Characterization of Human T Cell Responses to 2010-2011 Influenza Vaccines Open Access

Moseley II, Nelson (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/rb68xc666?locale=en
Published

Abstract



Characterization of Human T Cell Responses to 2010-
2011 Seasonal Influenza Vaccines


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

Table of Contents

Page

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

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