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Design and Evaluation of Single-Dose Polyanhydride Nanovaccines Against Bacterial Respiratory Pathogens Danielle Ann Wagner Iowa State University

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Design and Evaluation of Single-Dose Polyanhydride Nanovaccines Against Bacterial Respiratory Pathogens Danielle Ann Wagner Iowa State University Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2019 Design and evaluation of single-dose polyanhydride nanovaccines against bacterial respiratory pathogens Danielle Ann Wagner Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Allergy and Immunology Commons, Immunology and Infectious Disease Commons, and the Medical Immunology Commons Recommended Citation Wagner, Danielle Ann, "Design and evaluation of single-dose polyanhydride nanovaccines against bacterial respiratory pathogens" (2019). Graduate Theses and Dissertations. 17116. https://lib.dr.iastate.edu/etd/17116 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Design and evaluation of single-dose polyanhydride nanovaccines against bacterial respiratory pathogens by Danielle Ann Wagner A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Immunobiology Program of Study Committee: Michael Wannemuehler, Co-major Professor Balaji Narasimhan, Co-major Professor Bryan Bellaire Marian Kohut Randy Sacco The student author, whose presentation of the scholarship herein was approved by the program of study committee, is solely responsible for the content of this dissertation. The Graduate College will ensure this dissertation is globally accessible and will not permit alterations after a degree is conferred. Iowa State University Ames, Iowa 2019 Copyright © Danielle Wagner, 2019. All rights reserved. ii DEDICATION I dedicate this dissertation to my mother, Denise. For instilling in me a love of science and the determination to chase my dreams. iii TABLE OF CONTENTS Page LIST OF FIGURES ............................................................................................................ v LIST OF TABLES ............................................................................................................ vii ACKNOWLEDGMENTS ............................................................................................... viii ABSTRACT ....................................................................................................................... ix CHAPTER 1. LITERATURE REVIEW ............................................................................ 1 Rational Vaccine Design ............................................................................................... 1 Adjuvants: An Immunologist’s Secret Weapon ............................................................ 3 Bacterial Respiratory Diseases and Prevention Strategies ............................................ 9 Trained Innate Immunity ............................................................................................. 14 Humoral Immune Response ........................................................................................ 16 References ................................................................................................................... 25 CHAPTER 2. ROOM TEMPERATURE STABLE PSPA-BASED NANOVACCINE INDUCES PROTECTIVE IMMUNITY............................................ 40 Abstract ........................................................................................................................ 40 Introduction ................................................................................................................. 41 Materials and Methods ................................................................................................ 46 Results ......................................................................................................................... 50 Discussion .................................................................................................................... 57 Acknowledgments ....................................................................................................... 63 Conflict of Interest Statement ...................................................................................... 63 References ................................................................................................................... 63 CHAPTER 3. SINGLE-DOSE COMBINATION NANOVACCINE INDUCES BOTH RAPID AND LONG-LIVED PROTECTION AGAINST PNEUMONIC PLAGUE ........................................................................................................................... 70 Abstract ........................................................................................................................ 70 Introduction ................................................................................................................. 71 Material and Methods .................................................................................................. 75 Results ......................................................................................................................... 82 Discussion .................................................................................................................... 95 Acknowledgements ................................................................................................... 100 Author Contributions ................................................................................................. 100 Conflict of Interest Statement .................................................................................... 101 References ................................................................................................................. 101 iv CHAPTER 4. COMBINATION NANOVACCINE PROVIDES PROTECTION AGAINST YERSINIA PESTIS IN MICE WITH IMMUNOLOGICAL DEFICIENCIES .............................................................................................................. 106 Introduction ............................................................................................................... 106 Materials and Methods .............................................................................................. 108 Results ....................................................................................................................... 112 Discussion .................................................................................................................. 119 References ................................................................................................................. 123 CHAPTER 5. CO-ADJUVANT APPROACHES TO EARLY-ONSET PROTECTION ................................................................................................................ 126 Introduction ............................................................................................................... 126 Materials and Methods .............................................................................................. 129 Results ....................................................................................................................... 133 Discussion .................................................................................................................. 137 References ................................................................................................................. 140 CHAPTER 6. DISCUSSION .......................................................................................... 142 References ................................................................................................................. 145 APPENDIX: DOCK2 MUTATION PRESENCE IN ENVIGO FACILITIES .............. 147 v LIST OF FIGURES Page Figure 2.1 PspA nanovaccine characterization. ................................................................ 51 Figure 2.2 PspA nanovaccines are capable of initiating protective immune responses. ...................................................................................................... 53 Figure 2.3 Nanovaccines with 25-fold reduction in total protein provided protection against lethal challenge. ................................................................................ 56 Figure 2.4 Room temperature-stored PspA nanovaccine maintains efficacy after 60 days. .............................................................................................................. 58 Figure 3.1 Characterization of F1-V Nanovaccine. .......................................................... 83 Figure 3.2 Combination Nanovaccine provides rapid protective immunity against lethal Y. pestis challenge. .............................................................................. 85 Figure 3.3 Combination Nanovaccine provides long-lived protective immunity against lethal Y. pestis challenge. ................................................................. 88 Figure 3.4. Combination Nanovaccine provides long-lived antibody responses to F1-V. ............................................................................................................. 89 Figure 3.5 Combination Nanovaccine induces class-switched antibody responses to F1-V. ............................................................................................................. 90 Figure 3.6 Combination Nanovaccine induces long-lived antibody responses in BAL fluid against
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