Humoral Responses to SARS-CoV-2 Infection and mRNA Vaccination 公开

Abstract

First detected in 2019, SARS-CoV-2 remains a global pandemic with over 430 million individuals infected to date. Significant homology between SARS-CoV-2 and -1 allowed the rapid identification of the spike (S) protein, specifically the receptor binding domain (RBD), as a critical target for neutralizing antibodies. Given the rapid spread of the virus, characterizing potentially protective aspects of the immune response to infection was urgent. In a cohort of individuals hospitalized with severe COVID-19, we observed robust B cell responses, detecting expanded plasmablasts, activated RBD-specific memory B cells, and elevated titers of RBD- and S-specific antibodies. Depletion of RBD-specific antibodies from serum significantly reduced neutralizing activity in the majority of individuals. However, some donors retained significant residual neutralization activity, suggesting a potentially protective antibody subset targeting non-RBD epitopes. This study demonstrated that SARS-CoV-2 infection induces a robust humoral response and that RBD-specific antibodies are critical for circulating viral neutralization in infected individuals.

Soon after the emergence of SARS-CoV-2, hundreds of vaccines went into pre-clinical and clinical testing in an effort to combat the growing global pandemic. By the end of 2020, the U.S. had approved two mRNA-based vaccines from Moderna and Pfizer. While initial reports of efficacy were high for both vaccines, the emergence of several SARS-CoV-2 variants raised questions about the breadth and durability of the vaccine-induced humoral response. To this end, we analyzed the humoral response to either Moderna or Pfizer mRNA vaccination in a longitudinal cohort of naïve and recovered individuals. We found that, while vaccination induced SARS-CoV-2 specific humoral immunity in both groups, the antibody response was both more robust and durable in recovered individuals than naïve individuals and that vaccine responses positively correlated with initial responses to infection in recovered individuals. Despite the similarity of the mRNA vaccines, Moderna-vaccinated naïve individuals demonstrated a less reliance on RBD-specific antibodies for neutralization than Pfizer vaccinees. Taken together, these studies illustrate that both infection and vaccination against SARS-CoV-2 can elicit potent and protective humoral responses.

Table of Contents

CHAPTER 1: INTRODUCTION................................................................................................ 1

B CELLS IN VIRAL INFECTIONS........................................................................................... 2

B Cell Activation..................................................................................................................... 2

Extrafollicular Responses........................................................................................................ 3

Germinal Center Responses.................................................................................................... 5

Antibody Effector Functions................................................................................................... 7

SARS-CoV-2.............................................................................................................................. 9

SARS-CoV-2: Relationship to other human b-coronaviruses................................................ 9

Viral Structure and Replication............................................................................................. 11

Disease Pathology................................................................................................................. 14

HUMORAL RESPONSES TO SARS-CoV-2.......................................................................... 17

Lessons from Human Coronaviruses.................................................................................... 17

Antibody Responses to SARS-CoV-2 Infection................................................................... 20

B Cell Responses to SARS-CoV-2 Infection........................................................................ 25

COVID-19: TREATMENT AND PREVENTION................................................................... 29

Current SARS-CoV-2 Treatments........................................................................................ 29

SARS-CoV-2 Vaccination Strategies.................................................................................... 30

The Success of SARS-CoV-2 mRNA vaccines.................................................................... 32

THE EVOLUTION OF SARS-CoV-2...................................................................................... 35

Endemic Coronavirus Evolution: Evidence & Mechanisms................................................. 35

SARS-CoV-2: The Emergence of Viral Variants................................................................. 36

SUMMARY.............................................................................................................................. 38

CHAPTER 2: EVALUATION OF CELLULAR AND SEROLOGICAL RESPONSES TO ACUTE SARS-COV-2 INFECTION DEMONSTRATE THE FUNCTIONAL IMPORTANCE OF THE RECEPTOR BINDING DOMAIN      41

Abstract.................................................................................................................................. 42

Introduction........................................................................................................................... 43

Methods................................................................................................................................... 46

Results..................................................................................................................................... 52

Discussion................................................................................................................................ 59

Acknowledgements & Funding Information.................................................................... 64

Author Contributions.......................................................................................................... 64

Declaration of Interests..................................................................................................... 65

Figure 1. Acute COVID-19 patients exhibit loss of circulating memory B cells and expansion of plasmablasts. 66

Figure 2. RBD-specific memory B cells expand rapidly and exhibit high levels of activation in COVID-19 patients.       68

Figure 3. RBD-binding fraction of patient serum antibody strongly correlates with neutralization capacity  69

Figure 4. SARS-CoV-2 viral neutralization activity is mediated by RBD specific antibody in a majority of COVID-19 patients.................................................................................................................................................... 70

Supplemental Figure 1. CD4+ and CD8+ T cells decreased in COVID-19 patients..... 71

Supplemental Figure 2. RBD-specific MBCs are found in both the CD27+ and CD27- subsets 72

Supplemental Figure 3. RBD-specific IgG titers correlate with time from infection 73

Supplementary Table 1. Clinical & Serological Data Summary................................. 74

CHAPTER 3: PRE-EXISTING SARS-COV-2 IMMUNITY INFLUENCES POTENCY, BREADTH, AND DURABILITY OF THE HUMORAL RESPONSE TO SARS-COV-2 VACCINATION.............................................. 75

Summary.................................................................................................................................. 76

Introduction........................................................................................................................... 77

Methods................................................................................................................................... 79

Results..................................................................................................................................... 85

Discussion................................................................................................................................ 98

Acknowledgements............................................................................................................. 105

Author Contributions........................................................................................................ 106

Declaration of Interests................................................................................................... 106

Figure 1. RBD-specific memory B cells expand in naïve and recovered subjects following mRNA vaccination.   108

Figure 2. RBD-specific memory B cells upregulate CD71 following infection and vaccination.      109

Figure 3. Plasmablast responses in naïve and recovered individuals post SARS-CoV-2 mRNA vaccination.         111

Figure 4. Recovered individuals generate faster and more robust antibody responses to mRNA vaccination against SARS-CoV-2 than naïve individuals........................................................................................................ 113

Figure 5. Antigen-specific MBC and serological responses to SARS-CoV-2 infection correlate with responses to mRNA vaccination........................................................................................................................... 115

Figure 6. Naïve Moderna-vaccinated individuals retain greater neutralizing capacity after depletion of RBD-specific fraction of plasma............................................................................................................................... 117

Figure 7. Naïve vaccinees exhibit a faster decline in Spike, RBD, and NTD-specific IgG six months after vaccination than previously SARS-CoV-2 infected vaccinees................................................................... 118

Supplemental Table 1. Demographic information for Emory University SARS-CoV-2 immune surveillance and vaccination studies.................................................................................................................................... 119

Supplemental Figure 2. MSD-ELICA binding titers for SARS-CoV-2 isotypes and related antigens.           120

Supplemental Figure 3. MSD-ELICA titers to variant RBD and neutralization by vaccine brand  121

Supplemental Figure 4. RBD-specific antibody depletion by isotype and correlation of anti-Spike titers to RBD-specific neutralization..................................................................................................................... 122

Supplemental Table 1. Demographic information for Emory University SARS-CoV-2 immune surveillance and vaccination studies.................................................................................................................................... 123

Supplemental Table 2: Statistics for RBD-specific MBC. Median, mean, standard deviation, and n are listed for data reported in Figure 1.................................................................................................................................. 124

Supplemental Table 3. Statistics for total and RBD-specific plasmablasts. Median, mean, standard deviation, and n are listed for data reported in Figure 3............................................................................................ 125

Supplemental Table 4. Statistics for anti-spike antibody across seven timepoints in cohort 126

Supplemental Table 5. Statistics for anti-RBD antibody across seven timepoints in cohort 127

Supplemental Table 6. Statistics for anti-NTD antibody across seven timepoints in cohort 128

Supplemental Table 7. Statistics for anti-spike, -RBD, and -NTD antibody across seven timepoints in cohort grouped by past infection status.................................................................................................................... 129

CHAPTER 4.............................................................................................................................. 130

DISCUSSION............................................................................................................................. 130

CONCLUSION....................................................................................................................... 131

FUTURE CONSIDERATIONS.............................................................................................. 133

Autoimmunity and COVID-19............................................................................................ 133

Influences on B Cell Repertoire.......................................................................................... 135

OUR PANDEMIC FUTURE................................................................................................... 139

Emergence & Escape of Omicron....................................................................................... 139

“Future Vaccines” : Combatting Variants Before They Arise............................................ 141

SUMMARY............................................................................................................................ 144

Figure 1. Majority of plasmablasts induced in severe COVID-19 are of unknown antigen-specificity.       146

Figure 2. Antibody repertoires between recovered and vaccinated individuals are similar and share several public antibody clones..................................................................................................................................... 148

REFERENCES.......................................................................................................................... 149

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Immunology and Molecular Pathogenesis
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology
关键词	SARS-CoV-2 antibody B cell
Committee Chair / Thesis Advisor	Jens Wrammert, Emory University
Committee Members	Anice Lowen, Emory University Steven Bosinger, Emory University Mehul Suthar, Emory University Frances Eun-Hyung Lee, Emory University

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