Transcript Containing Pandemic Influenza at the Source Ira M. Longini, Jr. Dept. Biostatistics U. Washington Hutchinson Rsh Ctr.

Containing Pandemic Influenza
at the Source
Ira M. Longini, Jr.
Dept. Biostatistics
U. Washington
Hutchinson Rsh Ctr
Collaborators
M. Elizabeth Halloran
Azhar Nizam
Shufu Xu
Depts. Biostatistics, U Wash and Emory U
Derek Cummings
Johns Hopkins U.
Kumnuan Ungchusak
Wanna Hanshaoworakul
Thai Ministry of Health
Timothy C. Germann
Kai Kadau
Catherine A. Macken
Los Alamos National Laboratory
How Bad Could it Get?
• Current Avian A(H5N1) Influenza is SE Asia
– 165 cases, 88 deaths, 53% case fatality ratio
• Global pandemic, first wave about 6 - 9
months, 2 billion cases
– 1918 scenario: 10 - 50 million deaths
– Other scenarios: 2 – 7 million deaths
– Contrast
• 20 million AIDS deaths over 25 years
• 811 SARS deaths over 8 months
Containing Pandemic Influenza
at the Source
• It is optimal to stop a potential pandemic
influenza strain at the source
– Longini, et al. Science 309, 1083-7 (2005).
• Longini and Halloran. Science 310, 1117-18 (2005).
– Ferguson, et al. Nature 437, 209-14 (2005)
– Targeted antiviral prophylaxis with mobile stockpile
(WHO) ~ 5 million courses
– Quarantine, social distancing, school closing,
travel restrictions
– Pre or rapid vaccination with a possibly poorly
matched vaccine
Pandemic Influenza in the US or Other
Countries Once Spread is Global
• Hard to contain as it comes in
• Once widespread, slow transmission until well-match vaccine is
available
– Targeted antiviral prophylaxis
– Quarantine, social distancing, school closing, travel restrictions
– Rapid vaccination with a possibly poorly match vaccine
•
Germann, T.C., Kadau, K., Longini I.M. and Macken C.A.: Mitigation
strategies for pandemic influenza in the United States. (accepted – Feb
or March, 2006)
•
Halloran, M.E. and Longini, I.M.: Community studies for vaccinating
School children against influenza. Science 311 (Feb. 3, 2006).
TAP: Targeted antiviral prophylaxis
using neuraminidase inhibitors (oseltamivir/zanamivir)
80% school
80% ascertainment
CONTACTS
Household
Household cluster
Preschool/daycare
School
Workplace
100% household + HH cluster
80% preschool
60% workplace
Antiviral efficacies used in the model:
Oseltamivir
• Antiviral efficacy of reducing susceptibility to
infection: AVES = 0.48, [0.17, 0.67] 95% CI*
• Antiviral efficacy of reducing illness given infection:
AVED = 0.56, [0.10, 0.73] 95% CI*
• Antiviral efficacy of reducing illness with infection:
AVESD = 0.80, [0.35, 0.94] 95% CI*
– Mult.: AVESD = 1 – (1- AVES) (1- AVED) = 0.77
• Antiviral efficacy of reducing infectiousness to others:
AVEI = 0.80, [0.45, 0.93] 95% CI*
*data
from Welliver, et al. JAMA (2001); Hayden, et al. JID (2004); analysis
by Yang, Longini, Halloran, Appl Stat (in print); Halloran, et al. (in prep).
Prevaccination
•
Prevaccination with low efficacy
vaccine
– Low efficacy vaccine: VES = 0.30, VEI =
0.5
– 50% and 70% prevaccination of the
population and evaluate above
interventions
Preliminaries
Basic Reproductive Number: R0
• R0 > 1 for sustained transmission
• For pandemic influenza: 1 < R0 ≤ 2.4
– A(H3N2) 1968-69, R0 ≈ 1.7
– A(H1N1) 1918, second wave, R0 ≈ 2.0
– New variant, early spread: 1 < R0 ≤ 1.6
Reed-Frost Model
Stochastic process: discrete state space and time t0, t1, t2 ….
• Infectious agent natural history
– Infectious for one time unit
• Social contact structure
– Random mixing
– p = 1 – q, probability two people make
contact sufficient to transmit
• R0 = (n-1)p
Reed-Frost Model
 St 
I t I t 1 I t ( S t  I t 1 )
P( I t 1 St , I t )   (1  q ) q
, St  I t 1 ,
 I t 1 
St 1  St  I t 1 ,
Rt 1  Rt  I t ,
St  I t  Rt  n, t ,
P[ S (0)  n  1]  1, P[ I (0)  1]  1, P[ R(0)  0]  1
St , I t t 0,1,... is a Markovchain
See chain binomial chapter in the Encyclopedia Biostat., Vol 1, 593-7
Reed-Frost Model
R0  (n  1) p
Threshold theorem:
When R0  1, then no epidemic,
When R0 >1, then epidemic with probability
 1 
 1   
 R0 
I0
Simulated Reed-Frost
*
Model
Start with (S0,I0 ≥ 1)
 For each S0, generate random number x 
[0,1]
 If x ≥ qIo, then person becomes infected
 Repeat for next generation and update states
 Stop when S0= 0 or I0= 0

*First done by Elveback and Varma (1965)
*
*Source:
Elveback and Varma (1965)
Containment in SE Asia
Rural population of
500,000 in Thailand
Population matched to nonmunicipal area household-size and
age distributions.*
*Population and Housing Census 2000 data used where
available (www.nso.go.th); other National Statistical Office
reports and tables used as necessary.
12.5km
12.5km 12.5km
12.5km 12.5km 12.5km
12.5km
Population Characteristics
• 36 localities each of size
~14,000
• Total area: 75 km X 75 km = 5,625
km2
• Population density ~89/km2
Locality Characteristics
• ~ 28 villages, each of size ~ 138
households, ~ 500 people
• Villages are clustered
Within village clusters:
• Household are clustered
• Small & large playgroups
• Elementary, lower-secondary and
upper-secondary school mixing
groups
• Social groups
• Work groups
Social network incorporated from
the Nang Rong District study*



310 villages under study
Village size average  100 households
Main mixing groups under study
 Households
 Villages
 Hiring
tractors
 Temples
 Elementary schools
 Secondary schools
 Workplaces
*Faust,
et al., Soc Net (1999)
Distribution of travel distance to
work, school and social groups
100
80
%
60
40
20
0
0-15
16-30
31-45
Distance Traveled (km)
46+
Secondary school, work and social group
assignment


Localities are linked by secondary schools, work
groups and social groups
For residents of each locality, secondary school, work
group and social group locality is selected according to
distance distribution shown below (using most
Southwesterly locality as an example)
Zone6
Zone5
Zone
%
1
90
2
7
3
2
4-6
1
Zone4
Zone3
Zone2
Zone1
Distribution of travel distance to work,
school and social groups*
For residents of most Southwesterly locality:
Zone6
1% go beyond
zone 3
Zone5
Zone
%
1
90
2
7
3
2
4-6
1
Zone4
Zone3
2% go to zone 3
Zone2
7% go to zone 2
Zone1
90% stay in zone 1
Model calibration
Illness Attack Rate
Young Children
Older Children
Adults
Overall
Asian A(H2N2)
1957-58
35%
62%
24%
33%
Modeled
Pandemic
Strain
32%
46%
29%
33%
HK-Like
’68-69
34%
35%
33%
34%
Social Connectivity
Transmission

c daily adequate contact probability
 c(n-1)
average mixing group degree
x transmission probability given adequate
contact
 y relative susceptibility
 p = cxy overall transmission probability

Bipartite Graph
People
Places
1
1
2
2
•
•
•
•
•
•
•
•
•
•
n
m
Daily contact probabilities adults by mixing group
Children
Pre-School
Small
Large
Contact group
Playgroup Daycare
Small playgroups 0.35
Large playgroups
School
Elementary
Middle
High
Adults
0.25
Elementary school
0.062
Middle school
0.062
High school
0.060
Family
Child
0.60
0.60
0.60
0.60
0.60
0.30
Adult
0.30
0.30
0.30
0.30
0.30
0.40
Neighborhood
Cluster
Child
0.15
0.15
0.15
0.15
0.15
0.08
Adult
0.08
0.08
0.08
0.08
0.08
0.10
Hospital
Flu ward
Worker-worker
0.01250
Patient-worker 0.01000 0.01000
0.01000
0.01000
0.01000
0.01000
Patient-visitor 0.01000 0.01000
0.01000
0.01000
0.01000
0.01000
Other wards
0.00250
Workgroup
0.115
Social Groups 0.0024
0.0024
0.00255
0.00255
0.00255
0.0048
Weighted Person-to-Person Graph
1
c12
2
c2n
c2j
3
c1n
n
c3r
4
c4s
0.30
0.25
Clustering coefficient 0.2
Mean shortest path 10.6
0.20
Small World Network
0.05
0.10
0.15
Mean degree 4.6
0.00
Mass
Histogram of degree
0
5
10
15
Degree
20
25
Infection Transmission Process
Natural History Used for Influenza
Probability of
infecting others
Case serial interval = 3.2 days
Symptomatic (67%)
Asymptomatic (33%)
0
days
Latency
1.2d
Incubation
1.7d
Exposure and infection
Possibly symptomatic
3.5d
Intervention
Interventions considered




All interventions carried out in the localities as
triggered
80% targeted antiviral prophylaxis (TAP)
90% geographically targeted antiviral
prophylaxis (GTAP)
Localized household and household cluster
quarantine. Lifted when there are no more
local cases.
Interventions considered




TAP + pre-vaccination
TAP + localized household quarantine
TAP + localized household quarantine + prevaccination
Localized interventions begin 7, 14 and 21
days after outbreak is recognized, one day after
as cases appear locally
Results
R0*: Number of people infected by a single initial infective
350
Frequency
300
250
Average R0=1.4
200
150
100
50
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15
Number of secondary infections
* Based
on 1000 simulations
4000
No Intervention
Day 11
R0= 1.4
166,408 total cases
18
25
2000
Day
1000
0
0
25
50
75
100
125
Day
150
175
200
225
# Cases
11
6
18
47
25
153
50
Day 11
40
No. of cases
No. of cases
3000
18
25
30
20
10
0
0
25
Day
Illness attack rate by age-group and R0 (No Intervention)
0.7
Illness attack rate
0.6
R0=2.4
R0=2.1
0.5
0.4
R0=1.7
0.3
R0=1.4
0.2
0.1
R0=1.1
0
<1
1-5
6-10
11-14 15-17 18-44 45-64
Age (years)
65+
4000
Contained
GTAP 14 days after the first
detected case(~ day 18)
Day 18
2000
R0= 1.4
44 total cases
1000
0
0
25
50
75
100
125
Day
No. of cases
No. of cases
3000
150
175
200
225
30
Day 18
20
10
0
0
25
Day
4000
Not contained
GTAP 14 days after the first
detected case(~ day 18)
Day 18
2000
R0= 1.4
1925 total cases
1000
0
0
25
50
75
100
125
Day
No. of cases
No. of cases
3000
150
175
200
225
30
Day 18
20
10
0
0
25
50
75
100
125
150
175
200
225
No Intervention, R0 = 1.4
80% TAP, 14 day delay, R0 = 1.4
Simulated mean cases, escapes, courses and
containment proportion for various interventions
Cases per 1000
Intervention
Escapes
Courses
R0 = 1.4
Containment Ratio
R0 = 1.4
R0 = 1.7
R0 = 1.4
R0 = 1.7
No Intervention
229
361
742
1184
80% Targeted Antiviral Prophylaxis (TAP)
0.11
140
0.35
500
771
355259
1.00
0.35
90% Geographically Targeted Antiviral
Prophylaxis (GTAP)
0.06
54
0.16
183
26946
302488
1.00
0.60
80% TAP + 50% Pre-vaccination
0.01
0.49
0.06
2
66
3111
1.00
0.85
80% TAP + 70% Pre-vaccination
0.01
0.03
0.03
0.13
46
217
1.00
1.00
70% Quarantine
0.17
0.77
0.60
2
0.98
0.70
80% TAP + 70% Quarantine
0.05
0.14
0.2
1
379
1149
1.00
1.00
80% TAP + 70% Quarantine + 50% Prevaccination
0.02
0.04
0.06
0.19
132
285
1.00
1.00
-
R0 = 1.7
-
-
R0 = 1.4
-
-
R0 = 1.7
-
R0 sensitivity - cases
90% GTAP
Threshold
R0 sensitivity - courses
Delay in interventions sensitivity - cases
Conclusions

80% TAP and 90% GTAP would be effective in
containing pandemic influenza at the source if R0
≤ 1.4
 This
is true even up to a 21 day delay after the first
detected case, about 25 days after first infection
 At least 70% TAP or GTAP would be needed
 Fewer than 120,000 courses would generally be needed

Neither 80% TAP nor 90% GTAP would be
effective in containing pandemic influenza at the
source if R0 ≥ 1.7

350,000 courses would generally be needed

Prevaccination of the population with a low
efficacy vaccine makes a big difference, even
at the 50% coverage level
 With
50% of the population vaccinated, 80%
TAP would be effective in containing pandemic
influenza at the source if R0 ≤ 1.7, even up to 56
days delay. Prevaccination lowers the effective R
before the epidemic.
 With 70% of the population vaccinated, 80%
TAP would be effective in containing pandemic
influenza at the source if R0 ≤ 2, up to 56 day
delay
Household and neighborhood quarantine is
effective for R0 ≤ 1.7 up to 35 days delay,
becomes ineffective for R0 ≥ 2.1
 A combination of 80% TAP + quarantine is
effective even for an R0 as high as 2.4, while
adding prevaccination makes this
combination even more effective even up to
56 days delay.

Policy Implications



A mobile stockpile of oseltamivir has been created
by WHO. It will be deployed quickly after the
initial infection cluster is detected.
The outbreak is containable with targeted antiviral
prophylaxis if transmissibility is reasonably low
(R0 ≤ 1.4) and intervention occurs with 21 days of
first detected case.
Localized quarantine and other social distancing
measures would be important for containment for
viruses with higher transmissibility (R0 ≥ 1.7) .
Policy Implications Continued
The development and deployment of
vaccine for potential pandemic strains for
at-risk populations should move forward as
quickly as possible.
 Surveillance and detection of early
pandemic influenza transmission is
extremely important in all potentially at-risk
regions of the world.

Oseltamivir Stockpiles
WHO: 120,000 courses, soon 5 million
courses
 US: 4 - 5 million courses, increase to 75
million courses? H5N1 vaccine stockpile?
 Other Countries (e.g., U K, France, Finland,
Norway, Switzerland, New Zealand)

 20
- 40% population (one course) ordered
The End