaccine effectiveness adjusted by age groups (9–24, 25–44, 45–64, 65–84 and ≥ 85 years), sex, major chronic conditions(body mass index ≥40 kg/m2, cancer, liver cirrhosis, dementia, diabetes mellitus, immunodeficiency, heart disease, renal disease, respiratory disease, rheumatic disease and stroke), healthcare setting (primary healthcare and hospital), and month of swabbing.

b p < 0.05 for comparisons with the category ‘Current season vaccination + >2 prior doses’.

In separated analyses of outpatients and inpatients, vaccination only in the current season was protective for primary healthcare consultations but not for hospitalisations. In hospitalised patients however, a history of vaccination in the prior seasons appeared to confer enhanced protection, whether the inpatients were vaccinated or not in the current season (Figure).

Discussion and conclusion

Estimates of VE during the influenza season help guide health interventions aimed at reducing the impact of influenza in the population [10] and may help in the selection of strains to be contained in the next season’s vaccine. For the 2016/17 season in Navarre, when vaccination status in the prior influenza seasons was not considered, we found low VE (15%) in the whole pool of patients, null VE for hospitalised patients and better protection (48%) for outpatients; the higher protection level in outpatients is consistent with the early estimates reported from the Canadian Sentinel Practitioner Surveillance Network [11].

In the analysis considering vaccination history; however, better levels of protection were observed for many of the combinations of current and prior season vaccination, especially for hospitalised patients. The results of the overall analysis suggest that the protective effect of the influenza vaccination against A(H3N2) virus in Navarre in the early 2016/17 season ranged from 24% to 61%, depending on the vaccination status in the current and prior seasons.

The VE estimates were strongly related to the vaccination history. One or two vaccine doses over the four prior seasons maintained or increased the protection of the current season vaccination, but three or more prior doses had a negative interference with the current season vaccine effect. A similar interference was described in previous seasons by other authors [8,12], and inverse exposure-response association has been reported between repeated influenza vaccination and haemagglutinin antibodies titres for A(H3N2) virus [13].

Our results obtained from two independently recruited groups, inpatients and outpatients, were broadly consistent. The main difference was that vaccination only in the current season was protective for influenza cases attended in primary healthcare but not against influenza hospitalisations, which may be due to the poorer immune response among patients that need hospitalisation. Especially remarkable is the preventive effect observed for the vaccine doses received in prior seasons in individuals without current season vaccination.

This study has some limitations. Natural immunity due to exposure to influenza virus was not considered; however, in a previous study we demonstrated that it was not a relevant confounding factor or effect modifier of influenza VE [7]. Since these results are preliminary and have limited statistical power for some analyses, the final results for the season may be different. The study compared laboratory-confirmed cases with controls recruited in the same settings before either patient or physician knew the laboratory result, an approach that reduced selection bias [14]. We included patients recruited in primary care and hospitals, thus achieving representation of the whole spectrum of patients with influenza. The healthcare setting could have acted as a confounding factor, therefore the analyses were adjusted for this variable. This study evaluates a particular situation of circulating virus and composition of the vaccines; caution should be taken in generalising its outcome.

In conclusion, the results suggest that, overall, the different combinations of vaccination in the current and prior seasons were moderately effective against influenza A(H3N2) in the early 2016/17 season in northern Spain. In spite of the possible interferences between the effects of the current season vaccine and frequent prior vaccination, these findings highlight the net benefit of immunisation against influenza.


Primary Health Care Sentinel Network of Navarre

The members of the Primary Health Care Sentinel Network of Navarre are: I Abad, P Aldaz, R Ansorena, I Arceiz, E Arina, MA Arrechea, I Arribas, MD Artajo, B Azagra, N Aznarez, FC Bartolome, A Beguiristain, A Beltrán, M Bidarte, I Blanco, A Brugos, B Cano, MV Castresana, JC Cenoz, F Cia, B Compains, JR Corpas, F Cortés, B Churío, PC Cuevas, EM Da Costa, MR Díez, FJ Escribano, MJ Esparza, V Etayo, C Fernández Alfaro, B Flamarique, ML Garcés, FJ García Nicolás, AB German, A Giner, JO Guiu, JC Gurbindo, MJ Guruchaga, JA Heras, M Hernández Galindo, MC Hijos, S Indurain, B Iñigo, MC Irigoyen, JJ Jurio, MJ Lizaso, JJ Longás, MJ López, MT Maquirriain, M Mazquiaran, JJ Miner, M Moreno, MA Moros, U Navarro, M Orte, M Oscoz, P Palacio, J Palau, C Pérez Lecumberri, P Pérez Pascual, B Pérez Sanz, A Prado Virto, M Prado Santamaria, A Puig Arrastia M Ramos, BE Rípodas, M Rodríguez, MA Roncal, I Ruiz Puertas, C Sánchez, P Sarrasqueta, F Satrústegui, MA Senosiain, M Sota, ME Ursua, IA Urtasun, M Zardoya, ME Zubieta, F Elia, E Albeniz.

Network for Influenza Surveillance in Hospitals of Navarre

The members of the Network for Influenza Surveillance in Hospitals of Navarre are: A Navascués, P Artajo, C Beaumont, X Beristain, J Chamorro, C Ezpeleta, F Gallinas, F Gil, M Herranz, J Hueto, C Martín, L Moreno, S Martínez-Pérez, C Pérez, J Sesma (Complejo Hospitalario de Navarra), MT Ortega, JJ García Irure, M Torres (Hospital Reina Sofía, Tudela), F Lameiro, L Barrado, E Martín (Hospital García Orcoyen, Estella), M Arriazu, M Garcia Cenoz, A Barricarte, J Castilla (Instituto de Salud Pública de Navarra).

Acknowledgements

This study was supported by the Horizon 2020 program of the European Commission (agreement 634446); by the I-MOVE (Influenza Monitoring Vaccine Effectiveness in Europe) Network funded by the European Centre for Disease Prevention and Control; by La Caixa Foundation; and by the Carlos III Institute of Health with the European Regional Development Fund (ERDF) (CM15/00119, INT15/00182).

Conflict of interest

None declared.

Authors’ contributions

J Castilla, I Casado and I Martínez-Baz designed the study and coordinated the activities. I Martínez-Baz, I Casado and J Castilla undertook the statistical analysis. A Navascués, A Aguinaga, A Pérez-García, C Ezpeleta and F Pozo were responsible of the virological analysis and the interpretation of laboratory results. J Díaz-González, L Fernandino and I Casado participated in the data collection. J Castilla, C Ezpeleta, F Pozo and I Martínez-Baz wrote the draft manuscript, and all authors revised and approved the final version.


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