Sero-epidemiology of dengue viruses: The influence of preexisting immunity on disease severity and implications for vaccine development Public

Abstract

Dengue fever (DF) and dengue hemorrhagic fever (DHF) are important causes of morbidity and mortality globally. The four dengue virus serotypes (DENV-1 - DENV-4) co-circulate and cause annual epidemics in endemic regions such as Southeast Asia. Cross-reactive DENV antibodies have been linked to DHF in multiple epidemiological and immunological studies. However, cross-reactive antibodies have also been associated with protection from illness. The complex factors involved in whether a non-primary infection with DENV will be subclinical, DF, or develop into DHF are poorly understood. This remains a central issue in DENV immunology, and one that looms large as DENV vaccines approach licensure and implementation. These studies sought to address important knowledge gaps regarding DENV immunity in three complementary ways. The first study assessed how immunity to Japanese encephalitis virus (JEV), a related flavivirus, may influence the clinical severity of DENV infections, using data from a prospective, school-based cohort for asymptomatic and symptomatic DENV infections in Thailand that was conducted from 1998-2002. The study found a positive association between preexisting JEV antibodies and symptomatic (versus asymptomatic) DENV infection. The second study considered whether time between DENV infections was a significant predictor of DENV severity, using time as a proxy for the decay of cross-reactive antibodies. The same prospective cohort data were used as in study one, in addition to a second phase conducted from 2004-2007. There was evidence of a temporal trend in disease risk with time between first and second infections, with asymptomatic infections occurring at shorter intervals and DHF at longer intervals. The final study evaluated the nature of serotype interactions in multivalent DENV vaccines, using data from a factorial design clinical trial that evaluated all combinations of high and low dose serotype strains in tetravalent formulations. Analyses considered how adjustments in the dose of a serotype affected seroconversion to that and other serotypes. Both immunological interference and facilitation were observed to occur between DENV serotypes with respect to seroconversion as well as the occurrence of adverse events. Together, these three studies provide novel insights into the complex nature of DENV immunity in the setting of multiple serotype exposures.

Table of Contents

I. INTRODUCTION .......................................................................................................1

II. BACKGROUND

A. The Virus............................................................................................................ 8

B. Transmission

(i) The Vectors........................................................................................... 10

(ii) Transmission Cycles............................................................................. 13

C. Epidemiology

(i) History................................................................................................... 16

(ii) Present Distribution and Burden of Disease........................................ 18

(iii) Epidemic Characteristics..................................................................... 19

(iv) Prevention and Control....................................................................... 20

D. Clinical Aspects of DENV Infection............................................................... 21

E. Mechanisms of DHF

(i) DHF and Secondary Infection.............................................................. 23

(ii) Antibody-Dependent Enhancement.................................................... 24

(iii) Original Antigenic Sin......................................................................... 26

(iv) Viral Factors........................................................................................ 26

(v) Host Factors......................................................................................... 27

F. The Antibody Response to Infection................................................................ 27

(i) Dose-dependence of Cross-protection and Enhancement.................... 29

(ii) Temporal Shifts in Cross-protection and Risk of Enhancement.......... 30

(iii) Proposed Model of Trends in the Risk of Illness with

Secondary DENV Infection............................................................... 31

G. DENV Serological Assays - Methods, Capabilities, and Limitations............. 33

(i) Plaque Reduction Neutralization Titers (PRNTs)................................. 34

(ii) Hemagglutination Inhibition (HI)........................................................ 36

(iii) Enzyme-linked Immunosorbent Assays (ELISAs)............................. 36

H. The Future - Dengue vaccines.......................................................................... 36

I. References.......................................................................................................... 38

III. STUDY ONE: Preexisting immunity to Japanese encephalitis virus and the increased occurrence of symptomatic dengue infection

A. Abstract ........................................................................................................... 47

B. Introduction...................................................................................................... 48

C. Methods

(i) Study Population................................................................................... 50

(ii) Study Methods..................................................................................... 50

(iii) Characterization of Symptomatic Illness............................................ 50

(iv) Characterization of Asymptomatic Infections.................................... 51

(v) Characterization of DENV and JEV Antibody Status........................ 52

(vi) Inferring the Infecting Serotype......................................................... 53

(vii) Statistical Analyses............................................................................ 53

(viii) Human Subjects Research Approval................................................. 54

D. Results

(i) Descriptive Statistics............................................................................. 55

(ii) Factors Associated with Symptomatic Illness..................................... 55

(iii) Factors Associated with JEV Positivity.............................................. 56

(iv) Associations of JEV NAb Positivity with DENV Illness................... 56

(v) Duration of Illness................................................................................ 58

(vi) Titer of JEV NAbs.............................................................................. 58

(vii) Role of Infecting DENV Serotype.................................................... 58

(viii) Multivariate Model of JEV NAb Positivity and Symptomatic

DENV Infection............................................................................... 59

(viii) Serological Cross-reactivity Between JEV and DENV.................... 59

(ix) Relative Risk of Symptomatic Infection with JEV Antibodies.......... 59

E. Discussion......................................................................................................... 61

F. Acknowledgements........................................................................................... 66

G. References........................................................................................................ 67

H. Tables................................................................................................................ 71

I. Figures................................................................................................................ 77

J. Supplemental Tables........................................................................................... 81

IV. STUDY TWO : A shorter time interval between first and second dengue infections is associated with protection from clinical illness in a prospective school-based cohort in Thailand

A. Abstract ........................................................................................................... 85

B. Introduction...................................................................................................... 87

C. Methods

(i) Study Population................................................................................... 91

(ii) Acute Illness Specimens and Active Fever Surveillance..................... 91

(iii) Routine Blood Specimens and Detection of Seroconversions............ 92

(iv) Characterization of First-Detected and Second-Detected

Infections............................................................................................ 93

(v) Defining Baseline DENV Immunity and Other Immunological

Parameters............................................................................................. 94

(vi) Immunological Parameters.................................................................. 95

(vii) Inferring the Infecting Serotype........................................................ 95

(viii) Statistical Analyses........................................................................... 96

(ix) Human Subjects Research Approval................................................... 97

D. Results.............................................................................................................. 98

(i) Time from First to Second-Detected Infection and Clinical

Severity................................................................................................. 98

(ii) Predictors of the Time to Infection and the Severity of the Second- Detected Infection 99

(iii) Immunological Correlates of Infection Severity............................... 100

(iv) Modeling the Probability of Asymptomatic Infection over Time..... 100

E. Discussion....................................................................................................... 102

G. References...................................................................................................... 107

H. Tables.............................................................................................................. 110

I. Figures.............................................................................................................. 113

J. Appendices....................................................................................................... 120

V. STUDY THREE : Immunological interference and facilitation between dengue serotypes in tetravalent formulations

A. Abstract ......................................................................................................... 130

B. Introduction.................................................................................................... 132

C. Methods

(i) Data Sources: Monovalent and Tetravalent Clinical Trials................. 135

(ii) Quantification of Immunogenicity - Serological Methods................ 136

(iii) Quantification of Reactogenicity...................................................... 136

(iv) Statistical Analyses........................................................................... 137

(v) Human Subjects Clearance................................................................. 138

D. Results

(i) Descriptive Results.............................................................................. 139

(ii) Comparison of Monovalent and Tetravalent Formulations................ 139

(iii) Bivariate Analysis: Effects of Dose on Homologous and

Heterologous Serotypes in Tetravalent Formulations....................... 140

(iv) Multivariate Analysis: Effects of Dose on Homologous and Heterologous Serotypes in Tetravalent Formulations................................................................... 141

(v) Effects of Dose on Multitypic Immunogenicity................................ 141

(vi) Effects of Dose on Vaccine Reactogenicity..................................... 141

E. Discussion....................................................................................................... 143

F. Acknowledgements......................................................................................... 147

G. References...................................................................................................... 148

H. Tables.............................................................................................................. 151

I. Figures.............................................................................................................. 155

VI. CONCLUSIONS ..................................................................................................... 163

A. Dissertation Studies

a. Study One.......................................................................................... 165

b. Study Two......................................................................................... 167

c. Study Three....................................................................................... 170

B. Limitations..................................................................................................... 172

C. Strengths........................................................................................................ 175

D. Public Health Contributions

a. Interactions between Heterologous Flaviviruses............................... 177

b. Evidence of Cross-Protection and a Temporal Aspect to

Disease Risk....................................................................................... 180

c. Identifying Interactions in Multivalent Vaccines.............................. 183

E. References..................................................................................................... 186

VII. REFERENCES..................................................................................................... 190

About this Dissertation

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School	Laney Graduate School
Department	Epidemiology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology Biology, Virology Health Sciences, Epidemiology
Mot-clé	Kamphaeng Phet Clinical severity Thailand Japanese encephalitis virus DHF Epidemiology Antibodies Dengue virus
Committee Chair / Thesis Advisor	Berkelman, Ruth L, Emory University
Committee Members	Cummings, Derek, Johns Hopkins University Rothman, Alan, University of Rhode Island Endy, Timothy, SUNY Upstate Medical University Flanders, W Dana, Emory University McGowan Jr., John E, Emory University

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