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
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
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
Australian VE study sites 4
FluCAN sites 2012 15 hospitals All states & territories 5
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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
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
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 2003-7 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
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
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
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
WAIVE 2009-2011 2009 431 patients, 79 with ph1n1 Interim analysis of ED/GP patients 2009 VE = 36% (-18 to 66) against ph1n1 2010 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
Hospital-based surveillance FluCAN Influenza Complications Alert Network 2009 9 sites NHMRC 2011 8 sites VIC DH/ VIDRL/ANU 2010 15 sites DoHA 2012 15 sites DoHA 14
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
Factors associated with influenza 2010-11 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) <0.001 0.45 (0.31, 0.67) <0.001 Medical comorbidities 0.69 (0.49, 0.97) 0.03 0.91 (0.63, 1.31) 0.60 Influenza vaccination 0.43 (0.32, 0.59) <0.001 0.63 (0.45, 0.88) 0.01 Pregnancy 16.29 (4.56, 58.23) <0.001 10.36 (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
VIDRL sentinel surveillance sites 2012 17
VIDRL: VE 2007-11 by year 20-64 years Year Cases Controls Crude VE Adjusted VE 2007 153 195 63% (32, 80) 2008 75 213 33% (-47, 69) 2009 230 430-1% (-48, 32) 2010 102 207 86% (61, 95) 2011 95 303 51% (-4, 77) 58% (17, 79) 29% (-71, 71) -32% (-116, 19) 87% (61 to 96) 59% (4, 82) 18
VIDRL: VE 2007-11 by type and subtype (2009 omitted) 20-64 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
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 2007-8 and 2010-11 2010-11 Searched for eligible studies 1967-2011 2008-9 20-64 years 15-59 years 18-64 years 18-64 years Vaccine effect measure Effectiveness all strains Effectiveness all strains Efficacy all strains Total Participants With influenza Without influenza 1,573 655 918 2,511 1,117 1,394 32,470 578 31,892 VE (95% CI) 62% (43,75) 41% (-3, 66) 59% (51,67) Efficacy 60% matched strains (44,72) 14,859 277 14,582 Efficacy nonmatched strains 42% (30, 52) (1)Valenciano, M., et al., Estimates of pandemic influenza vaccine effectiveness in Europe, 2009-2010: results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) multicentre case-control study. PLoS Med, 2010. 8(1): p. e1000388. (2)Osterholm, M.T., et al., Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis, 2012. 12(1): p. 36-44. (3)CSL Limited. Clinical Trials. http://www.csl.com.au/s1/cs/auhq/1196562649386/page/1255926192957/tabslandingpage.htm 2012 [cited 16/2/2012]; 20
Influenza vaccine effective estimates by year and influenza circulating and vaccine strains Year VE, adjusted (95% CI) Vaccine Predominant circulating strain (H1, H3, B) 2007 58% (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) 2008 29% (-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) 2009-32% (-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) 2010 87% (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) 2011 59% (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
Randomized Controlled Trials of Trivalent Inactivated Influenza Vaccine Drifted H3N2 and Influenza B, varied efficacy 22
Randomized Controlled Trials of Trivalent Inactivated Influenza Vaccine Matched H3N2 and B lineage mismatch, varied efficacy 23
FluCAN 2012 1042 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
Interim VE FluCAN 2012 All patients Influenza A Influenza B Age >65 years Age <65 years Medical comorbidities No comorbidities -.2 0.2.4.6.8 Vaccine effectiveness 25
VIDRL VE 2012 interim estimates, all ages Cases Cases vacc (%) Controls Controls vacc (%) Crude VE Adjusted VE All 213 36 (17%) 322 89 (28%) 47% (20 to 65) 48% (11 to 70) H3N2 166 32 (19%) 322 89 (28%) 39% (5 to 60) 43% (-1 to 68) 26
Summary VE Australian studies 2007-2012 VIDRL 2007-11(2009 omitted) 62% (43,75) WAIVE 2008 58% (9,81) 68% (26,86) FluCAN 2010-11 37% (12,55) FluCAN 2012 interim 39% (21,53) 53% (32,67) <65 years VIDRL 2012 interim 48% (11,70) 50% (11,73) 20-64 years 27
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 18-65 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
Randomized Controlled Trials of Trivalent Inactivated Influenza Vaccine Efficacies from the same flu season in US and Europe 29