Outline. Summary of 2017 season; vaccine coverage and effectiveness. Influenza A/H3 vaccine problems season new vaccines and programs

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Charla Hodges
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1 Influenza Allen Cheng Professor of Infectious Diseases Epidemiology, Monash University Director, Infection Prevention and Healthcare Epidemiology Unit, Alfred Health

2 Outline Summary of 2017 season; vaccine coverage and effectiveness Influenza A/H3 vaccine problems 2018 season new vaccines and programs

3 Surveillance pyramid Deaths Notified deaths NSW influenza/pneumonia FluCAN hospital mortality ICU Hospitalisations Emergency department Primary care FluCAN FluCAN-PAEDS FluCAN FluCAN-PAEDS EpiLog (Qld) NSW, WA ED ILI surveillance Sentinel GP surveillance systems Notification data (NNDSS) Mild respiratory tract symptoms FluTracking Call centre data Absenteeism Asymptomatic illness

FluCAN 2012-17 21 hospitals (incl 6 paediatric hospitals) 17 hospitals used for surveillance All

4 FluCAN hospitals (incl 6 paediatric hospitals) 17 hospitals used for surveillance All states/territories Metropolitan/regional Temperate/tropical >14% of national bed capacity (TSANZ/ASID collaboration 2009)

5 Incidence density test-negative Vaccinated Not vaccinated Flu Non flu ILI Exposure Outcome Case = influenza Control = non influenza ILI matched for date of presentation Case/control status assigned when test result known Adjust for confounders

6 2017 season 4259 cases at surveillance hospitals (excluding 4 PAEDS sites - >2x 2016) 78% chronic comorbidities 31% influenza B (~ admissions nationally) Mortality 155/4236 (3.7%)

7 Severity proportion admitted to ICU Overall 8.7% Paediatric 10.1% Non-elderly adults 11.1%; Elderly 6.3% Indigenous Australians (10.0%) Pregnant women (8.7%).

8 VE analysis Patients admitted with acute respiratory symptoms at sentinel sites All lab-confirmed influenza (n=4974) Sample of test negative patients (n=2264) Vaccination status not ascertained (n=1228) Vaccination status not ascertained (n=493) Vaccination status ascertained (n=3746) Vaccination status ascertained (n=1771)

9 Vaccine coverage 61% 17% 53% 76%

10 Vaccine effectiveness (reduction in risk of hospitalisation in vaccinated compared to unvaccinated)

11 Historical context All types year VE (95% CI) % Weight All Subtotal (I-squared = 66.2%, p = 0.011) 0.40 (0.02, 0.64) 0.38 (0.23, 0.51) 0.50 (0.33, 0.63) 0.50 (0.40, 0.59) 0.49 (0.38, 0.58) 0.19 (0.02, 0.32) 0.44 (0.39, 0.49) Elderly Subtotal (I-squared = 67.5%, p = 0.009) 0.41 (-0.62, 0.79) 0.36 (0.11, 0.54) 0.53 (0.22, 0.71) 0.49 (0.31, 0.62) 0.42 (0.23, 0.56) (-0.59, 0.08) 0.40 (0.31, 0.49)

12 Summary of 2017 season 2017 was a big flu season for hospitals A/H3N2 and B/Yamagata dominant strains Much higher activity than 2014, 2015, 2016 Vaccination in 2017 Small reduction in the risk of hospitalisation with influenza. Estimated vaccine effectiveness: 23% (95% CI: 9%, 35%) similar to 2016 but much less than 2015 Based on point estimates, VE: Higher in non-elderly adults (50%) than the elderly (7%) Higher in A/H1 (51%) and influenza B (26%) than A/H3 (21%).

13 Limitations Likely underestimate of true influenza burden Much greater burden when estimating excess admissions/mortality Observational case control study Potential selection biases Misascertainment Unmeasured confounding

14 The perfect storm A/H3 subtype predominating Tends to affect elderly Genetically diverse subtype compared to A/H1 and B Egg adaptation of H3 vaccine strain Fewer vaccine candidates Difficult to match against diverse H3 strains Poorly protective vaccine-induced antibodies Vaccine poorly immunogenic in high risk groups A/H3 vaccine issues

15 H3N2 diversity Significant genetic diversity within H3N2 circulating strains Various clades recent strains in 3C.2a1 Recent diversification in 2a1 clade Singapore vaccine strain (2018) 3C.2a1 clade Hong Kong vaccine strain ( ) Nextstrain.org

16 Changes in 2018 Change to vaccine components H3N2: A/Hong Kong/4801/2014 to A/Singapore/INFIMH /2016 B: in TIV, B/Brisbane/60/2008 to B/Phuket/3073/2013 New vaccines Adjuvanted TIV High dose TIV Paediatric program Jurisdictional programs for <5 year olds

17 New vaccines for elderly FluZone HD 4x antigen content of standard IIV TIV (not QIV) Evidence of increased protection in RCT 24% more effective than TIV Two seasons with predominant H3 Also protection demonstrated against nonspecific endpoints eg pneumonia 24% represents relative protection If standard vaccine 40% effective, expect 50% effectiveness with new vaccine DiazGrandos NEJM 2014

18 New vaccines for elderly - Fluad MF59 adjuvanted vaccine Also TIV (not QIV) Evidence of increased protection in observational study Hospitalisation with influenza 17% more effective than TIV Multiple seasons Mennino AJE 2012

19 Events in 2018 Vaccine shortages Usual consumption predictable 7-9 million doses/year No major changes after 2009 pandemic >10 million doses (>30% increase on 2017) Sufficient to vaccinate >90% of elderly Shortages in May-June - patchy Supply restored July Implications for purchase order next year? Implications for messaging about vaccine timing?

20 2018 season (to 3 Sept 2018) 328 cases at surveillance hospitals (excluding 4 PAEDS sites) 58% chronic comorbidities (vs 78% in 2017) 18% influenza B Mortality 1/221 (0.6%)

21 Severity proportion admitted to ICU Overall 9.7% Paediatric 12.1% Non-elderly adults 8.6%; Elderly 7.9% Indigenous Australians (14.3%) Pregnant women (9.7%).

22 VE analysis 2018 interim Patients admitted with acute respiratory symptoms at sentinel sites All lab-confirmed influenza (n=395) Sample of test negative patients (n=370) Vaccination status not ascertained (n=87) Vaccination status not ascertained (n=87) Vaccination status ascertained (n=308) Vaccination status ascertained (n=283)

23 Vaccine coverage % 17% 53% 76% 0 <18 years years 65+ years <18 years years 65+ years No comorbidities Comorbidities

24 Vaccine effectiveness (reduction in risk of hospitalisation in vaccinated compared to unvaccinated) All patients Flu A A/H1N1* A/H3N2* Flu B 0 of 7 H3N2 cases vaccinated Target population Risk factors Elderly Non elderly adults Children VE

25 UK paediatric influenza program Paediatric program gives both direct and indirect protection Greater effect if more children vaccinated (and if uptake rapid) May be more cost effective than vaccinating elderly Hodgson Lancet Pub Health 2017

26 Mandatory vaccination of HCW? For Very high coverage ensured, precedent established Nosocomial influenza can be severe in inpatients Influenza vaccine less immunogenic in elderly, immunosuppressed Some evidence that vaccinating staff reduces risk in patients (low quality evidence) When effective, vaccine is probably cost effective in reducing staff illness Against Reasonable coverage achievable without mandate; if offered, most staff will get vaccinated Difficult to justify if vaccine poorly protective Continuous masking not supported by evidence Better protection from respiratory viruses achieved by addressing presenteeism Practical issues in re-deploying unvaccinated staff; specialized areas, medical contraindications

Healthcare workers 100% 90% 80% 70% 46.9 38.7 5.1 2.5 3.3 7 14.

27 Healthcare workers 100% 90% 80% 70% % 5.1 did not respond 50% 40% 30% 20% declined vaccinated 10% 0% Alfred Health (all campuses)

28 Conclusions Vaccine effectiveness better in 2018 New vaccines in elderly Mostly H1N1 Mostly children Available tools to reduce impact of influenza Improve vaccine coverage esp in vulnerable groups More immunogenic vaccines. Improving childhood immunisation and indirect protection Research required Evaluate effectiveness of new vaccines Determine whether alternative vaccine platforms may reduce adaptation problems Universal flu vaccine

29 Acknowledgements FluCAN investigators Dominic Dwyer Mark Holmes Louis Irving Grant Waterer Tony Korman Louise Cooley Anna Howell Deb Friedman Peter Wark Graham Simpson John Upham Simon Bowler Sanjaya Senenayake Tom Kotsimbos Paul Kelly PAEDS/AusVaxSafety Kristine Macartney Christopher Blyth Helen Marshall Julia Clark Josh Francis Jim Buttery FluCAN is funded by the Commonwealth Department of Health PAEDS-FluCAN sites are funded by a NHMRC Partnership Grant Thanks to Jill Garlick, Janine Roney and study staff at each site Infection Prevention Unit, Alfred Health Pauline Bass Kristine Heinrich- Morrison Sue McLellan Jonathan Chrimes Systematic review TGA, OHP, NCIRS Michelle Giles, Sush Krishnaswamy

30 A/Singapore/INFIMH /2016 A/Hong Kong/4801/2014

31 A/Michigan/45/2015 A/California/7/2009

Update on Paediatric Influenza

Update on Paediatric Influenza ISG Annual Scientific Meeting 3 & 4 February 2018 Dr Margie Danchin Paediatrician, Department of General Medicine, RCH Senior Research Fellow, Vaccine and Immunisation Research