Evaluating the promise of a transmissible vaccine. Scott L. Nuismer

Transcription

1 Evaluating the promise of a transmissible vaccine Scott L. Nuismer

2 Effective vaccines exist for 24 infectious diseases of humans

3 Vaccines have had amazing successes Eradicated smallpox Driven polio to the brink of extinction Localized elimination of measles, mumps, and rubella Variola (Smallpox) Despite these successes challenges remain

4 Immunizing a large enough fraction of the population ρ = 1 1 R 0 Influenza SARS Smallpox

5 Immunizing rapidly enough Influenza SARS Smallpox

6 What if we could develop a vaccine that transmits? Vaccine Transmission Influenza Vaccine Transmission Influenza

7 We already have In principle, any live vaccine can transmit Unintentional transmissible vaccines Mumps Oral Polio Vaccine Rubella Chickenpox Rotavirus Influenza Vaccine transmission engineered for wildlife Myxoma in rabbits Ebola in fruit bats (under development) Hantavirus in deer mice (under development)

8 Two paths to a transmissible vaccine Attenuation Recombination Pathogen genome Pathogen genome Vector genome Vaccine genome Vaccine genome Examples Oral Polio Vaccine (OPV) Examples Myxoma virus in rabbits Ebola in fruit bats Hantavirus in deer mice

9 The current state of affairs Transmissible vaccines have been created accidentally Transmissible vaccines are being developed for wildlife applications Remarkably, we don t even know how well they might work! Our goal is to quantify benefits and risks using mathematical models

10 Three questions 1. Could vaccine transmission facilitate disease eradication? 2. Could vaccine transmission speed vaccination? 3. What are the consequences/challenges of vaccine evolution?

11 A general modeling framework General model structure Key assumptions Susceptible hosts (S) Pathogen infected hosts (W) Vaccine infected hosts (V) Resistant hosts (R) Single well-mixed population Perfect vaccine Perfect cross-immunity Direct vaccination: σ Vaccine transmission: Pathogen transmission: Vaccine recovery : β V β W δ V Pathogen recovery: δ W

12 Focus on weakly transmissible vaccines Vaccines with R 0 < 1 Require continuous direct vaccination On average, each infection produces less than one additional infection Weak transmission guarantees vaccine dies off W/O continued direct vaccination

13 Probability of reversion Focus on weakly transmissible vaccines Weak transmission minimizes evolution (Antia et al. 2003) Vaccine R 0 Weak transmission reduces opportunities for vaccine evolution

14 Q1: Can vaccine transmission facilitate pathogen eradication? U.S. CDC Hantavirus Vaccine Transmission

15 Modeling eradication of an endemic disease Susceptible hosts (S) Pathogen infected hosts (W) Vaccine infected hosts (V) Resistant hosts (R) ds dt = b 1 σ β VSV β W SW ds (1 σ)b σb dv dt = bσ + β VSV δ V V dv δ W W δ V V dw dt = β WSW δ W W (d + v)w dr dt = δ VV + δ W W dr β W SW β V SV

16 How much do we need to vaccinate to eradicate disease? Traditional vaccine Transmissible vaccine σ crit = 1 1 R 0,W σ crit = 1 R 0,V R 0,W 1 1 R 0,W Hantavirus Are there benefits of vaccine transmission even when eradication fails?

17 How much is disease incidence reduced? f Incidence = σr 0,V R 0,W (R 0,V R 0,W )(1 R 0,W (1 σ)) Hantavirus

18 Q2: Can vaccine transmission prevent an epidemic? 2009 Influenza Deaths: 284, Ebola Deaths: 11,310 Vaccine Transmission 2003 SARS Deaths: 774

19 Modeling the rate of epidemic spread Susceptible hosts (S) δ W W Pathogen infected hosts (W) Vaccine infected hosts (V) Resistant hosts (R) σ δ V V ds dt = σs β VSV β W SW dv dt = σs + β VSV δ V V dw dt = β WSW δ W W dr dt = δ VV + δ W W β W SW β V SV

20 Scenario 1: Anticipatory vaccination September 30, Dallas Texas First case of Ebola in North America March 25, 2014 Ebola outbreak begins in West Africa

21 Scenario 1: Anticipatory vaccination 1 τ R R 0,w σ γ v + γ v σ 0,v R 0,w R 0,w 1 Log (γ v σ R 0,w 1+ γ v σ Ebola Vaccine transmission provides substantial advantages

22 Scenario 2: Reactionary vaccination Can vaccine transmission reduce the size of an epidemic once it has begun? Vaccine Transmission

23 Scenario 2: Reactionary vaccination Vaccine transmission offers the greatest advantages when an epidemic is (just) anticipated

24 Q3: What are the consequences and challenges of vaccine evolution? Attenuated vaccine Recombinant vector vaccine Pathogen genome Pathogen genome Vector genome Vaccine genome Vaccine genome Evolution Evolution??

25 Evolution in attenuated vaccines Vaccine derived polio outbreaks (since 2000) OPV attenuated by only 2-3 genetic changes In areas with low immunization rates, long chains of transmission can occur (vaccine R 0 > 1) Creates opportunities for reversion to wild type virulence and transmission Obvious negative consequences at the individual level

26 Modeling evolution in attenuate vaccines Vaccine infected hosts (V) Pathogen infected hosts (W) ds dt = b 1 σ β VSV β W SW ds dv dt = bσ + β VSV δ V V dv rv Evolution (r) dw dt = β WSW δ W W d + v W + rv dr dt = δ VV + δ W W dr

27 Evolution in attenuated vaccines Reversion weakens, but does not eliminate, benefits of vaccine transmission

28 Modeling evolution in recombinant vector vaccines Pathogen infected hosts (W) Vaccine infected hosts (V) Evolution Vector infected hosts (C) Andrew Basinski Recovery Recovery Recovery Evolution suppressed if: Resistance Pathogen Vaccine Resistance Pathogen Vector Vaccine Resistance Vector Vaccine σ > c 1 1 R 0,vec

29 Evolution in recombinant vector vaccines R 0,w = 2.0 R 0,w = 3.0 (e.g., Ebola) (e.g., SARS) Direct vaccination more efficient Direct vaccination more efficient The more costly the insert, the greater the rate of direct vaccination required to suppress evolution

30 Evolutionary consequences Attenuated vaccine Consequence: Reversion to high virulence Recombinant vector vaccine Consequence: Reversion to vector backbone Challenge: Reducing individual level risk Challenge: Overcoming competition Solutions: Engineering evolution proof attenuation? Solutions: Engineering evolution proof insertion? Swamping

31 Conclusions Weakly transmissible vaccines can be very effective Wide variety of applications The challenges/risks are primarily evolutionary

32 Acknowledgements Chris Remien Jim Bull Ryan May Andrew Basinski Rustom Antia Tanner Varrelman