Challenges of Influenza Control

W. Paul Glezen, M.D.

Baylor College of Medicine Houston

Newly Recognized Respiratory Agents 1. SARS coronavirus – SARS - CoV 2. Human metapneumonvirus - hmpv 3. Avain influenzaviruses a) A (H5N1) b) A (H7N7) 4. Hendra – Nipah viruses

Hemagglutinin Subtypes of Influenza A Virus

Adapted with permission from Levine AJ.

Viruses

. 1992;165.

Influenza Epidemic Disease – Texas, 2003-2004 Year 2000-2001 2001-2002 2002-2003 2003-2004 Month Epidemic Started November 2000 January 2002 November 2002 October 2003 Virus A (H1N1) A (H3N2) B ( Victoria Lineage ) A (H3N2)

Influenza Virus Nomenclature

Type of Nucleoprotein

A/USSR/90/77

Hemagglutinin Neuraminidase

(H1N1)

Virus Type Geographic Origin Strain Number Year of Isolation Virus Subtype

Antigenic Variants of Influenza A (H3N2) and Changing Hemagglutinin Amino Acid Positions Year Variant 1968-72 A/Hong Kong/68 1972-73A/England/72 1974-75 A/Port Chalmers/73 1975-76 A/Victoria/75 1977-78 A/Texas/77 1980-83 A/Bangkok/79 1984-85 A/Philippines/73 1985-86 A/Stockholm/85 1987-88 A/Sichuan/87 1989-90 A/Shanghai/87 1991-92 A/Beijing/89 1993-94 A/Beijing/92 1994-95 A/Shangdong/93 1995-96 A/Johannesburg/94 1996-97 A/Wuhan/95 1997-00 A/Sydney/97 2001-02 A/Panama/99 Smith etal J Infect Dis 2002;185:980-5.

ESTIMATED ANNUAL AGE-SPECIFIC INFLUENZA DEATHS FOR 1990-1991 THROUGH 1998-1999 SEASONS* Age Group < 1 1 - 4 5 - 49 50 - 64 65+ Influenza A(H1N1) 0 34 501 348 1954 Totals 2,837 *Thompson, WW, et al, JAMA 2003; 289:179-86 Influenza Influenza A(H3N2) B 3 103 1,685 3,360 34,866 40,017 85 38 383 684 7,159 8,349 Total 88 175 2569 4,392 43,979 51,203

Season 1990-1991 1991-1992 1992-1993 1993-1994 1994-1995 1995-1996 1996-1997 1997-1998 1998-1999 Mean (SD) Estimated Annual Influenza-Associated Deaths for 1990-1991 Through 1998-1999 Seasons Using the Influenza Model A(H1N1) 1,988 6,518 1,190 173 572 14,727 0 66 293 2,836 (4,909) All-Cause Deaths No. of Influenza Deaths A(H3N2) 6,033 45,928 19,892 48,923 33,767 23,605 55,937 70,701 55,367 40,017 (20,656) B 17,549 566 19,030 404 7,129 7,509 12,609 649 9,698 8,349 (7,105) Total 25,570 53,012 40,112 49,500 41,468 45,841 68,546 71,416 65,358 51,203 (15,081)

Abbreviations: NA, not applicable.

*Pneumonia and influenza estimates are based on the 1990-1991 through 1997-1998 seasons.

Thompson WW et al.

JAMA

. 2003;289:179-186.

AGE-SPECIFIC ANNUAL AVERAGE RATES FOR INFLUENZA-ASSOCIATED HOSPITALIZATIONS, 1979-2001 Age < 5 5 - 49 50 - 64 65-69 70-74 75-79 80-84 >85 Totals Number 21,156 47,745 39,198 22,168 40,552 31,319 34,640 57,350 294,128 Rate/10,000 11.4

2.8

11.1

23.0

49.2

48.9

82.9

166.9

11.5

Year 1990-91 1991-92 1992-93 1993-94 1994-95 1995-96 1996-97 1997-98 1998-99 1999-00 2000-01 ANNUAL INFLUENZA-ASSOCIATED HOSPITALIZATIONS, U.S., 1990-2001 Rate/10,000 Predominant Virus Number B A(H3N2) B+A(H3N2) A(H3N2) 221,412 326,331 304,898 322,736 A(H3N2)+B 288,417 A(H1N1)+(H3N2) 296,312 A(H3N2)+B A(H3N2) 490,246 530,225 A(H3N2)+B A(H3N2) A(H1N1)+B 503,896 544,909 316,588 8.8

12.8

11.9

12.4

11.0 11.2 18.3

19.6

18.4

19.7 11.3

US Population Dynamics

Year Population No. Density (millions) per sq. mi.

Urban(%) Air Travel (millions) US International 1918 1957 1968 2002 2025 100 175 200 282 350 28 50 56 80 97 51 70 74 79 80 n.a.

49 162 632 ?

n.a.

52 ?

Estimated number of persons, influenza vaccine target groups, United States, July 1, 2002 Group Population (millions) Increased Risk Aged > 65 y Chronic illness Pregnant women Other children aged 6-23 mo Other (healthy) target groups Health care personnel aged < 65 y Household contacts of persons at increased risk Other persons aged 50-64 y Total, target groups Total, persons aged > 6 mo 82.8

35.6

39.7

2 5.5

102.6

7 75.5

20.1

185.4 286.4

O’Mara etal, Infect Med 2003 (Nov) 548-54.

Problems With Targeting High Risk Patients

 

High risk patients are not easily accessible for vaccination Many high risk patients are debilitated or immunocompromized and fail to respond optimally to vaccine

Influenza Surveillance In Texas 2003-04 Season

250 200 150 100 50 0 40 41 42 43 44 45 46 47 48 49 50 51 52 53 Week 1 Temple Waco Houston Austin B-Cs Total

Update: Influenza Activity, US. January 18--24, 2004 - Centers for Disease Control and Prevention. www.cdc.gov/flu. MMRW January 30, 2004 / 53(03);63-65

Influenza Mortality in U.S. Children 2003/04 152 Children <18 years reportedly died of Influenza-related causes* <6 months old 6-23 months old 2-5 years old >5 years old ACIP high-risk condition Other underlying medical condition Previously healthy Unknown 11% 30% 22% 37% 27% 31% 40% 2%

*70 percent of these children had not been vaccinated.

Bhat N.

ACIP

, June 23, 2004.

Influenza Virus Infection and Illness Rates Houston Family Study, 1976-1984

50 40 Infection ARI LRI 30 20 10 0 <2 2-5 6-10 11-17 Age (years) 18-24 25-34



35

Impact of Influenza on School Children and Their Families Influenza-associated outcomes Rate/100* Excess illness episodes Secondary illness episodes (family members) Days of work missed by parents Average school days missed/child 28* 22* 20* 2.25*

*Prospective cohort study of 313 children (K-8) in 216 families followed during 1 influenza season.

Neuzil KM, et al.

Arch Pediatr Adolesc Med.

, 2002;156:986-991.

Excess Hospitalizations per 10,000 Children/Year

110 100 90 80 70 60 50 40 30 20 10 0 104 50 19 9 4 <6 mo 6 to <12 mo 1 to <3 y Patient Age 3 to <5 y 5 to <15 y

*Values are weighted averages of annual excess hospitalizations for a population of 10,000 persons within the specified age group. Neuzil KM et al.

N Engl J Med.

2000;342:225-231.

20 10 0 30 30 20 10 0 30 20 10 0 <5 Respiratory Virus Infections Associated with Hospitalizations for Acute Respiratory Conditions, Houston, 1991-1995 5-17 Influenza Viruses Parainfluenza Viruses 18-44 Age (years) 45-64



65

Bacterial Disease in Children with Proven Precursor Influenza 1. Severe Pneumococcal Pneumonia in Previously Healthy Children: The Role of Preceding Influenza Infections. O’Brien KL et al. Clin Infect Dis 2000;30:784-9.

2. Risk-Factors for Meningococcal Disease in Victoria, Australia, in 1997. Robinson P et al. Epidemiol Infect 2001;127:261-8.

3. Is Bacterial Tracheitis Changing? A 14-Month Experience in a Pediatric Intensive Care Unit. Bernstein T et al. Clin Infect Dis 1998;27:459-62 4. Glezen WP. Prevention of Acute Otitis Media by Prophylaxis and Treatment of Influenza Virus Infections. Vaccine 2001; 19:S56-S58.

Other Complications of Influenza

• • •

Acute myositis Neurologic

–

Reye’s syndrome

–

Encephalopathy

–

Febrile convulsions Cardiac

–

Pericarditis

–

Myocarditis

Rationale for Alternative Approaches



School children and working adults are the major spreaders of influenza in the community and introducers into the household



School children have the highest annual attack rate for influenza

Rationale for Alternative Approaches



Immunization of school children and working adults to:

  

decrease absenteeism for school and work decrease visits for medical care decrease antibiotic prescriptions

Influenza Vaccinations in Japanese School Children D B A C (A) all cause baseline (B) all cause excess (C) P & I baseline Reichert, TA Seminars Pediatr Infect Dis; 13:104-11 (D) P& I excess

Site of CAIV-T Field Trial Central Texas

Non-randomized, Open Label Field Trial of Trivalent Cold Adapted Influenza Vaccine (CAIV-T) in Central Texas, 1998-2001 Indirect Effectiveness (Herd Immunity) – Age-specific rates of medically-attended acute respiratory illness (MAARI) for the intervention site compared to those for the comparison sites.

Direct Effectiveness and Adjusted Efficacy – MAARI rates in CAIV-T recipients compared to rates in 9,325 age-eligible non-recipients at the intervention site and adjusted for culture-positive MAARI.

Total Effectiveness – MAARI rates in CAIV-T recipients compared to rates in 16,264 age-eligible non-recipients in the comparison sites.

Safety: a) Occurrence of serious adverse events (SAEs) for 42 days after vaccination b) Occurrence of rare events associated with natural influenza virus infection c) Comparison of MAARI rates 0-14 days after vaccination to the pre vaccination.

MAARI Rates in the Intervention and Comparison Sites during Influenza Outbreaks for SWHP Members > 35 years old MAARI rates per 100 person-season Overall effectiveness (1-RR) Year Intervention site: T-B Comparison site: W/B-CS 95% CI 1997-98; base line 9.3

9.2

0 -0.03-0.05

1998-99; Year 1 1999-00; Year 2 2000-01; Year 3 12.0

12.2

15.1

13.1

15.0

17.8

0.08

0.18

0.15

0.04-0.13

0.14-0.22

0.12-0.19

CAIV-T Direct Effectiveness for all MAARI and Adjusted Efficacy for Culture-Positive MAARI with both Influenza A(H1N1) and B, Temple-Belton, TX, 2000-01 Age (years) Direct (95% CI) Effectiveness Adjusted (95% CI) Efficacy

1.5-4 5-9 10-18 Total Subsets

0.20* 0.25

0.14

0.18

(0.14,0.25) (0.15,0.34) (0.01, 0.26) (0.11,0.24) Influenza A(H1N1) Influenza B *statistically significant in bold numbers 0.91

0.80

0.70

0.79

(-0.34,0.99) (0.26,0.95) (0.13,0.90) (0.51,0.91)

0.92

0.66

(0.42,0.99) (0.09,0.87)

Safety Summary

• • • •

Years 1, 2, 3 and 4: 18,780 doses of CAIV-T have been administered to 11,096 children in this community-based, open-label trial No CAIV-T vaccine attributable serious adverse event has been observed No CAIV-T vaccine attributable rare or unusual adverse event has been observed Six pregnancies originating proximal to receipt of vaccine were uncomplicated (healthy full-term infants).

CAIV-T FIELD TRIAL Summary

1. Safe-side effects do

not

increase direct medical costs.

2. Direct Effectiveness a. Protection inversely related to age (VEadj 0.70-0.91) b. Persists through two seasons c. Heterovariant d. Single dose is sufficient 3. Indirect Effectiveness (Herd Immunity) – For proportion vaccinated compatible with Longini Model.

Implications for Control of Both Interpandemic and Pandemic Influenza

   School children have the highest attack rates for influenza.

School children are the principle spreaders of influenza.

School children are accessible for rapid distribution of influenza vaccine.

Acknowledgements

W. Paul Glezen – Control of Epidemic Influenza Grant Co-Investigators: Consultants: Pedro A. Piedra – PI, Baylor College of Medicine Mangusha Gaglani – PI, Scott & White Clinics Gayla Herschler – Coordinator, S & W Mark Riggs – Biostatistics, S & W Claudia Kozinetz – Analysis and Data Management, Ira Longini – Emory University Elizabeth Halloran – Emory University BCM Vaccine: Program Officer: Paul Mendelman, MedImmune Vaccines Colin Hessel, Biostatistics, Safety Analysis, MedImmune Linda Lambert - NIAID