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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

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containing pandemic influenza at the source

Containing Pandemic Influenza at the Source

Ira M. Longini, Jr.

Dept. Biostatistics

U. Washington

Hutchinson Rsh Ctr

collaborators
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
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 source5
Containing Pandemic Influenza at the Source
  • It is optimal to stop a potential pandemic influenza strain at the source
    • Longini, et al.Science309, 1083-7 (2005).
      • Longini and Halloran. Science310, 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
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).
slide7

CONTACTS

Household

Household cluster

Preschool/daycare

School

Workplace

80% ascertainment

80% school

100% household + HH cluster

80% preschool

60% workplace

TAP: Targeted antiviral prophylaxis

using neuraminidase inhibitors (oseltamivir/zanamivir)

antiviral efficacies used in the model oseltamivir
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
  • 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
basic reproductive number r 0
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 t 0 t 1 t 2
Reed-Frost ModelStochastic 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

Reed-Frost Model

See chain binomial chapter in the Encyclopedia Biostat., Vol 1, 593-7

reed frost model14
Reed-Frost Model

Threshold theorem:

When R0 1, then no epidemic,

When R0>1, then epidemic with probability

simulated reed frost model
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)

slide16

*

*Source: Elveback and Varma (1965)

slide18

Rural population of 500,000 in Thailand

Population matched to non-municipal 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.

slide19

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
slide20

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
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)

secondary school work and social group assignment

Zone6

Zone5

Zone4

Zone3

Zone2

Zone1

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)
  • Zone %
  • 90
  • 7
  • 2
  • 4-6 1
distribution of travel distance to work school and social groups24
Distribution of travel distance to work, school and social groups*

For residents of most Southwesterly locality:

  • Zone %
  • 90
  • 7
  • 2
  • 4-6 1

Zone6

1% go beyond zone 3

Zone5

Zone4

Zone3

2% go to zone 3

Zone2

7% go to zone 2

Zone1

90% stay in zone 1

model calibration
Model calibration

Illness Attack Rate

Modeled

Asian A(H2N2) Pandemic HK-Like

1957-58 Strain ’68-69

Young Children 35% 32% 34%

Older Children 62% 46% 35%

Adults 24% 29% 33%

Overall 33% 33% 34%

transmission
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
Bipartite Graph

People

Places

1

1

2

2

•••••

•••••

n

m

weighted person to person graph
Weighted Person-to-Person Graph

c12

1

2

c2n

c2j

c1n

n

3

c3r

c4s

4

slide34

Mean degree 4.6

Clustering coefficient 0.2

Mean shortest path 10.6

Small World Network

slide36

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

Possibly symptomatic

1.7d

3.5d

Exposure and infection

interventions considered
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 considered39
Interventions considered
  • TAP + pre-vaccination
  • TAP + localized household quarantine
  • TAP + localized household quarantine + pre-vaccination
  • Localized interventions begin 7, 14 and 21 days after outbreak is recognized, one day after as cases appear locally
slide41

R0*: Number of people infected by a single initial infective

Frequency

Average R0=1.4

Number of secondary infections

* Based on 1000 simulations

slide42

No Intervention

R0= 1.4

166,408 total cases

Day # Cases

11 6

18 47

25 153

Day 11

18

25

No. of cases

Day

Day 11

18

25

No. of cases

Day

slide44

Contained

GTAP 14 days after the first detected case(~ day 18)

R0= 1.4

44 total cases

Day 18

No. of cases

Day

Day 18

No. of cases

Day

slide45

Not contained

GTAP 14 days after the first detected case(~ day 18)

R0= 1.4

1925 total cases

Day 18

No. of cases

Day

Day 18

No. of cases

slide49

Simulated mean cases, escapes, courses and containment proportion for various interventions

90 gtap
90% GTAP

Threshold

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

Conclusions
slide55
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
slide56
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
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
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
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
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