dengue vaccines: herd immunity considerations · models of dengue transmission herd immunity...
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Dengue Vaccines: Herd ImmunityConsiderations
Derek Cummings
Johns Hopkins Bloomberg School of Public Health
Fondation Merieux, October 27, 2010
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Outline
1 Introduction
2 Models of Dengue Transmission
3 Herd Immunity ConsiderationsImmune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
4 Conclusions
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Dengue Virus
Mosquito-borne flavivirusFour antigenically distinctserotypesEstimated 50-100 millioninfections annuallyPresentation ranges fromasymptomatic to severe form(DHF)2 ◦ cases are 50 times aslikely to have DHF
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune Enhancement
Apoptosis ofnaive T cells
Interferon γ
Antibody-dependentenhancement
Expansion oflow a�nitycross-reactiveT cells
Secretion ofvasoactivecytokines:TNFαInterleukin 2Interferon γ
Non-neutralising antibody
Fcγ receptor
Dengue virus
Platelet
Plasma leakageDengue virus and antibody complexing withplatelets and activating clotting cascade
Endothelium
Antigenpresentation
HLA-peptide
Monocyte
Memory T-cell
T-cellreceptor
Farrar, NEJM, 2009
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Challenges of Vaccine Development
Cannot contribute to immunopathogenesisNeeds to generate neutralizing immunity to all fourserotypes
avoid virus-to-virus interference or flavivirus interference
Needs to create long-lasting immunity
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Status of vaccine development
On hold
The candidate produced bySanofi Pasteur is soon tobegin phase III trialsThis candidate is yearsahead of others indevelopment
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Questions
Can vaccinations lead to increased secondary infections?What are the characteristics of these vaccines?What is the impact of non-immunized individuals?
What will be the effect of the age shift on symptomatic andsevere cases?What fraction of the population will we have to vaccinate?
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Dengue Transmission Model Structure
S E I
Vectorpopula/on
Age specific model with cross immunity, immune enhancementand SEI model of vectors
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Vaccination
%''"%'Zij
!" #$" %$" #$&" %''"!" #$" %Z #$&" %'X Yi Ci Zi Yij
Vaccine provides all or nothing immunity to all or a subset ofserotypes with some probability
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Results of hypothetical vaccination 1
R0 = 4, φ = [1.5,1.5,1.5,1.5], v = [0.5,0.5,0.5,0.5]
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Results of hypothetical vaccination 2
R0 = 4, φ = [1.5,1.5,1.5,1], v = [0,0,0,0.98]
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Results of hypothetical vaccination 3
R0 = 4, φ = [1.5,1.5,1.5,1.5], v = [0,0,0,0.6]
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Model parameterization
0 5 10 15 20 25 30
1980 1985 1990 1995 2000 2005
0.00.2
0.40.6
0.8
Year
Inc. p
er 10
00
0.00.2
0.40.6
0.8
Year
Inc. p
er 10
00
0.05
0.0
0.1
Age
Model was parameterized to match dominant multiannualperiodicity of all serotype incidence data as well as proportionof incidence occurring at each age.
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Hypothetical vaccines
Scenario 1: Single dose delivered at 1 year of age with 0.9independent probability of generating immunity to eachserotype reaching 90% of targeted children
Scenario 2: Three doses delivered at 12 months, 18 monthsand 24 months with 0.9 independent probability of gainingimmunity to each serotype at third dose reaching 90% oftargeted children
Scenario 3: Three doses delivered at 12 months, 18 monthsand 24 months with 0.1, 0.2 and 0.9 probability of gainingimmunity to each serotype at 1st, 2nd and 3rd doserespectively reaching 90% of targeted children
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Reduction in incidence
Over 5 years Over 10 yearsScenario 1 29.0% 87.1%Scenario 2 18.1% 79.5%Scenario 3 22.9% 84.4%
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Age as a risk factor for severe disease
2 4 6 8 10 12 14
0.4
0.6
0.8
1.0
1.2
1.4
Age (Years)
Odd
s of
DH
F
Using hospital based datafrom Thailand, we havefound a increasing odds ofDHF compared to DF uponsecondary exposure withage (Fried, PloS NTDS,2010)Vaccine will shift average toolder individuals, thus theirseverity will impact overallimpact of vaccine
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Age changes in Thailand
DHFIncidenceinThailand
Inc.per100
0
Average age of medicallyattended dengue illness inThailand has doubled in thelast 15 yearsDuring this period, theincidence of DHF hasremained fairly constant
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Age changes associated with Demographic Changes
The Impact of the Demographic Transition on Dengue inThailand: Insights from a Statistical Analysis andMathematical ModelingDerek A. T. Cummings 1*, Sopon Iamsirithaworn 2, Justin T. Lessler 1, Aidan McDermott 3, RungnapaPrasanthong 2, Ananda Nisalak 4, Richard G. Jarman 4, Donald S. Burke 5, Robert V. Gibbons 4
1980 1990 2000
0.06
0.10
0.14
Year
λλ i
a
Mean λλi,1985−2005
Freq
uenc
y
0.05 0.07 0.09 0.11
010
b●
% change in λλi,1985−2005
Freq
uenc
y
−70 −50 −30 −10 0
015
●
c
Recent increases in agespecific incidence linked todemographic changesAging of population hascontributed to a halving ofthe force of infection and adoubling of the mean age ofDHF cases
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Changes in demography
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Results of age specific simulations with changes indemography
Inc.per1000Second.Infec/ons
Year
AgeClass
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Age changes associated with Demographic Changes
The Impact of the Demographic Transition on Dengue inThailand: Insights from a Statistical Analysis andMathematical ModelingDerek A. T. Cummings 1*, Sopon Iamsirithaworn 2, Justin T. Lessler 1, Aidan McDermott 3, RungnapaPrasanthong 2, Ananda Nisalak 4, Richard G. Jarman 4, Donald S. Burke 5, Robert V. Gibbons 4
1980 1990 2000
0.06
0.10
0.14
Year
λλ i
a
Mean λλi,1985−2005
Freq
uenc
y
0.05 0.07 0.09 0.11
010
b●
% change in λλi,1985−2005
Freq
uenc
y
−70 −50 −30 −10 0
015
●
c
Recent increases in agespecific incidence linked todemographic changesAging of population hascontributed to a halving ofthe force of infection and adoubling of the mean age ofDHF cases
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Role of Immune Individuals in Population
Immune individuals provide blood mealsAn increase in the proportion of immune individualsreduces contact between infectious and susceptibleindividualsReduction in contact between infectious and susceptibleindividuals reduces the hazard that each susceptibleindividual experiencesAnother example of herd immunity effects
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Calculating the Basic Reproductive Number fromForce of Infection
Force of infection can be used to estimate the fraction ofthe population susceptible to infectionApply hazard to population to estimate fraction susceptible.Use theoretical results that 1/(fraction susceptible)estimates basic reproductive number1 = R = sR0
1s = R0
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Estimates of Basic Reproductive Number
R0 associated with more rainfall, higher temperatures andlarger population density
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Immune enhancement of transmissionVaccine performanceAge effects of VaccinationBasic Reproductive Number
Estimates of Basic Reproductive Number
Spatial variation in R0 suggests that 78% of the country wouldhave to be targeted compared to 88% of the country without
spatially targeting vaccine
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Conclusions
We find through simulation that vaccines could conceivablyincrease transmission but only vaccines that would not beconsidered for licensureDemographic changes have lead to herd immunity effectsreducing the hazard that young people experienceWe find spatial heterogeneity in the basic reproductivenumber across ThailandSuggests that optimal vaccination strategies may bespatially heterogeneous
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
At equilibrium 1=R=sR0
1/s=R0
I
S I
S
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Cumula&
vepropo
r&on
ofinciden
ceofd
enguebyageinBangkok
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Using Age data to estimate the Force of Infection
Cumula&
vepropo
r&on
ofinciden
ceofd
enguebyageinBangkok
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Estimating the Force of Infection
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Fitting models to cumulative age specific incidence
Cumula&
vepropo
r&on
ofinciden
ceofd
enguebyageinBangkok
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Estimates of the Force of Infection
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IntroductionModels of Dengue Transmission
Herd Immunity ConsiderationsConclusions
Partnership with WHO, v2V and Sanofi Pasteur
Organizing a meeting in late summer of modeling groups,epidemiologists and vaccine experts.
Working meeting meant to apply multiple modeling approachesto assess Sanofi Pasteur’s candidates
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