Viral Evolution During Monoclonal Antibody Treatment of SARS-CoV-2 Patients Restricted; Files Only

Abstract

SARS-CoV-2 mutations conferring immune escape can arise during prolonged infections of immunocompromised patients. Without an effective endogenous immune response, pressures such as monoclonal antibody treatment may select for such mutations, some of which could serve as a key element in the emergence of new variants of concern. To explore the role of monoclonal antibody treatment in the emergence of immune escape mutations during prolonged immunocompromised patient infections, we combined two longitudinal case studies with an extensive literature review. Our case studies utilized viral genomic sequencing of longitudinal nasopharyngeal samples to analyze intra-host viral evolution of patients treated with either single-agent or combination monoclonal antibodies. We observed the emergence of multiple immunologically important mutations, emphasizing the importance of closely monitoring viral evolution at the individual level. Additionally, the literature review identified 77 immunocompromised patients with immune escape mutation emergence during monoclonal antibody treatment. Interestingly, mutations associated with neutralization evasion and those found in variants of concern were frequently observed among the literature and primary data. Therefore, this study underscores the importance of closely monitoring SARS-CoV-2 intra-host evolution and understanding the implications of antibody treatment in immunocompromised patients.

Table of Contents

Acknowledgements..........................................................i

Contents....................................................................ii-iii

List of Figures................................................................iv

List of Tables...................................................................v

Chapter 1 Introduction....................................................2

1.1 SARS-CoV-2 in Immunocompromised Patients............3

1.2 Monoclonal Antibody Treatment................................4

1.3 Study Rationale.........................................................5

Chapter 2 Literature Review.............................................6

2.1 Introduction..............................................................4

2.2 Methods....................................................................4

2.2.1 Building a Comprehensive Literature Search.............4

2.2.2 Analyzing Immune Escape Probability......................6

2.3 Results......................................................................6

2.3.1 Literature Search Findings.......................................6

2.3.2 Clinical Characteristics..........................................10

2.3.3 Viral Evolution......................................................10

2.3.4 Monoclonal Antibody Authorization

   and VOC Prevalence....................................................16

2.4 Discussion...............................................................19

Chapter 3 SARS-CoV-2 Evolution and Immune Escape in

   ImmunocompromisedPatients Treated with

   Bamlanivimab.............................................................21

3.1 Introduction.............................................................21

3.2 Methods...................................................................22

3.2.1 Sample Collection..................................................22

3.2.2 Genomic Sequencing and Analysis of

   SARS-CoV-2…………………………….…………………....…..23

3.2.3. Pseudovirus Neutralization Assay...........................24

3.3

Results..........................................................................24

3.3.1 Clinical Courses Overview of P2 and P3...................26

3.3.2 Immune Responses................................................28

3.3.3 Intra-Host Viral Evolution......................................29

3.3.4 Neutralization Assay..............................................31

3.4 Discussion...............................................................32

Chapter 4 PWH with SARS-CoV-2 Infection Treated with

   Monoclonal Antibody Cocktail.....................................34

4.1 Introduction............................................................34

4.2 Methods..................................................................35

4.2.1 Sample Collection.................................................35

4.2.2 SARS-CoV-2 Library Assembly...............................35

4.2.3 iSNV Analysis.......................................................36

4.3 Results....................................................................36

4.3.1 Clinical Synopsis...................................................36

4.3.2 Consensus Mutations and iSNVs.............................37

4.3.3 Deep Mutational Scanning Analysis........................40

4.4 Discussion...............................................................42

Chapter 5 Conclusions...................................................43

Bibliography.................................................................45

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Genetics Biology, Virology Biology, Evolution and Development
Keyword	Evolution Therapeutic Antibodies Resistance COVID-19 Mutation Immune Escape Monoclonal Antibodies SARS-CoV-2 Variant of Concern
Committee Chair / Thesis Advisor	Anne Piantadosi, Emory University
Committee Members	Michal Arbilly, Emory University Nicole Gerardo, Emory University Stephanie Pouch, Emory University

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