Seasonal Influenza:Vaccines & Prevention

Kristin Nichol, MD, MPH, MBAProfessor of Medicine

University of MinnesotaChief of Medicine and Director

Primary Care Service LineMinneapolis VA Medical Center

Minneapolis, MN

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

Epidemic Influenza Continuesto 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

Options for Preventingand Controlling Influenza

• Hand hygiene

• Respiratory hygiene/cough etiquette

• Contact avoidance

• Antivirals

• Immunization

CDC. Preventing the Flu. www.cdc.gov/flu/protect/stopgerms.htm

Influenza Vaccines: A Trivalent Defense

CDC. MMWR Morb Mortal Wkly Rep. 2005;54(RR-8).

Type AH3N2

Type AH1N1

Influenza

Protection

Type B

Trivalent Inactivated (TIV) and Live Attenuated Influenza Virus (LAIV) Vaccines

Category TIV LAIV

Administration &immune response

IM Serum antibodies

Intranasal Mucosal immunity

Formulation Inactivated Live attenuated

Safety (side effects) Sore arm Runny nose

Growth medium Chick embryos Chick cells

Storage Refrigerated Frozen

Indication >6 mo (healthy & HR) 5–49 yrs (healthy)

MMWR. 2005;54 (RR-8).

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)

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.

Influenza Vaccine Efficacy in Healthy Adults

Serologically Confirmed Influenza

Illness

Clinical ILI

RRR ARR RRR ARR

Figure 01.01 69% (54%-79%) 6.1/100 22% (9%-33%) 13.5/100

Figure 01.02 70% (56%-80%) 6.8/100 25% (13%-35%) 12.1/100

Demicheli V, et al. Cochrane Library 2004; issue 3.

Effectiveness of Influenza Vaccination in High Risk Persons < 65 Years of Age

Age Group & Outcome Vaccine 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.

Influenza VE in Community Dwelling Elderly (Results of 2 Meta Analyses)

Outcomes Vu, et al. Jefferson, et al.

Lab confirmed influenza -- 81% (-101% - 98%)

Clinical ILI 35% (19% - 47%) -5% (-89% - 42%)

Hospitalizations for

Pneumonia & Influenza 33% (27% - 38%) 27% (21% - 33%)

Respiratory Conditions 30% (25% - 35%) 22% (15% - 28%)

Cardiovascular Disease -- 24% (18% - 30%)

All Cause Mortality 50% (45% - 56%) 47% (39% - 54%)

Vu T, et al. Vaccine. 2002;20:1831.Jefferson T, et al. Lancet. 2005;366:1165-74.

Influenza VE in LTCF Elderly(results of 2 meta analyses)

Outcome Gross, et al. Jefferson, et al.

Respiratory Illness/ILI 56% (39% to 68%) 23% (6% - 36%)

Pneumonia 53% (35% to 66%) 46% (30% - 58%)

Hospitalization 48% (28% to 65%) 45% (16% - 64%)

Death 68% (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.

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.

Sensitivity of Symptoms

68

93

64 59 56

0

10

20

30

40

50

60

70

80

90

100

Fever Cough Fever & Cough Fever & Cough& Nasal

Congestion

Fever & Cough& Sore Throat

Sen

sitiv

ity (

%)

....

.

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

Sensitivity of Laboratory Diagnostic Tests

56 6171

0

10

20

30

40

50

60

70

80

90

100

Culture Serology RT-PCR

Sen

sitiv

ity (

%)

....

.

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

42.4

79

16.5

186.4

271.5

44.8

0

50

100

150

200

250

300

Work loss days Impairedproductivity

days

Health careprovider visits

No. P

reve

nte

d b

y Vac

cinat

ion

(per

100

0)

Febrile URI / Peak Outcome Period

Any Symptom / Total Outcome Period

Impact of More Sensitive Outcomes on ARRMore sensitive outcomes will have a higher ARR – ie they are more inclusive

Nichol KL. Virus Res 2004; 103: 3 – 8.

CEA Studies of Influenza Vaccination of Children

Country ResultsCost

SavingCost

EffectiveNot 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.

CEA Studies of Influenza Vaccinationof Working Adults Around the Globe

Country ResultsCost

SavingCost

EffectiveNot 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.

CEA Studies of Influenza Vaccinationof the Elderly Around the Globe

Country Results

CostSaving

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.

Expansion of Goals for Influenza Vaccination – Everyone Can Benefit

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

• OthersCDC. MMWR. 2005;54 (RR-8).

Influenza and Pneumococcal Vaccination Rates Are Still Too Low

MMWR 2001;50(25):532-537. NHIS (‘01, ’03, Jan – Jun ‘04).

2010 Goal

Disparities by Age: Influenza & Pneumococcal Vaccination of High Risk Persons, 2003

69.964.2

4937.1 34

0

20

40

60

80

100

Elderly Diabetes < 65 Asthma < 65

Influenza Pneumococcal

MMWR. 2004;53:1007.

Disparities by Race: Influenza & Pneumococcal Vaccination of Elderly Persons, 2004

59.3

72.9

4834.8

61.6

34.5

0

20

40

60

80

100

Influenza Pneumococcal

Hispanic White Black

NHIS early release estimates, Jan – Jun 2004.

Influenza Vaccination Coverage2004-05

2003(NHIS)

2004-05 (BRFSS)

Adults Elderly 65.5% 62.7%

HR Adults 18 – 64 34.2% 25.5%

HCWs 40.1% 35.7%

Non-priority Adults 19.6% 8.8%

Children Children 6 – 23 mos 7.7% 48.4%

HR Children 2 – 17 -- 34.8%

Non-priority children -- 12.3%

CDC; MMWR. 2005; 54:304-7.

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