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Arnold S. Monto University of Michigan School of Public Health Ann Arbor, MI

Indirect Benefits of Vaccinating Healthy Children: Inactivated Vaccines. Arnold S. Monto University of Michigan School of Public Health Ann Arbor, MI. Indirect Protection - Issues. Community or population intervention How many replications? Methods? How many years?

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Arnold S. Monto University of Michigan School of Public Health Ann Arbor, MI

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  1. Indirect Benefits of Vaccinating Healthy Children: Inactivated Vaccines Arnold S. Monto University of Michigan School of Public Health Ann Arbor, MI

  2. Indirect Protection - Issues • Community or population intervention • How many replications? • Methods? • How many years? • Can indirect protection be produced with no evidence of direct protection? • Depends on transmission characteristics • More difficult with high Ro • The need for annual revaccination • What is the effect?

  3. Vaccination of School Age Children - Method • The A (H3N2) pandemic. • Monovalent inactivated vaccine available, but not generally. • Study ongoing in Tecumseh, Michigan. • Surveillance of acute illnesses going on in neighboring communities – need for adjustment. • Ability to identify period of virus transmission.

  4. Doses of Inactivated Vaccine AdministeredTecumseh, MI Monto et al. J Infect Dis. 1970; 22:16-25.

  5. Titers of HAI Antibody After Vaccination Number Tested 35 35 30 28 128 Reciprocal Geometric Mean Titer 63 93 48 52 61 Grade Kindergarten-3rd 4th-6th 7th-9th 10th-12th Total Monto et al. J Infect Dis. 1970; 122:16-25.

  6. Three Week Moving Mean Rates of Respiratory Illness – Tecumseh and Adrian, Michigan Hong Kong Influenza September October November December January 1969 1968 Monto et al. J Infect Dis. 1970; 122:16-25.

  7. Three Week Moving Mean Rates of Respiratory Illness, January-March, 1969 – Tecumseh and Adrian, Michigan Hong Kong Influenza Influenza Type B 1969 January February March Monto et al. J Infect Dis. 1970; 122:16-25.

  8. Age-specific Weekly Mean Rates of Respiratory Illness During the Period of Hong Kong Influenza (H3N2) Transmission. Tecumseh and Adrian, MI Monto et al. J Infect Dis. 1970; 22:16-25.

  9. Novgorod Study - Method • Two year study – Russian City of Novgorod. • Russian vaccines used. Live attenuated and inactivated. • Russian vaccines typically one year out of date. • Randomized by school to receive live attenuated, inactivated vaccines or placebo. • Informed consent necessary. Varying participation by school.

  10. Total Children with Respiratory Illness Onsets and Number of Influenza A (H3N2) Isolates in Specimens Collected During Epidemic Period Start of Epidemic Period End of Epidemic Period Rudenko et al. J Infect Dis. 1993; 168:881-7.

  11. Vaccine Efficacy for Completely Vaccinated Children1 January – 4 March 1990 Total Number Age Vaccine Group No. (%) with Illness % Efficacy (95% Confidence Interval) 7-10 years Live Placebo 11-14 years Live Placebo 7-10 years Inactivated Placebo 11-14 years Inactivated Placebo 2525 2331 2168 1837 2062 2331 1914 1837 430 (17.0) 567 (24.3) 281 (13.0) 495 (27.0) 380 (18.4) 567 (24.3) 363 (19.0) 495 (27.0) 30.0 (21.7-37.4) 51.9 (45.1-57.9) 24.2 (14.9-32.5) 29.6 (20.7-37.5) Rudenko et al. J Infect Dis. 1993; 168:881-7.

  12. Regression Analysis Relating Vaccination Rate in Schools in Which Children Received Vaccine or Placebo to Proportion Ill in Unvaccinated Children or Staff Rudenko et al. J Infect Dis. 1990; 161:781-3.

  13. Percent of Children Who Received Live Vaccine in Each School vs. Percent of Staff Who Were Ill in That School, 1990-1991 Rudenko et al. J Infect Dis.1990; 161: 781

  14. Vaccination of Day Care Children - Method • Day care attendees ages 24-60 months vaccinated twice with either inactivated influenza or hepatitis A vaccine as placebo. • Infections in vaccinated and control individuals assessed serologically as are illnesses meeting a case definition. • Illnesses in contacts of these children assessed – stratification by whether others in the household themselves received vaccine.

  15. Vaccine Efficacy Stratified by Prevaccination Hemagglutination Inhibition (HI) Titers Vaccinated No. (%) 95% CL Prevaccination HI Titer Control No. (%) VE Influenza A(H3N2)  5  10 Total Influenza B  5  10 Total Any Influenza (A[H3N2] or B)  5  10 Total 5/21 (24) 0/25 (0) 5/46 (11) 11/35 (32) 0/11 (0) 11/46 (24) 7/17 (41) 6/29 (21) 13/46 (28) 4/19 21) 4/32 (13) 8/51 (16) 17/35 (49) 5/16 (31) 22/51 (43) 7/16 (44) 19/35 (59) 26/51 (51) -0.13 1.0 0.31 0.35 1.0 0.45 0.06 0.62 0.45 -2.28, 0.62 -1.51, 1.00 -0.95, 0.73 -0.17, 0.63 -1.13, 1.0 -0.02, 0.69 -1.01, 0.56 0.16, 0.81 0.05, 0.66 Hurwitz et al. J Infect Dis. 2000; 182:1218-21.

  16. Effectiveness of Influenza Vaccination in Day Care Children in Reducing Respiratory Illnesses Among Unvaccinated Household Contacts • Household • Contact Age • Group, y • 0-4 • 5-17 •  18 • 0-4 • 5-17 • 18 • 0-4 • 5-17 •  18 Control Children Contacts, No. (Attack Rate) 9/13 (0.69) 22/31 (0.71) 33/71 (0.46) 5/13 (0.38) 11/31 (0.35) 7/71 (0.10) 4/13 (0.31) 11/31 (0.35) 6/71 (0.08) Vaccinated Children Contacts, No. (Attack Rate) 11/16 (0.69) 10/28 (0.36) 32/69 (0.46) 7/16 (0.44) 2/28 (0.07) 4/69 (0.06) 5/16 (0.31) 2/28 (0.07) 4/69 (0.05) Vaccine Effectiveness % 0 50 0 -14 80 41 -2 80 31 Respiratory Illness Any With Fever With Temperature of  38ºC (101ºF) P Value .48 .007 .50 .62 .01 .20 .51 .01 .28 Hurwitz et al. JAMA. 2000; 284:16776-82.

  17. Respiratory-Related Morbidity Among Unvaccinated 5- to 17-Year Old Household Contacts of Study Children Control Children Contacts, No. (Attack Rate) (n = 31) 12 (0.39) 7 (0.23) 12 (0.39) 9 (0.29) 9 (0.29) 18 (0.58) Vaccinated Children Contacts, No. (Attack Rate) (n = 28) 3 (0.11) 0 (0.00) 1 (0.04) 1 (0.04) 1 (0.04) 9 (0.32) Vaccine Effectiveness 72 100 91 88 88 45 P Value .02 .04 .007 .02 .02 .03 Event Missed School Adult Missed Work Physician Visits Earache Antibiotics Prescribed Over-the-Counter Medications Used Hurwitz et al. JAMA. 2000; 284:16776-82.

  18. Household-Based Costs and Benefits of Vaccinating Day Care Children - Summary • Use data from previous studies (2 years) of vaccination children in day care. • No statistically significant differences in household costs of respiratory illnesses. • Detailed results varied by year. • There was overall variability in the results, making absolute conclusions difficult. • Sample size a potential problem.

  19. The Japanese Experience with Vaccinating Schoolchildren - Background • In Japan, vaccination of school children began in 1962 and became obligatory in 1977. • Levels of coverage 50-85%. • Patients allowed to refuse in 1987; program discontinued in 1994. • Little or no vaccine used in older individuals. • Excess mortality (all-cause and P&I) reviewed.

  20. Reichert et al. N Engl J Med. 2001; 344:889-96.

  21. 1950 2000 Population Pyramid, Japan, 1950 - 2000 Male Female Male Female Age Population (thousands) Population (thousands)

  22. The Association of Resident Influenza Vaccination Status in Nursing Home Size with the Occurrence of Influenza Outbreaks in a Subset of 45 Nursing Homes: 1989-90, Lower Michigan Arden et al. Amer J Pub Health. 1995; 85:399-401

  23. SV = Staff Vaccinated SO = Staff not vaccinated Mortality in Geriatric Long-term Hospital Sites Where HCW Were Vaccinated Potter et al. J Infect Dis.1997; 175:4.

  24. PV Patients vaccinated PO Patients not vaccinated Potter et al, J Infect Dis.1997; 175:4. Mortality in Geriatric Long-term Hospital Sites Where Patients Were Vaccinated

  25. Vaccination Uptake and Mortality Among Patients for Each Hospital Carman et al. Lancet. 2000; 355:93-7.

  26. Vaccination Uptake in Healthcare Workers and Mortality Among Patients for Each Hospital Carman et al. Lancet. 2000; 355:93-7.

  27. Odds Ratios for the Impact of HealthCare-Worker Vaccination on Mortality in Patients Carman et al. Lancet. 2000; 355:93-7.

  28. Summary • Few studies designed specifically to examine issues of indirect protection. • Studies use various designs: blinded assignment to vaccine or placebo, vaccination of all eligibles in specific age groups, observational. • Difficult to use standards applied to RCTs to interpretation of results. • Evidence suggest indirect protection has been produced, but precise quantification difficult.

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