Characterization of Human T Cell Responses to 2010-2011 InfluenzaVaccines 公开

Abstract

The goal of influenza-specific T cell research is to develop effective methodologies for exploiting T cell immunity in influenza vaccination. Theoretically, this may be achieved by boosting CD4 T cell populations that provide help for influenza-specific CD8 T cells and B cells or by directly inducing the expansion of CD8 T cells specific for highly conserved influenza epitopes. Interest in this area has been fueled by studies that demonstrate pre-existing T cell immunity against both seasonal and antigenically variant influenza strains in the general population, raising the question of whether it is possible to enhance influenza vaccine efficacy by targeting these populations. The suitability of this approach is difficult to assess, because human T cell responses to influenza vaccination are poorly understood. To address this issue, we performed an investigation to characterize human T cell responses to 2010-2011 seasonal influenza vaccines. We first developed a recombinant vesicular stomatitis virus (rVSV)-based quantitative T cell assay that was optimized for use in human influenza-specific T cell studies. Using this system, we measured vaccine-induced CD4 and CD8 T cell responses in adult donors following the administration of trivalent inactivated influenza vaccine (TIV) or live, attenuated influenza vaccine (LAIV). We investigated responses against various external and internal proteins across multiple influenza A strains. Pre-existing T cell populations specific for external and internal influenza proteins were observed in most donors. Although we noted modest vaccine-associated CD4 T cell responses specific for external proteins in specific donors, trial members as a group did not demonstrate significant boosting of baseline influenza external protein-specific CD4 T cell responses. LAIV was more effective than TIV in generating CD4 T cell responses specific for internal proteins while both vaccines were ineffective in boosting external or internal protein-specific CD8 T cell responses. Overall, we conclude that current seasonal influenza vaccine formulations are poor inducers of T cell responses and propose that new technologies specifically engineered to target T cells will likely be warranted in order to establish effective and long-lived influenza-specific T cell immunity.

Table of Contents

Chapter 1: Introduction 1

1.1 Background and classification 1

1.2 Transmission and pathology of influenza viruses 2

1.3 Influenza pathogenesis 3

1.4 Influenza virus morphology and genome structure 4

1.5 Life cycle of influenza viruses 6

1.6 Antigenic variation and pandemic influenza 7

1.7 History of influenza vaccines 10

1.8 Influenza vaccine composition 11

1.9 Humoral immunity to influenza 12

1.10 Murine T cell responses to influenza 14

1.11 Human T cell responses to influenza 18

Chapter 2: Use of Replication Restricted Recombinant Vesicular Stomatitis Virus Vectors for Detection of Antigen-Specific T Cells 24

Abstract 26

Introduction 27

Materials and Methods 31

Results 36

Discussion 44

Figure Legends 48

Figures 51

Chapter 3: Characterization of human T cell responses to 2010-2011 seasonal influenza vaccines 63

Abstract 64

Introduction 66

Materials and Methods 70

Results 74

Discussion 84

Figure Legends 90

Figures 93

Tables 107

Supplementary Figures 112

Chapter 4: Discussion 113

References 123

List of Figures

(listed in order of appearance within each chapter)

Chapter 2

2.1 VSV is monocyte tropic 51

2.2 Optimization of assay parameters for flow cytometric detection of T cell responses by VSV-ΔG antigen delivery 55

2.3 Effects of carryover antigen 57

2.4 Optimization of MOI 58

2.5 Evaluation of T cell responses to a range of antigens encoded by VSV-ΔG vectors 60

2.6 VSV-ΔG vectors drive the proliferation of antigen-specific T cells in vitro 61

Chapter 3

3.1 Visualization of influenza-specific T cells using rVSV vectors 93

3.2 CD4 T cell responses to external influenza proteins 95

3.3 Vaccine-induced CD4 T cell responses specific for external influenza proteins are cross-reactive 98

3.4 Comparison of post-vaccination IgG-secreting ASC levels and CD4 T cell responses to external influenza proteins at day 7 100

3.5 CD4 T cell responses to internal influenza proteins 101

3.6 CD8 T cell responses to internal influenza proteins 104

S3-1 Sequence alignments of M1 from A/PR/08/34, A/AA/06/60, and A/Cal/04/09 112

List of Tables (listed in order of appearance within each chapter)

Chapter 3

Table 1 Demographic information for influenza vaccine trial participants 107

Table 2 Influenza proteins included in the our study of human T cell responses to 2010-2011 seasonal influenza vaccines 108

Table 3 Analysis of human vaccine-associated CD4 T cell responses to external influenza proteins via mixed linear model 109

Table 4 Analysis of human vaccine-associated CD4 T cell responses to internal influenza proteins via mixed linear model 110

Table 5 Analysis of human vaccine-associated CD8 T cell responses to internal influenza proteins via mixed linear model 111

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology Biology, Virology
关键词	T cell Influenza Human
Committee Chair / Thesis Advisor	Altman, John D, Emory University
Committee Members	Speck, Sam, Emory University Jacob, Joshy, Emory University Steinhauer, David, Emory University

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