1. Seasonal Influenza: Vaccines & Prevention Kristin Nichol, MD, MPH, MBA Professor of Medicine University of Minnesota Chief of Medicine and Director Primary Care Service Line Minneapolis VA Medical Center Minneapolis, MN

2. Overview Trivalent inactivated (TIV) and live attenuated influenza virus (LAIV) vaccines Efficacy & effectiveness in children, adults, elderly Cost effectiveness of vaccination Vaccination rates Remaining issues

3. Epidemic Influenza Continues to Have a Huge Annual Impact + Avg respiratory & circulatory = 294,000 1979-80 thru 2000-01. * Avg all cause, 1976-77 thru 1998-99. **Avg all cause 1990-91 thru 1998-99. MMWR. 2005;54 (RR-8). Thompson et al. JAMA. 2003;289:79. Thompson et al. JAMA. 2004;292:1333. Adams PF et al. Vital Health Stat. 1999;10(200). Estimates for the US Cases:25 – 50+ million Days of illness:100 – 200 million Work & school loss:Tens of millions Hospitalizations:85,000 – 550,000 + Deaths:34,000* – 51,000** Costs:Billions of dollars

4. Options for Preventing and Controlling Influenza Hand hygiene Respiratory hygiene/cough etiquette Contact avoidance Antivirals Immunization CDC. Preventing the Flu. www.cdc.gov/flu/protect/stopgerms.htm

5. Influenza Vaccines: A Trivalent Defense CDC. MMWR Morb Mortal Wkly Rep. 2005;54(RR-8). Type A H3N2 Type A H1N1 Influenza Protection Type B

6. Trivalent Inactivated (TIV) and Live Attenuated Influenza Virus (LAIV) Vaccines CategoryTIVLAIV Administration & immune response IM  Serum antibodies Intranasal  Mucosal immunity FormulationInactivatedLive attenuated Safety (side effects)Sore armRunny nose Growth mediumChick embryosChick cells StorageRefrigeratedFrozen Indication>6 mo (healthy & HR)5–49 yrs (healthy) MMWR. 2005;54 (RR-8).

7. Outcome / case definition & RRR vs ARR Typical kinds of outcomes assessed in VE studies –Cause specific (specific outcomes) Infection Lab confirmed illness (LC ILI) LC Influenza + otitis media –“All cause” (sensitive outcomes) Clinical illness (ILI) without lab confirmation Complications –Otitis media –Pneumonia hospitalization –Death Cause specific outcomes provide highest RRR because there is less “noise” But this does not mean that the lower RRR seen with all cause outcomes means that the vaccine is less effective (ie the ARR would be the same or greater if it could be measured)

8. Influenza Vaccine Efficacy in Children Study & Vaccine Efficacy (lab / cx confirmed) Effectiveness (clinical illness) Cochrane [1] Live attenuated Inactivated 79% (48% - 92%) 65% (47% - 76%) 38% (33% - 43%) 28% (22% - 33%) Negri et al [2] Live attenuated Inactivated 80% (53% - 91%) 65% (45% - 77%) 34% (31% - 38%) 33% (22% - 42%) 1. Jefferson TJ, et al. Lancet. 2005;365:773-80. 2. Negri E, et al. Vaccine. 2005;23: 2851-61.

9. Influenza Vaccine Efficacy in Healthy Adults Serologically Confirmed Influenza Illness Clinical ILI RRRARRRRRARR Figure 01.0169% (54%-79%)6.1/10022% (9%-33%)13.5/100 Figure 01.0270% (56%-80%)6.8/10025% (13%-35%)12.1/100 Demicheli V, et al. Cochrane Library 2004; issue 3.

10. Effectiveness of Influenza Vaccination in High Risk Persons < 65 Years of Age Age Group & OutcomeVaccine Effectiveness (95% CI) < 18 yrs, high-risk GP visits for ARD/CVD 43% (10% - 64%) 18 – 64 yrs, high-risk GP visits for ARD/CVD Hospitalizations for ARD/CVD Death (any cause) 26% (7% - 47%) 87% (39% - 97%) 78% (39% - 92%) 65 yrs & older GP visits for ARD/CVD Hospitalizations for ARD/CVD Death (any cause) 7% (-11% - 23%) 48% (7% - 71%) 50% (23% - 68%) Hak E, et al. Arch Intern Med 2005; 165: 274.

11. Influenza VE in Community Dwelling Elderly (Results of 2 Meta Analyses) OutcomesVu, et al.Jefferson, et al. Lab confirmed influenza--81% (-101% - 98%) Clinical ILI35% (19% - 47%)-5% (-89% - 42%) Hospitalizations for Pneumonia & Influenza33% (27% - 38%)27% (21% - 33%) Respiratory Conditions30% (25% - 35%)22% (15% - 28%) Cardiovascular Disease--24% (18% - 30%) All Cause Mortality50% (45% - 56%)47% (39% - 54%) Vu T, et al. Vaccine. 2002;20:1831. Jefferson T, et al. Lancet. 2005;366:1165-74.

12. Influenza VE in LTCF Elderly (results of 2 meta analyses) OutcomeGross, et al.Jefferson, et al. Respiratory Illness/ILI56% (39% to 68%)23% (6% - 36%) Pneumonia53% (35% to 66%)46% (30% - 58%) Hospitalization48% (28% to 65%)45% (16% - 64%) Death68% (56% to 76%)60% (23% - 79%) Gross PA, et al. Ann Intern Med. 1995;123: 518 – 27. Jefferson TJ, et al. Lancet. 2005;366:1165-74.

13. Influenza Vaccination Has Downstream Benefits Vaccination of school children –Lower illness rates in the community Tecumseh, MI study [1] Texas study [2] –Lower death rates in the elderly Japanese experience [3] Vaccination of children in households [4] –Lower illness rates in school-aged siblings –Fewer work loss days among parents Vaccination of healthcare workers –Lower death rates in residents of LTCFs [5] 1.Monto AS et al. J Infect Dis. 1970;122:16. 2.Piedra PA et al. Vaccine. 2005;23:1540. 3.Reichert T, et al. NEJM. 2001;344:889. 4.Hurwitz ES. JAMA. 2000;284:1677. 5.Carman WF, et al. Lancet. 2000;355:93.

14. Sensitivity of Symptoms Adapted from Monto AS, et al. Arch Intern Med 2000; 160: 3243-7.

15. Sensitivity of Laboratory Diagnostic Tests Based on data from 533 US subjects included in neuraminidase trials. Zambon M et al. Arch Intern Med 2001; 161: 2116-22.

16. Impact of More Sensitive Outcomes on ARR More sensitive outcomes will have a higher ARR – ie they are more inclusive Nichol KL. Virus Res 2004; 103: 3 – 8.

17. CEA Studies of Influenza Vaccination of Children CountryResults Cost Saving Cost Effective Not Cost Saving– Cost Effective ? USA multiple studies [1] √√ Hong Kong [1] √ Argentina (high risk children 6 mos to 15 yrs) [1] √ US High risk children [2] √ US non-high risk children [2] √ (break-even ~$30/dose) √ (not cost saving if vacc costs > break-even threshold) 1. Nichol KL. Vaccine. 2003;21. 2. Meltzer MI. Vaccine. 2005;23:1004.

18. CEA Studies of Influenza Vaccination of Working Adults Around the Globe CountryResults Cost Saving Cost Effective Not Cost Saving – Cost Effective ?? USA multiple studies [1,2]√√√ Canada (HCW’s) [1]√ UK [1]√ √ (for British Army) France [1]√ Finland [1] √ (inefficient delivery) Hong Kong [1]√ Brazil [1]√ UK (HTA 2003) [3] √ £ 10,184/QALY South Africa [4] √ (BCR 5:1) 1. Nichol KL. Vaccine. 2003;21:1769. 2. Rothberg MB. Am J Med. 2005;118:68. 3. Turner D et al. HTA. 2003;7(35). 4. Martin DJ. Occup Health SA. 1997;3:23.

19. CEA Studies of Influenza Vaccination of the Elderly Around the Globe CountryResults Cost Saving Cost Effective Not Cost Saving– Cost Effective ?? USA – multiple studies√√ Canada√ England, France, Germany, the Netherlands √√ New Zealand√ Taiwan√ Hong Kong√ Nichol KL. Vaccine. 2003;21:1769.

20. Expansion of Goals for Influenza Vaccination – Everyone Can Benefit

21. ACIP Recommendations 2005-06 High Priority –High risk for serious complications Age 65+ Chronic medical conditions Conditions that compromise respiratory function or ability to handle secretions Residents of LTCFs Pregnant women Children/adolescents on chronic ASA Rx Children 6 to 23 months of age –Likely to be high risk (ages 50–64) –Persons who can transmit to high risk groups Special emphasis on HCWs Others CDC. MMWR. 2005;54 (RR-8).

22. Influenza and Pneumococcal Vaccination Rates Are Still Too Low MMWR 2001;50(25):532-537. NHIS (‘01, ’03, Jan – Jun ‘04). 2010 Goal

23. Disparities by Age: Influenza & Pneumococcal Vaccination of High Risk Persons, 2003 MMWR. 2004;53:1007.

24. Disparities by Race: Influenza & Pneumococcal Vaccination of Elderly Persons, 2004 NHIS early release estimates, Jan – Jun 2004.

25. Influenza Vaccination Coverage 2004-05 2003 (NHIS) 2004-05 (BRFSS) Adults Elderly65.5%62.7% HR Adults 18 – 6434.2%25.5% HCWs40.1%35.7% Non-priority Adults19.6%8.8% Children Children 6 – 23 mos7.7%48.4% HR Children 2 – 17--34.8% Non-priority children--12.3% CDC; MMWR. 2005; 54:304-7.

26. Summary Influenza is a bad disease (for everyone) and current vaccines provide many benefits (for everyone) Current vaccines are underused Current vaccines are imperfect Roles for –More effective vaccine delivery To expanded target groups (?) –More timely availability and adequate quantities of vaccine –Better vaccines