Mathematical Models for the Control of Infectious Diseases With Vaccines

Transcription

1 Mathematical Models for the Control of Infectious Diseases With Vaccines Ira Longini Department of Biostatistics and Center for Statistical and Quantitative Infectious Diseases (CSQUID), University of Florida and Hutchinson Research Center, Gainesville, FL and Seattle, WA

2 Today s Talk Stochastic model for vaccine efficacy Example with everything Modeling dengue transmission Dengue vaccine Modeling strategies for dengue vaccines Vaccination strategies modeled by our group Influenza, dengue, cholera, typhoid, malaria, measles, pertussis, smallpox, HIV, TB, others

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5 Some 20 Years Ago...

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7 Hazard function for infection λ(t) = cπp t c contact rate π per-contact transmission probability p(t) probability contact is with an infected person at time t, e.g., p(t) = I(t)/n

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14 Dengue Modeling Dengue threatens roughly 30% of the planet s population and is expanding due to climate change, urbanization and global transportation

15 Individual-level stochastic dengue transmission model Determine optimal vaccination strategies Predict the effectiveness and impact of vaccination strategies Estimates given to GAVI Help with statistical analysis of dengue transmission and vaccine efficacy Help with the design of phase IV vaccine effectiveness studies First introducers Subsequent introduction of vaccine in other countries and regions

16 Components of the transmission model Geographic Structure and Connectivity Vector density, movement, biting Natural history of infection and illness Human Vector Epidemiology of dengue in region Immune profile Serotype-specific incidence of dengue

17 Components of the control model Vaccination Vaccine efficacy against all four serotypes VE S, VE P, VE SP, VE I Vaccination strategy Route vaccination of 2 year-olds Catch-up older age groups Coverage, targeting Vaccine effectiveness and impact Direct, overall, total, indirect (herd effects)

18 Model: Natural history of dengue Human SEIR is linked to mosquito SEI model Humans and mosquitoes infect each other when they are in the same setting

19 Model: human movement People are at home in the morning and evenings. People may go to work or school during the day.

20 Model: mosquito movement Each mosquito is associated with a setting (house, workplace, school). Mosquitoes often migrate to adjacent setting. Occasionally, mosquitoes migrate to distant setting.

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22 Population: Geography of Bang Phae District Population density (1km 2 resolution) from GRUMP ( Households placed randomly within each 1km 2 cell to match the density estimates. 394 schools and many workplaces added. Area includes 207,000 people living in 600 square kilometers.

23 Modeling pre-existing immunity We simulate an 11% infection attack rate per year for naive individuals with the observed proportion of serotypes. Infection by a serotype confers lifelong immunity to that serotype.

24 Results

25 Basic Reproductive Number, R 0 R 0 = 5.4 R 0 = 5.1

26 Effective Reproductive Number, R R = 2.3 R 0 = 2.3 R = 2.0 R = 2.6 R = 1.8

27 Bang Phae Simulation

28 Vaccination

29 Preclinical evaluation In vitro and in vivo genetic and phenotypic stability Envelope Glycosylation Yellow Fever Virus 17D cdna C prm E Non-Structural genes (NS) Safety and immunogenicity - Human cells in vitro (DCs, Hep. cells) - Monkey model - Non clinical safety (NCS) prm E PUO-359/TVP-1140 PUO-218 PaH881/ (TVP-980) Exchange with prm/e genes of wt DEN Theoretical issues and GMO aspects Reversion to virulence Recombination? X? Vector transmission Breadth of protection 4 Chimeric cdnas Viscerotropism ADE 4 individual chimeric dengue viruses (CYD 1-- 4) Individually transcribed to RNA RNA transfection in Vero cells Scale up and Industrial Development Scale-up - Phase I to phase III process Building of Facilities Clinical development (Phase I to Phase III, non-endemic / endemic areas) Safety / Viremia Immunogenicity (PRNT 50, CMI) B T Preparation of vaccine launch Vaccine to Vaccination

30 Results of Phase IIb Vaccine Trial (CYD23): Intent to Treat Analysis * VE SP1-4 : 34.9 ( ) (Crude) VE SP1 : 61.2 ( ) VE SP2 : 3.5 ( ) VE SP3 : 81.9 ( ) VE SP4 : 90.0 ( ) * Sabchareon, et al. Lancet (2012)

31 Many Vaccine Efficacy Effects Where Not Estimable Immunological/infection data were available on 8% ( 300) of the participants Correlates, surrogates, sieve analysis VE S =? VE P =? Symptoms about same in vaccine and placebo arms VE I =?

32 Overall Efficacy vs Proportion of Serotype 2 Circulating VE SP Proportion of total that is serotype 2

33 Modeling Dengue Vaccine: Two Scenarios 1. Protection against all four serotypes VE SP1-4 = 0.70 (all-or-none protection) 2. No protection against one serotype VE SPi = 0, for one of i = 1,2,3 or 4 VE SPj i = 0.70 for all j i, j = 1,2,3,4, e.g., VE SP2 = 0, VE SP1 = VE SP3 = VE SP4 = 0.70

34 Overall effectiveness and impact Overall effectiveness VE overall = 1 (r vac /r novac ) r vac overall incidence rate with vaccination campaign r novac overall incidence rate with no vaccination in a comparable population

35 Single Season Impact

36 Protection against all four serotypes: VE SP = 0.7

37 Dengue Vaccine Effectiveness One Year From the Model VE SP = 0.7 Strategy Coverage Target % Coverage Overall % VE overall 2-14 yrs yrs yrs yrs

38 Overall vaccine effectiveness with lack of protection against one serotype, VE S = 0.7

39 Overall vaccine effectiveness VE SP = 0.7, coverage 70%, 2-46 yrs, 52% total population Vaccine Action VE Overall Tetravalent 82 Missing DENV 1 60 Missing DENV 2 54 Missing DENV 3 68 Missing DENV 4 75

40 Longer-term Impact with good protection against all four serotypes

41 Simulated epidemic over ten years

42 Vaccination Roll-out: Up to age 14 Vaccinate 70% of 2-14 year olds over 3 years Year One: Vaccinate 2-4 year olds Year Two: Vaccinate 6-9 year olds + 2 yo Year Three: Vaccinate year olds + 2 yo Then vaccinate only 2-year-olds.

43 Vaccination Roll-out Up to age 44 Vaccinate 70% of 2-44 year olds over 9 years Year One: Vaccinate 2-4 year olds + 2 yr olds Year Two: Vaccinate 6-9 year olds + 2 yr olds.... Year Nine: Vaccinate year olds + 2 yr olds Then vaccinate only 2-year-olds.

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46 Overall Impact of Vaccination in per 100,000 People at Risk, SE Asia

47 Conclusions So Far At first, limited quantities of vaccine should be concentrated in children A cascading introduction of vaccine as it becomes available, reaching 70% of each target age cohort, should be effective for control Routine vaccination of 2 year-olds Rapid catch-up in older age groups Adult vaccination may be necessary to achieve control goals

48 Conclusions So Far A vaccine that protects against only three serotypes could still be effective Such a vaccine is from 10 35% less effective than a vaccine that protects against all four serotypes Depends on relative transmission frequencies of the four serotypes in a region More study is being carried out, including a multicenter phase III vaccine trial

49 Funding NIH NIAID (R01-AI039129, R37-AI32042, R01-AI097405) NIGMS (U01-GM070749, R25- GM089694) Gates Dengue, TB, Cholera Private Dengue, Influenza, etc.

50 Thank you

51 Vaccination Roll-out: Up to age 14

52 Vaccination Roll-out Up to age 44

53 Rough Dengue Dynamics Generation Interval infected person infected mosquito exposed person latent + ½ infect + bite + extr. inc. 20 days Serial interval: empirical evidence