Influenza VE studies in Australia

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Stewart Greer
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Health, Australian National University Allen Cheng Associate Professor of Infectious Diseases

1 Influenza VE studies in Australia Heath Kelly Head, Epidemiology Unit, Victorian Infectious Diseases Reference Laboratory Adjunct Professor, National Centre for Epidemiology and Population Health, Australian National University Allen Cheng Associate Professor of Infectious Diseases Epidemiology, Monash University Deputy Head, Infection Prevention and Healthcare Epidemiology, Alfred Hospital 1

2 Influenza surveillance Death Nationally notified deaths (NNDSS) NSW Influenza/pneumonia deaths Hospitalisation Primary care FluCAN Paediatric surveillance (ANZICS) Sentinel GP surveillance Notification data NSW, WA ED ILI surveillance Community FluTracking Call centre data Absenteeism 2

3 Three VE studies Victorian Infectious Diseases Reference Laboratory Sentinel general practices Since 2003 All ages Western Australian Influenza Vaccine Effectiveness (WAIVE) study GP and Emergency Department, Paediatric Referral Hospital Since 2008 Children aged 6-59 months Influenza Complications Alert Network (FluCAN) Hospitalised adults Since 2009 Adults >18 years 3

4 Australian VE study sites 4

5 FluCAN sites hospitals All states & territories 5

6 6

7 The 3 VE studies Test negative design (TND) Study Design & Setting Ages Co-variates VIDRL TND in general practices All Age, gender, month of onset, time between onset & swab, comorbidities (from 2011) WAIVE TND in GP and one Children s Hospital 6-59 months Age, gender, preterm birth, Indigenous status, co-morbidities FluCAN TND in adult hospitals Adults >18 yrs Age, gender, co-morbidities, Indigenous status, pregnancy, nursing home resident 7

8 PCR +ve PCR ve Exclusions Sentinel GP ILI presentations Vaccinated Unvaccinated Swabbed Age Sex Symptom onset Vaccination Comorbidity Cases Controls VE = [1 OR] x 100% Adjust for age, month of swab collection, comorbidity, other co-variates Stratify by type/subtype and age group 8

9 Why the TND? VIDRL TND could be added to routine surveillance data from sentinel general practices Adopted after theoretical framework published Proof of concept study WAIVE Very difficult recruiting controls without respiratory illness in hospitalised patients 2008 Changed to TND for ease of control selection FluCAN TND could be added to newly established hospital surveillance scheme after 2009 VE not part of original proposal 9

10 WAIVE hospital component 2008 Case control study with PCR positive influenza cases and non-ili controls matched for age and Aboriginality Controls not tested for influenza Admitted within 1 week of case Recruited 26 cases (from 35 screened) and 50 controls 10 influenza A and 16 influenza B cases 10

11 WAIVE 2008 lessons Control selection difficult in hospital Time to recruitment Brief inpatient admissions Most children hospitalised in winter had respiratory symptoms thus excluded as potential controls Solution Do not match Use test-negative controls 11

12 Fully vaccinated WAIVE 2008 VE 2 doses >21 days apart and >14 days before symptom onset Vaccinated cases = 7% & controls = 30% VE in ED/GP VE = 58% (8,91) with flu negative controls VE = 68% (26,86) with controls positive for another respiratory virus 12

13 WAIVE patients, 79 with ph1n1 Interim analysis of ED/GP patients 2009 VE = 36% (-18 to 66) against ph1n vaccination program suspended because of increase in number of children with febrile convulsions following receipt of vaccine from CSL Vaccine coverage ~16% before suspension of program Coverage ~30% in preceding 2 years 2011 continued problems with vaccine uptake 13

14 Hospital-based surveillance FluCAN Influenza Complications Alert Network sites NHMRC sites VIC DH/ VIDRL/ANU sites DoHA sites DoHA 14

15 FluCAN objectives Fill gap in surveillance between community surveillance and ICU/death surveillance Describe clinical features and epidemiology Estimate vaccine coverage in patients at risk of hospitalisation Estimate vaccine effectiveness against hospitalisation 15

16 Factors associated with influenza Factors Crude OR (95% CI) p Adjusted OR (95% CI) p Female 1.28 (0.96, 1.70) 0.10 Age 65 years 0.33 (0.23, 0.47) < (0.31, 0.67) <0.001 Medical comorbidities 0.69 (0.49, 0.97) (0.63, 1.31) 0.60 Influenza vaccination 0.43 (0.32, 0.59) < (0.45, 0.88) 0.01 Pregnancy (4.56, 58.23) < (2.86, 37.58) <0.001 Indigenous 0.84 (0.37, 1.90) 0.67 Resident in nursing home 0.53 (0.17, 1.66) 0.28 Crude VE: 57% Adjusted VE 37% 16

17 VIDRL sentinel surveillance sites

18 VIDRL: VE by year years Year Cases Controls Crude VE Adjusted VE % (32, 80) % (-47, 69) % (-48, 32) % (61, 95) % (-4, 77) 58% (17, 79) 29% (-71, 71) -32% (-116, 19) 87% (61 to 96) 59% (4, 82) 18

19 VIDRL: VE by type and subtype (2009 omitted) years Influenza Adjusted VE (95%CI) All 62%(43,75) H1N1 31%(-107,77) ph1n1 88%(64,96) H3N2 52%(14,73) B 65%(17,86) 19

20 Comparison of contemporary estimates VE in working age adults from community-based studies using the endpoint of PCR detected influenza Study and setting Design Years Age group Observational study, Australia Pooled observational study, Europe [1] Systematic review, vaccines licensed in the USA [2] Vaccine licensure study, Australia and New Zealand [3] Test negative design Test negative design from seven countries Mantel-Haenszel random effects model metaanalysis Randomised controlled trial and Searched for eligible studies years years years years Vaccine effect measure Effectiveness all strains Effectiveness all strains Efficacy all strains Total Participants With influenza Without influenza 1, ,511 1,117 1,394 32, ,892 VE (95% CI) 62% (43,75) 41% (-3, 66) 59% (51,67) Efficacy 60% matched strains (44,72) 14, ,582 Efficacy nonmatched strains 42% (30, 52) (1)Valenciano, M., et al., Estimates of pandemic influenza vaccine effectiveness in Europe, : results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) multicentre case-control study. PLoS Med, (1): p. e (2)Osterholm, M.T., et al., Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis, (1): p (3)CSL Limited. Clinical Trials [cited 16/2/2012]; 20

21 Influenza vaccine effective estimates by year and influenza circulating and vaccine strains Year VE, adjusted (95% CI) Vaccine Predominant circulating strain (H1, H3, B) % (17,79) A/New Caledonia/20/99 (H1N1) A/Wisconsin/67/2005 (H3N2) B/Malaysia/2506/67/2004 (Victoria lineage) 95% A/Solomon Island/3/2006-like 2 70% A/Brisbane/10/2007-like 67% B/Florida/4/2006-like (Yamagata lineage) % (-71,71) A/Solomon Islands/3/2006 (H1N1) A/Brisbane/10/2007 (H3N2) B/Florida/4/2006 (Yamagata lineage) 100% A/Brisbane/59/2007-like 100% A/Brisbane/10/2007-like 59% B/Florida/4/2006-like (Yamagata lineage) % (-116,19) A/Brisbane/59/2007 (H1N1) A/Brisbane/10/2007 (H3N2) B/Florida/4/2006 (Yamagata lineage) 93% A/California/7/2009-like 96% A/Brisbane/10/2007-like 55% B/Brisbane/60/2008-like (Victoria lineage) % (61,96) A/California/7/2009 (H1N1)-like virus A/Perth/16/2009 (H3N2)-like virus B/Brisbane/60/2008-like virus (Victoria lineage) 99% A/California/7/2009-like 100% A/Perth/16/2009-like 100% B/Brisbane/60/2008-like (Victoria lineage) % (4,82) A/California/7/2009 (H1N1)-like virus A/Perth/16/2009 (H3N2)-like virus B/Brisbane/60/2008-like virus (Victoria lineage) 100% A/California/7/2009-like 100% A/Perth/16/2009-like 99% B/Brisbane/60/2008-like (Victoria lineage) 21

22 Randomized Controlled Trials of Trivalent Inactivated Influenza Vaccine Drifted H3N2 and Influenza B, varied efficacy 22

23 Randomized Controlled Trials of Trivalent Inactivated Influenza Vaccine Matched H3N2 and B lineage mismatch, varied efficacy 23

24 FluCAN patients admitted to the 15 FluCAN hospitals with confirmed influenza 84% of admissions were with influenza A (untyped) 47% of patients were >65 years of age 76% of patients had medical co-morbidities Vaccine coverage was estimated at 73% in patients >65 years 61% in patients with medical comorbidities 24

25 Interim VE FluCAN 2012 All patients Influenza A Influenza B Age >65 years Age <65 years Medical comorbidities No comorbidities Vaccine effectiveness 25

26 VIDRL VE 2012 interim estimates, all ages Cases Cases vacc (%) Controls Controls vacc (%) Crude VE Adjusted VE All (17%) (28%) 47% (20 to 65) 48% (11 to 70) H3N (19%) (28%) 39% (5 to 60) 43% (-1 to 68) 26

27 Summary VE Australian studies VIDRL (2009 omitted) 62% (43,75) WAIVE % (9,81) 68% (26,86) FluCAN % (12,55) FluCAN 2012 interim 39% (21,53) 53% (32,67) <65 years VIDRL 2012 interim 48% (11,70) 50% (11,73) years 27

28 Conclusion VE estimates from Australian observational studies over 6 years are consistent with metaanalysis of studies using PCR endpoint Efficacy shown in 8/12 seasons in 10 RCTs VE = 59% (51-67) adults aged years Observational effectiveness estimates 6/17 analyses in 9 studies showed protection VE median = 62% Range = 47%-72% for significant protection (95%CI excluded zero) Osterholm et al. Lancet ID 2011;26Oct online 28

29 Randomized Controlled Trials of Trivalent Inactivated Influenza Vaccine Efficacies from the same flu season in US and Europe 29

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