Modeling the Effects of Vaccination on Dengue Pathogenesis Evolution Restricted; Files Only

Abstract

Theory on evolution of viral replication posits that parasites face trade-offs between transmission and the duration of infection, as both cannot simultaneously be optimized. A higher transmission rate requires higher parasite replication, whereas longer durations of infection (e.g., via a lower clearance rate) requires lower parasite production. Under some circumstances, this trade-off can lead to the evolution of an intermediate level of parasite production, which maximizes the parasite’s reproduction rate. Such fitness trade-offs have been empirically demonstrated in dengue. Further, a quantitative analysis of these trade-offs indicate that viral transmission potential depends on dengue’s epidemiological context. Specifically, in the case of dengue, peak viral load is highly associated with the manifestation of dengue hemorrhagic fever or dengue shock syndrom (DHF/DSS). Here, we examine how a licensed dengue vaccine (Dengvaxia) may impact the evolution of dengue strains that cause DHF/DSS. Dengvaxia is a recombinant live-attenuated, imperfect vaccine that is thought to act like a silent infection. As such, vaccination with Dengvaxia would alter the epidemiological context in which dengue transmits, which in turn should impact virulence-associated selection pressures on the virus. To examine the potential effect of Dengvaxia vaccination on dengue evolution, we develop a nested, multi-scale model of viral replication and transmission. The model includes deterministic within-host dynamics, which differ by host infection status and the replication phenotype of a viral strain. The model also includes epidemiological dynamics simulated through an individual-based model in a dengue-endemic context. By introducing vaccination into the population, we examine whether Dengvaxia would select for strains that cause more or less DHF/DSS cases. We place our findings in the context of the imperfect vaccine-driven virulence evolution literature.

Table of Contents

Abstract iii

Acknowledgements v

1 Introduction 1

1.1 DengueBackground ................................. 1

1.2 OverviewofCurrentDengueVaccines ...................... 3

1.2.1 Sanofi-Pasteurvaccine(Dengvaxia) .................... 3

1.2.2 Otherdenguevaccinecandidates ..................... 4

1.3 Disease Severity Evolution and Potential Vaccine Effects . . 5

2 Methods 7

2.1 Within-HostModel.................................. 7

2.2 EpidemiologicalModel............................. 9

2.3 Interface Between Epidemiological Model and Within-Host Dynamics . . . . 11

2.4 ParameterValuesandInitialConditions.... 12

3 Results  15

4 Discussion  25

About this Master's Thesis

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Population Biology, Ecology & Evolution
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Epidemiology Biology, Ecology
Keyword	vaccination pathogenesis dengue evolution
Committee Chair / Thesis Advisor	Katia Koelle, Emory University
Committee Members	Ben Lopman, Emory University Jacobus de Roode, Emory University Gonzalo Vazquez-Prokopec, Emory University

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