1. DoD Influenza Surveillance and Vaccine Effectiveness Armed Forces Health Surveillance Center (AFHSC) Naval Health Research Center (NHRC) United States Air Force School of Aerospace Medicine (USAFSAM) DoD Global Influenza Network Partners Presentation to the Vaccines and Related Biological Products Advisory Committee (VRBPAC) - 27 February 2013 CDR Michael Cooper, PhD** **Representing the DoD CONUS and OCONUS lab-based influenza surveillance activities

2. Disclaimer The views expressed in this presentation are those of the author and do not reflect the official policy or position of the Department of Defense or the U.S. Government. 2

3. Briefing Outline PURPOSE: Provide a concise update to the VRBPAC on DoD influenza surveillance activities, 2012-2013 1.Strain Circulation 2.Molecular Analyses 3.Vaccine Effectiveness 3

4. Breadth of DoD Influenza Surveillance Global Virus Surveillance – Approximately 400 locations in over 40 countries Military; Local government/academic – Extensive characterization capabilities within the DoD Culture, HAI, PCR (battery), Sequencing, Serology (HI, MN) – Rapid sharing of results with CDC and/or regional WHO reference centers ~40,000 samples collected and analyzed in fiscal year 2012 ~450 sequences submitted to GenBank in fiscal year 2012 Comprehensive Epidemiology and Analysis Capabilities – 1.4 Million Active Duty records (health care utilization, immunizations, deployment, reportable diseases, etc) Medical Surveillance Monthly Reports, Ad-hoc requests, Studies/analyses, Routine reports/summaries Weekly influenza reports Vaccine safety and effectiveness studies 4

5. GEIS-Supported Influenza Surveillance Footprint In 2012: --Over 40 countries --Over 400 sites 5

6. # Specimens Tested % Positive for Influenza Strain Circulation 6

7. # Specimens Tested % Positive for Influenza # Specimens Tested 7

8. % Positive for Influenza # Specimens Tested 8

9. % Positive for Influenza # Specimens Tested 9

10. Summary of Circulating Strain Activity Predominately flu A/H3N2 across all regions with the exception of Southeast Asia where there was a mix of all three subtypes Globally, influenza activity is low to moderate this season Recruits & Shipboard: activity is low, primarily flu A/H3N2 North America: moderate activity, predominately flu A/H3N2 10

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12. PHYLOGENETIC ANALYSIS 12

13. Summary of Phylogenetic Analysis for A/H1N1 pdm09 HA 2012-2013 This tree is anchored in A/California/07/2009 Low numbers of samples in North America and overall Sequences continue to fall in to groups 6 and 7 which are covered by the current vaccine 13

14. Low numbers of viruses sequenced due to limited cases circulating in DoD populations. Majority (53%) of A(H1N1)pdm09 sequences, from June-September, came from areas typically observing non-northern hemisphere Influenza seasons (AFRIMS, NAMRU6). The phylogenetic tree of the A(H1N1)pdm09 HA gene demonstrates that recently circulating viruses belong to genetic groups 6 and 7; with group 6 possessing D97N mutation and group 7 possessing A197T mutation. Influenza A(H1N1)pdm09 HA Phylogenetic Analysis 2012 -2013 USAFSAM/PHE 2510 5th Street, WPAFB, OH 45433 14

15. Summary of Phylogenetic Analysis for A/H3N2 HA 2012-2013 This tree is anchored in A/Perth/16/2009 271 sequences most of which were collected between DEC and JAN from the US 68% belong to group 3C which is in agreement with the vaccine 21% of sequences belong to groups 5 and 6; we will continue to monitor these Greater diversity was observed in our overseas specimens 15

16. USAFSAM/PHE 2510 5th Street, WPAFB, OH 45433 3C.1 16

17. Summary of Phylogenetic Analysis for B HA 2012-2013 Overall in our network 58% of our Bs were Victoria linage Yamagata: Since 1 DEC 87% of our sequences have been Yamagata –10% group in to clade 3 like the current vaccine (B/Wisconsin/01/2010) –90% group in to clade 2 which is similar to the WHO recommendation –The Yamagata tree was anchored to B/Florida/04/2006 Victoria: The majority of B Victoria were collected from June –Sept 2012 in tropical and Southern Hemisphere locations - 95% of B Victoria group with the Victoria vaccine recommendation -The Victoria was anchored to B/Ohio/012005 17

18. USAFSAM/PHE 2510 5th Street, WPAFB, OH 45433 18

19. USAFSAM/PHE 2510 5th Street, WPAFB, OH 45433 19

20. VACCINE EFFECTIVENESS (VE) 20

21. Preview Mid-year estimates provided by: –US Air Force School of Aerospace Medicine (USAFSAM), –Naval Health Research Center (NHRC) –Armed Forces Health Surveillance Center (AFHSC) Case-Control studies, logistic regression used to estimate VE –Two studies used case-test negative control method, one study used healthy controls 21

22. Adjusted Estimates of Vaccine Effectiveness –Population: Military members and dependents (CONUS and OCONUS) –Analyses by flu subtype and vaccine type –Models adjusted for age and week collection –Controls (1008) are test-negative for flu –Cases (628) confirmed by RT-PCR and viral culture –Significant VE range from 39.54% to 48.69% –Overall estimates were statistically sig as were estimates for flu A H3 (alpha 0.05) USAF School of Aerospace Medicine (USAFSAM) 22

23. Crude and adjusted influenza vaccine effectiveness (VE) estimates, mid-season (September 30, 2012- January 26, 2013), US Air Force School of Aerospace Medicine’s DoD Global, Laboratory- based, Influenza Surveillance Program CasesControlsSubtype Vaccine Type OR crude VE crude (95%CI) OR adj. VE adjusted a (95%CI) 6281008 OverallAny 0.7524.63%(7.89%, 38.32%)0.5644.11%(28.47%, 56.32%) 469 b 708 b LAIV 0.7821.95%(0.65%, 38.68%)0.6039.54%(17.73%, 55.57%) 462716 TIV 0.7327.23%(7.25%, 42.91%)0.5346.67%(29.09%, 59.89%) 87261 BAny 0.4258.35%(31.70%, 74.60%)0.6138.57%(-9.32%, 65.48%) 37111 H1Any 1.38-38.44%(-209.16%, 38.01%)1.1-9.79%(-181.51%, 57.18%) 5021008 H3Any 0.7623.90%(5.61%, 38.64%)0.5247.56%(31.84%, 59.65%) 370 b 708 b LAIV 0.7623.74%(1.00%, 41.26%)0.5644.33%(22.78%, 59.87%) 373716 TIV 0.7624.05%(1.60%, 41.38%)0.5148.69%(30.62%, 62.06%) Note: OR, odds ratio; VE, vaccine effectiveness; TIV, trivalent inactivated influenza vaccine; LAIV, live attenuated influenza vaccine a Vaccine effectiveness estimates were adjusted for age group and week of collection, except for H1. H1 was adjusted for age, week of collection and geographic region. b LAIV specific estimates excluded vaccinated and unvaccinated individuals outside the recommended range (2-49). There was one vaccination outside this age range. NOTES: 1) For age group <9 years, two vaccinations are recommended; for this study, this age group was handled the same as the older age groups with respect to vaccination (a subject was considered vaccinated if one influenza vaccination was received at least 14 days prior to specimen collection date). 2) Overall adjusted VE was calculated using multivariable logistic regression with adjustment for age (collapsed into age groups of <5, 5-17, 18-28, 29-35, and 36+) and time period (collapsed into periods of weeks 40-44, 45-48, 49-52, and 1-4). Adjusting for time period in quartiles rather than 4-5 week periods [VE 42% (28%, 57%)] and including only USNORTHCOM cases and controls [VE 42% (26%, 55%)] had little effect on the overall adjusted model. An Active Duty only model is not presented as 89% of both cases and controls were vaccinated. DoD Mid-Season Vaccine Effectiveness: 2012-2013 23

24. Naval Health Research Center (NHRC) Adjusted Estimates of Vaccine Effectiveness –Population: Civilians only Dependents S California and Illinois Civilians at clinics and hospitals near US-Mex border –Only H3 could be evaluated; no analyses on vaccine type –Models adjusted for age, location of treatment, days with symptoms, hospitalization status –Cases (139) confirmed by RT-PCR or viral culture –Controls (290) are test-negative –Vaccination Rates: cases 16%, controls 45% –Overall, adjusted VE was 72%; 85% for A/H3; both sig at 0.05 24

25. NHRC- Vaccine Effectiveness (VE) *Adjusted for age group, site, days with symptoms upon presentation, and hospitalization status (input./output.) Vaccine Effectiveness Estimates CasesControlsVE (crude)VE (adjusted*) Overall13929077 (62, 86)72 (52, 84) A/H39029082 (62, 91)85 (69, 92) B4029054 (4, 78)41 (-30, 74) 491 ILI cases enrolled between 12/9/12 and 1/26/13 –429 with known vaccination status –Lab-confirmed influenza by CDC RT-PCR assay –VE = 1 – Odds ratio 25

26. AFHSC Matched Case-Healthy Control Study of VE –Population: Active component service members (CONUS and OCONUS) –Lab-confirmed flu cases (647)(rapid, RT-PCR, or culture) –Healthy Controls (2644) Medical encounter for musculoskeletal or mental health condition with no respiratory conditions reported No medical encounters for influenza during season Matched to cases by sex, age, date (+/- 3 days), and location –Models adjusted for 5-yr vaccination status (Y/N) Overall and vaccine-type VE calculated 26

27. Vaccine Type Cases n (%) Controls n (%) Crude OR (95% CI) Adjusted OR (95% CI)* Vaccine Effectiveness (95% CI) Overall 647 (87)2644 (91)0.62 (0.47-0.82)0.65 (0.49-0.86)35 (14-51) TIV 2359870.61 (0.45-0.82)0.65 (0.47-0.88)35 (12-53) LAIV 40716350.63 (0.47-0.85)0.66 (0.49-0.88)34 (12-51) Unvaccinated 97 (13)272 (9)Ref OR=Odds Ratio; *Adjusted for vaccination status in 5 years prior AFHSC VE Estimates 27

28. Limitations Generalizability –Subjects were sick enough to seek medical attention, can’t comment on vaccine impact for less severe cases –Active Duty mil pop is highly immunized, this could cause an underestimation of true VE (potential method issues and biological effects such as attenuated immune response with repeated exposures) –Population is younger and healthier, can’t comment on vaccine impact older, high-risk pops –Low statistical power for H1 and B analysis Vaccination Data –Some vaccination data relied on patient recall 28

29. Summary The DoD maintains a robust surveillance system with capacity to assess mid-season and end-of-season VE and molecular characterization of circulating viruses Overall, estimates of VE indicate moderate (but statistically significant) protection Analysis of our network’s specimens supports continued use of the current A/H1N1 and B Victoria (for quadrivalent ) vaccine strains and following recommendations of the WHO Northern Hemisphere changes for A/H3N2 and B Yamagata vaccine strains 29

30. Acknowledgement AFHSC Dr. Angelia Eick-Cost Ms. Zheng Hu Dr. Jose “Toti” Sanchez Ms. Alice Tsai LT Jennifer Cockrill MAJ Ronald Burke COL James Cummings CAPT Kevin Russell AFRIMS Dr. Ans Timmermans Ms. Tippa Wongstitwilairoong MAJ Stefan Fernandez LTC Samuel Yingst 65th MEDICAL BRIGADE MAJ Matt Brown MAJ Bryan Gnade LRMC/PHCR-Europe Ms. Michele Balihe MAJ Edward Ager COL Kathryn Ellis NAMRU-2 Mr. Agus Rachmat CDR Steven Newell CAPT (s) Patrick Blair NAMRU-3 Mr. Ehab Amir Mr. Emad M. Elassal Ms. Caroline Fayez Ms. Mary Younan LT Cheryl Rozanski NAMRU-6 Mr. Vidal Felices Lt Col Eric Halsey LCDR Maya Williams 30

31. Acknowledgement NHRC Mr. Anthony Hawksworth Dr. Chris Myers CDR Gary Brice USAFSAM Mr. Jan Abshire Ms. Linda Canas Mr. Joshua Cockerham Mr. Benjamin Connors Ms. Laurie DeMarcus Ms. Laurel Lloyd Ms. Allison Seidel Mr. James Smith Ms. Katie Tastad Dr. Elizabeth Macias Capt Robel Yohannes Maj Kristine Fumia Maj Shauna Zorich Lt Col Victor Macintosh Lt Col Jody Noe Col Paul Sjoberg USAMRU-K Dr. Wallace Bulimo Mr. Cyrille Djoko Dr. Bernard Erima Mr. Derrick Mimbe Dr. Lucy Ndip Mr. James Njiri Dr. Karen Saylors LTC Eyako Wurapa WRAIR Dr. Huo-Shu Houng MAJ Richard Jarman 31

32. Thanks, Alice! Good Luck! 32

33. Questions CDR Michael Cooper, PhD Head, Dept. of Respiratory Infections Surveillance Tel: 301-319-3258 E-mail: Michael.Cooper38@us.army.milMichael.Cooper38@us.army.mil CAPT Kevin L. Russell, MD, MTMH Director, AFHSC Tel: 301-319-3240 E-mail: Kevin.Russell4@us.army.milKevin.Russell4@us.army.mil 33

34. YearMethodsResults VE adjusted 95% CIReference 2010-2011 Case-ControlHealthy Controls Eick-Cost, AA, Tastad KJ, Guerrero AC, Johns MC, Lee S-e, et al. (2012) Effectiveness of Seasonal Influenza Vaccines against Influenza- Associated Illness among US Military Personnel in 2010-2011: A Case Control Approach. PLoS ONE 7(7): e41435. doi:10.1371/journal.pone.0041435. Logistic Regression Overall16%(-1,45) Test Negative Controls Control Groups Overall29%(-6,53) -Healthy TIV53%(25,71) -Test Negative LAIV-13%(-77,27) A/H358%(21,78) A/H1-38%(-211,39) B34%(-122,80) 2011-2012 Case-ControlTest Negative Controls MacIntosh VM, Tastad KJ, Eick-Cost AA, et al. (2013) Mid-Season Influenza Vaccine Effectiveness 2011-2012: A Department of Defense Global, Laboratory-Based, Influenza Surveillance System Case-Control Study Estimate. Vaccine, 10.1016/j.vaccine.2013.01.022. Logistic Regression Overall77%(57,87) TIV75%(48,88) Control Group LAIV74%(48,87) -Test Negative A/H377%(52,89) TIV 74%(38,89) LAIV78%(47,91) A/H170%(0,91) B75%(-2,94) DoD Vaccine Effectiveness Summary: 2010-2012 34

35. NHRC VE Lower VE against type B influenza No evidence of reduced VE in elderly Hospitalized patients had lower incidence of influenza 35