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
and age groups vaccinated
• Is there an indirect effect in
households?
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.
Doses of Inactivated Vaccine
Administered
Tecumseh, MI
Group
Number
Total
Vaccinated Enrolled Percentage
Elementary school
1,908
2,077
91.9
Junior high school
432
515
83.9
High school
819
1,090
75.1
Total
3,159
3,682
85.8
Monto et al. J Infect Dis. 1970; 22:16-25.
Titers of HAI Antibody After
Vaccination
Grade
Kindergarten-3rd
4th-6th
7th-9th
10th-12th
Total
Number Reciprocal Geometric
Tested
Mean Titer
35
35
30
28
128
63
93
48
52
61
Monto et al. J Infect Dis. 1970; 122:16-25.
Age-specific Weekly Mean Rates of Respiratory
Illness During the Period of Hong Kong Influenza
(H3N2) Transmission. Tecumseh and Adrian, MI
Percent Per Week - Mean
Adrian (Adjusted)
Tecumseh
18
16
14
12
10
8
6
4
2
0
0-4
5-9
10-14
15-19
20-29
30-39
40+
Age Groups (Years)
Monto et al. J Infect Dis. 1970; 22:16-25.
Novgorod Study - Method
• Two year study – Russian City of Novgorod.
• Russian vaccines used. Live attenuated and
inactivated.
• Russian vaccines at that time one year
behind WHO recommended composition.
• Randomized by school to receive live
attenuated, inactivated vaccines or placebo.
• Informed consent necessary. Varying
participation by school.
Regression Analysis Relating Vaccination Rate in
Schools in Which Children Received Vaccine or Placebo
to Proportion Ill in Unvaccinated Children or Staff
B eta (95%
C onfidence Interval)
r2
-1.47 (-1.82,-1.15)
.86
Inactivated
-0.23 (-0.72,0.26)
.11
Placebo
-0.20 (-0.65,0.25)
.07
-1.15 (-1.15,-1.63)
.51
Inactivated
0.04 (-0.38,0.46)
.00
Placebo
-0.25 (-0.91,0.41)
.06
V accine G roup
% of Ill Staff vs.
% of Students Vaccinated
Live
% of Ill N on-vaccinated C hildren vs.
% of Students Vaccinated
Live
Rudenko et al. J Infect Dis. 1993; 167: 881-7
Percent by School of Children
Vaccinated with Live Vaccine
Percent of Children Who Received Live
Vaccine in Each School vs. Percent of Staff
Who Were Ill in That School, 1990-1991
70
60
50
40
30
20
10
0
0
5
10
15
20
25
30
35
40
45
Percent Ill in Staff
Rudenko et al J Infect. Dis 1993; 167 :881-7
Protective Effectiveness on Nonrecipients of Immunizing
Children and Adolescents With Influenza Vaccine
Nonrecipients in Vaccine colony
Influenza
(n=1271)
Hepatitis
(n=1055)
Influenza
detected by
PCR
39 (3.1)
80 (7.6)
Person-days
of follow-up
182 866
151 902
No. of
cases/10,000
person-days
2.13
5.27
Study Group
Protective
Effectiveness of
influenza Vaccine
(95% CI)
P
Value
Simple, 61 (8-83)
Adjusted, 61 (8-83)
.03
.03
Loeb M et al JAMA 2010;303:943-950
Protective Effectiveness on Nonrecipients of Immunizing
Children and Adolescents With Influenza Vaccine
(continued)
Nonrecipients in
Vaccine colony
Study Group
Vaccine tested by HAI
Influenza
(n=1271)
Hepatitis
(n=1055)
≥4-Fold increase in
serum titers,
A/Brisbane/59/2007
H1N1
66(9.2)
81(13.4)
A/Brisbane/10/2007,
H3N2
256(35.9
A/Brisbane/60/2008
24(3.4)
Relative Risk (95% CI)
P
Value
Simple, 0.59(0.33-1.01)
.06
259(42.3) Simple, 0.74(0.47-1.10)
.15
38(6.3)
Simple, 0.54(0.29-1.00)
.05
Loeb M et al JAMA 2010;303:943-950
Protective Effectiveness In Healthy Participants who Received
Vaccine
Vaccine colony
Influenza
Hepatitis
A
502
445
41(8.2)
79(17.8)
Person-days of follow
up
70377
58954
Incidence of Influenza,
No. of cases/10000
person-days
5.83
13.4
Subgroups Number
Influenza detected by
PCR, NO. (%)
Protective Effectiveness
of influenza Vaccine
(95% CI)
Simple, 55( CI-21 to 84)
P
Value
.11
Loeb M et al JAMA 2010;303:943-950
Ct value by vaccination status for laboratory confirmed
influenza A H3N2 positives from 2004-05, 2005-06 and 200708 influenza seasons
Intervention
LAIV
N (%)
TIV
N (%)
Placebo
N (%)
<25
17 (22.1)
13 (31.7)
18 (40.9)
25-30
26 (33.8)
10 (24.4)
16 (36.4)
>30-<40
34 (44.2)
18 (43.9)
10 (22.7)
Ct value
Petrie et al. J Infect Diseases 2011;203: 1309-15