I-MOVE Monitoring of the influenza vaccine effectiveness in , , 2008-2012

Jesús Castilla Institute of Public Health of Navarre

This activity has been supported by: - Government of Navarre - ECDC (I-MOVE network) - Carlos III Institute of Health, Government of Spain.

1 Monitoring of the influenza VE in Navarre

• Setting: Navarre, Spanish region with 642,051 inhabitants.

• Navarre Health Service provides health care, free at point

of service, in primary health care centers and hospitals.

• Health care computerised database – Medical records of patients (hospital, primary health care, laboratory, vaccination register..). – Updated by the doctors and nurses when they are seeing the patients. – Coverage: 630,673 (97%).

• For monitoring VE we use: – Baseline variables: demographic, chronic conditions, use of health care services. – Regional vaccination register. – Communicable disease reporting of ILI from GPs and hospitals. – Laboratory results. Two laboratories perform RT-PCR and one of them viral culture. – Hospital discharges. – Deaths

2 Influenza vaccination programme in Navarre

1. Vaccine – The regional government annually purchases ~120,000 doses (19% of population). – Trivalent non-adjuvanted vaccine of subunits.

2. Free of charge offered to: • ≥60 years old. • <60 years old with comorbidity or risk factors. • Others: health care workers, other professions, institutionalised.

3. Campaign in October and November.

3 Vaccine coverage by age in the 2011-2012 Excluding institutionalised population and health care workers % 80 Coverage in all ages: 15% 69 67 66 70 ≥65 years: 58% 64 59 60 56

50 44 40 31 30 26 20 12 7 5 10 3 4 3 3 2 1 2 2 3 0 1- 5- 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85- 90- 95- 100- Age (years)

4 Influenza surveillance in Navarra, 2011-2012

Automatic reporting of all MA-ILI cases (European definition)

Swabbing and reporting of Whole population all hospitalized patients with n=642,051 influenza-like illness (ILI)

Population covered by the GP sentinel network Swabbing of all MA-ILI n=98,599 (15%) <5 days from symptom onset

Cohort study population (excluding population not covered by the Public Health Care Service, institutionalized population, health care workers and children <6 months): 619,648 (96%)

Sentinel network: 76 GP and pediatricians

5 Influenza vaccination campaign 2011-12 Doses of influenza vaccine and MA-ILI cases per day

Doses Vaccine coverage in Cases 8000 non-institutionalized population: Doses of influenza vaccine 800 - All ages: 15% 7000 - ≥65 years old: 58% MA-ILI 700

6000 112 days 600

5000 500

4000 400

3000 300

2000 200

1000 100

0 0 t t c v i eb br br -d -a 3-oc 9-ene 3-ene 6-f 5-mar 2-a 17-oct 31-oc 14-nov 28-no 12-dic 26 2 20-feb 19-mar 16-abr 30

6 Objectives

 To evaluate the effectiveness of the influenza vaccine in preventing:

 MA-ILI

 Laboratory-confirmed influenza in primary health care

 Hospitalization with laboratory-confirmed influenza

 All-cause deaths

 To provide early reliable estimates of the VE. Weekly updated results starting before or in the peak.

7 Vaccine effectiveness in preventing MA-ILI in the cohort population. 2011-2012, week 50 to 20

MA-ILI 11701 (50.6 per 1000 PY) Unvaccinated 231,104 PY No cases Population N= 619,648 269,320 person-years MA-ILI Vaccinated 919 (24.0 per 1000 PY) 38,216 PY

No cases

Crude VE 52% (49% to 56%) < 18 years 34 % (18% to 46%) Adjusted VE* 29% (24% to 35%) 18-64 years 31 % (23% to 39%) ≥ 65 years 25 % (14% to 34%)

*Cox regression model adjusted by sex, age (10-year groups), urban/rural, migrant, major chronic conditions, visits to the GP in the previous year, children in the household. Stratified by GP, high risk condition, age (<18; 18-64; ≥65 years)

8 Swabbing in MA-ILI by health care setting and week, 2011-2012

160 450 Hospitalized patients (n=194) 400 140 Primary care sentinel network (n=669)

Incidence of MA-ILI (n=13,581) 350 120

300 100 250 80 200 60 150 Patientsswabbed 40 100 Rate per 100,000 per Rate inhabitants

20 50

0 0 40 42 44 46 48 50 52 2 4 6 8 10 12 14 16 18 20 Week

9 Incidence of MA-ILI and laboratory results by week, 2011-2012

160 450 Influenza negative patients Influenza B (n=28) 400 140 Influenza A/H3N2 (n=382) Influenza A(H1N1)2009 (n=1) 350 120 Incidence of MA-ILI

Study period 300 100 250 80 200 60 150 Patientsswabbed 40 100 Rate per 100,000 per Rate inhabitants

20 50

0 0 40 42 44 46 48 50 52 2 4 6 8 10 12 14 16 18 20 Week

10 Characterization of influenza strains. Navarra 2011-12 (n=113/411)

100%

B/Brisbane/60/2008(Victoria) 80% B/Brisbane/3/2007(Yamagata)

60% B/Bangladesh/3333/20/07(Yamagata) A/StPetersburg/100/2011(nH1N1) 40% A/Iowa/19/2010(H3N2) A/Stockholm/18/2011(H3N2) 20% A/England/259/2011(H3N2) A/Victoria/361/2011(H3N2) 0% Primary care Hospital

Results provided by the WHO National Influenza Centre – Madrid, Spain

11 VE in preventing laboratory-confirmed influenza. Test- negative case-control analysis of all swabbed patients. Week 50 to 20

Vaccinated: 50 Influenza (+) n = 411 (54.5%) Unvaccinated: 361

Swabbed patients n = 757

Vaccinated: 65

Influenza ( - ) n = 346 Unvaccinated: 281

Crude VE: 41%; 95% CI, 11% to 60% Adjusted VE*: 31%; 95% CI, -21% to 60%

•Logistic regression adjusted by sex, age group (<5, 5-24, 25-44, 45-64, 65-84, >85), major chronic condition (0, 1, >1), hospitalization in previous year, visits in previous year, setting (hospital/outpatient), period (week 50-3, 4-10, 11-20)

12 VE in preventing laboratory-confirmed influenza, 2011-2012 Test-negative case-control design % 100

80

60

40 31 30 31 29 20 19

0

-20

-40 All patients Target Primary Hospitalized Influenza population care patients A/H3N2 for patients vaccination

13 VE in preventing hospitalization with laboratory-confirmed influenza in the target population for vaccination.

Influenza (+) A Hospitalization with ILI Vaccinated Influenza (-) 17,886 PY B

No C High risk population 49,616 PY Influenza (+) A Hospitalization with ILI Unvaccinated Influenza (-) B 31,730 PY

No C

Cohort analysis: A vs. B+C Test-negative case-control analysis: A vs. B

14 VE in preventing hospitalization with laboratory-confirmed influenza in target population for vaccination

Season 2010-2011*** Adjusted VE (95% CI)

Cohort analysis 58% (16% to 79%)*

Test negative case-control 59% (4% to 83%)**

Season 2011-2012 Adjusted VE (95% CI)

Cohort analysis 20% (-148% to 74%)*

Test-negative case-control 19% (-214% to 79%)**

* Cox regression adjusted by sex, age, urban/rural, major chronic conditions, hospitalization in the previous year, visits in previous year, pneumococcal vaccination. **Logistic regression adjusted by sex, age, major chronic condition, hospitalization in the previous year, visits in previous year, pneumococcal vaccination and epidemiological period. *** Vaccine 2012; 30:195-200.

15 VE in preventing laboratory-confirmed influenza by time after vaccination, 2011-2012 Test-negative case-control design %100

80

60 61

40 42 31 20

0

-20

-35 -40 Total <100 days 100-119 days ≥120 days

16 VE in preventing laboratory-confirmed influenza by season and health care setting Test-negative case-control design 100

89 91 80 72 67 60 59

40 31 Vaccine effectiveness (%) effectiveness Vaccine 20 19

0 Primary Primary Hospital Primary Hospital Primary Hospital care care care care 2008-2009 2009-2010 2010-2011 2011-2012

17 VE in preventing laboratory-confirmed influenza in Navarra and Europe (I-MOVE) Test-negative case-control design 100

89 80 72 72 67 60 59 56

40 31 27

Vaccine effectiveness (%) effectiveness Vaccine 20

0 Navarre I-MOVE Navarre I-MOVE Navarre I-MOVE Navarre I-MOVE Europe* Europe* Europe* Europe* 2008-2009 2009-2010 2010-2011 2011-2012

*Population with indication for vaccination. I-MOVE, By cortesie of M Valenciano and E Kissling Valenciano et al PlosMed 2011; Kissling et al PlosOne 2012

18 Early estimates of the VE in preventing laboratory-confirmed influenza. Cumulative analysis up to different dates. Test-negative case-control design 100

80

64 66 61 60 59 58

46 40 35 31 33 31 Vaccine effectiveness (%) effectiveness Vaccine 20

0 8Jan 15Jan 22Jan* 26Feb 26Mar 26Feb 4Mar 4Apr 22Apr 20May 2010-2011 season 2011-2012 season

*Euro Surveill 2011;16(7):pii=19799 .

19 All-cause deaths in Spain per day, 2011-2012

17% excess in mortality

Source: SVGE. Weekly report of influenza surveillance in Spain, Nº 310, 24 May 2012

20 VE in preventing all-cause deaths in non- institutionalised people ≥65 years

%100

80 High influenza activity period

60

46 40 41 30 28 20 13 9 3 0 -2 1

-20 49-51 52-2 3-5 6-8 9-11 12-14 15-17 18-20 21-23 24-26 27-29 Weeks Cox regression adjusted for age, sex, prevalent major chronic conditions, new diagnoses of major chronic conditions, dependence, hospitalisations in the previous year, GP visits in the previous year, cohabiting with children, migrant status, pneumococcal vaccine, change in influenza vaccination rutine, GP

21 VE in preventing all-cause deaths in population aged 65 or more. Week 3 to 18

Deaths 406 (28.4 per 1000 PY) Unvaccinated 14,285 PY N=44,058 Survival Population N= 104,710 33,913 person-years Deaths Vaccinated 704 (35.9 per 1000 PY) 19,628 PY N=60,652 Survival

Crude VE -27 % (-43% to -12%) Adjusted VE* : 17% (1% to 31%)

*Cox regression model adjusted by sex, age (5-year groups), urban/rural, migrant, major chronic conditions, visits to the GP in the previous year, children in the household, pneumococcal vaccination, discontinuing influenza vaccination rutine, GP,

22 Strengths • Real-time estimations • VE against several outcomes. • Laboratory-confirmed cases. • Same methodology in subsequent years. • More than one design to evaluate the same outcome. • Financially sustainable. Based on routine activities (surveillance and vaccination programme).

Limitations • Study size could be small to obtain conclusive results in seasons with low incidence or low VE. • Results might be not generalizable to other regions and countries. • We need some external funds to maintain a high number of laboratory tests and to obtain early results.

Conclusion Navarre is a good site for annual monitoring of influenza VE.

23 I-MOVE study team in Navarra

Primary Health Care Director Office: Julio Morán, GP Sentinel Network of Navarre Fernando Elía, Esther Albeniz. CS Alsasua: H. Selles; CS : M Moreno, MA. Senosiain Virology laboratory, Complejo Hospitalario de CS San Jorge: MT Virto, J Ulibarri, J Agreda, C Bernués, J. Navarra: Víctor Martínez Artola, Carmen Ezpeleta. Zubicoa, M. ; Virology laboratory, Clínica Universidad de Navarra: CS Rochapea: M Sota, Gabriel Reina. CS Chantrea: F Cortes; CS Barañain I: F Perez Afonso; Surveillance in hospitals: Judith Chamorro, Pilar CS Barañain II: J Gamboa; Artajo, Mercedes Gabari, Jorge Núñez, Maite CS Sangüesa: JJ Longás; CJ Gurbindo; Ortega, Montse Torres, Francisco Lameiro. CS Azpilagaña: C Cherrez; CS Ermitagaña: MA Roncal, O Lecea, P Pérez Pascual, E Alvarez, Servicio Navarro de Salud: Nerea Álvarez J Sola, S Revuelta, EM Da Costa, A. Puig, U Navarro, J Berraondo, Institute of Public Health of Navarre: Manuel García JM Vizcay, C Maurer Cenoz, Maite Arriazu, Fátima Irisarri, Agurtzane CS II Ensanche: B Flamarique, P Uhalte, FJ Orozco, MJ Esparza, Zabala, Marcela Guevara, Aurelio Barricarte, Jesús A Martinez Diaz, MM Del Burgo, J De Prado, K Ayerdi, JJ Arana, MA Rodríguez González, A Arza, ML Pérez Del Valle, Castilla. P González Lorente WHO National Influenza Center: Instituto de Salud CS : MJ Guruchaga, J Díez Espino Carlos III: Francisco Pozo. CS Villava: A Brugos, S Buil, JC Cenoz, B Iñigo, C Fernández Alfaro, B Cano, B , CS Iturrama: F Bruque CS Zizur: MA Pous International coordination: EpiConcept: A Moren, M Valenciano CS San Juan: A Gulina, L Fanlo, E Arina, ML Garces, P Aldaz, IA Urtasun, MJ Vigata, MS Indurain, I Arceiz, B Churio, N Goñi, ME Ursua, E Ridruejo, I Ruiz Puertas Funding CS Tudela Oeste: MJ Guillorme, MP León, M D Artajo, JO Guiu, C European Centre for Disease Control (ECDC). Bolea, J Guillen, M Orte, CS : SE Juan Belloc; Instituto de Salud Carlos III, Government of Spain CS Corella: JA Heras CS Buñuel: M Doiz CS Estella: J Palau, FJ Escribano, I Abad, A Prado; CS Viana: A Roig Residencia Amma-Argaray: J. Baleztena. Casa Misericordia: F. Cía.

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