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Alpaca Polyclonal Igg Antibodies Protect Against Lethal Andes Virus Infection

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Alpaca Polyclonal Igg Antibodies Protect Against Lethal Andes Virus Infection Alpaca Polyclonal IgG Antibodies Protect Against Lethal Andes Virus Infection by Patrycja Magdalena Sroga A thesis submitted to the Faculty of Graduate Studies of The University of Manitoba In partial fulfillment of the requirements of the degree of Master of Science Department of Medical Microbiology and Infectious Diseases University of Manitoba Winnipeg Copyright © 2020 by Patrycja Magdalena Sroga Abstract Hantaviruses remain a global health issue as the number of infections continues to rise from year to year. Andes virus (ANDV), a South American Hantavirus strain carried by the long- tailed pygmy rice rat Oligoryzomys longicaudatus, causes over 200 infections each year in Argentina and Chile. The virus is transmitted through inhalation of infected rodent excreta, however numerous reports have confirmed person-to-person cases as well. ANDV is responsible for causing Hantavirus Pulmonary Syndrome and the lack of an approved therapeutic and/or vaccine is a problem as the fatality rate ranges from 30-50% between outbreaks. Recent animal studies have documented the potential of using antibodies as an effective treatment for Andes virus infections. The central hypothesis of this thesis is that neutralizing alpaca IgG antibodies produced through DNA vaccination will provide protection against lethal ANDV challenge within the Golden Syrian hamster model. This hypothesis was addressed by vaccinating alpacas and generating hyperimmune Andes virus-specific polyclonal IgG antibodies. Afterwards, these antibodies were evaluated in a bioavailability and protection study within the lethal Golden Syrian hamster model. Purified neutralizing polyclonal IgG alpaca antibodies were found to be 100% protective against lethal ANDV hamster infection when administered at days +1 and +3 post challenge. The success of this study provides promising proof of concept data that neutralizing alpaca PcIgG antibodies have the potential to be a highly effective and novel treatment for ANDV infections. i Dedication This thesis is dedicated to my parents, Barbara and Norbert, and brother, Thomas. Thank you for your love, support, and encouragement to pursue my dreams. ii Acknowledgements First and foremost I would like to thank my supervisors Dr. Michael Drebot and Dr. David Safronetz for the opportunity to work within the Special Pathogens group. With your guidance and support, I have gained not only the skills but the confidence to challenge myself in regards to research. I would also like to thank my committee members, Dr. Blake Ball and Dr. Janilyn Arsenio. Thank you for your enthusiasm and support throughout this journey. I would like to thank Dr. Darryl Falzarano and the Veterinary team at VIDO-Intervac/ University of Saskatchewan for the opportunity to collaborate, as well as their expertise throughout this project. Thank you to Angela Nelson and the Department of Medical Microbiology for your constant support and guidance throughout this journey. Thank you to my fellow graduate students and close friends Jasmine Frost and Lauren Garnett, for the numerous coffee pick-me-ups and the chance to vent following failed experiments. Thank you to my fellow lab members, Derek, Bryce, Angela, Yvonne, Geoff, Rob, and the entire Special Pathogens team. Thank you for your friendship and always being there to help. Finally, thank you to my friends and family for always supporting me. I am incredibly lucky to have such wonderful people in my life. iii Table of Contents Abstract ........................................................................................................................................ i Dedication .................................................................................................................................... ii Acknowledgements ................................................................................................................... iii Table of Contents ...................................................................................................................... iv List of Tables ............................................................................................................................. vi List of Figures ........................................................................................................................... vii Chapter 1. Introduction ........................................................................................................... 1 1.1 Origin and Early History of Hantaviruses .............................................................................. 1 1.1.1 Old World Hantaviruses and HFRS ................................................................................................. 1 1.1.2 New World Hantaviruses and HPS/ HCPS ................................................................................... 4 1.2 Phylogeny and Transmission Routes of Hantaviruses ......................................................... 7 1.3 History of Andes Virus Outbreaks ........................................................................................ 10 1.4 Andes Virus Structure and Replication ................................................................................ 12 1.4.1 ANDV Structure .................................................................................................................................. 12 1.4.2 ANDV Replication Cycle ................................................................................................................. 13 1.5 Andes Virus Transmission and Pathogenesis ...................................................................... 15 1.5.1 Person-to-Person Transmission of ANDV ................................................................................. 15 1.5.2 Pathogenesis of HPS/HCPS ............................................................................................................. 18 1.6 Vaccines and Treatments for HPS/HCPS ............................................................................ 20 1.6.1 Diagnosis, Vaccines, and Antivirals ............................................................................................. 20 1.6.2 Passive Transfer Animal Studies ................................................................................................... 22 1.7 Human IgG Antibodies ............................................................................................................. 23 1.8 Alpaca IgG Antibodies ............................................................................................................. 26 1.8.1 Structure and Function of Alpaca IgG Antibodies ................................................................... 26 1.8.2 Current Advancements with Heavy-Chain Antibodies .......................................................... 30 1.9 Study Rationale, Hypothesis, and Objectives ...................................................................... 32 Chapter 2. Material and Methods ....................................................................................... 34 2.1. Animal Cell Lines ..................................................................................................................... 34 2.2 Methods ........................................................................................................................................ 34 2.2.1 Vaccine Design and Preparation .................................................................................................... 34 2.2.2 Preparation of Plasmid Vaccine ..................................................................................................... 34 2.2.3 Tissue Culture Transfection ............................................................................................................. 35 2.2.4 Western Blot and LI-COR Imaging .............................................................................................. 36 2.2.5 Ethics ....................................................................................................................................................... 37 2.2.6 Alpaca Vaccination Schedule ......................................................................................................... 38 2.2.7 Plaque Reduction Neutralization Test (PRNT) ......................................................................... 39 2.2.8 Purification of Alpaca PcIgG and IgG Subtype Antibodies ................................................. 40 2.2.9 Dialysis and Concentration of PcIgG and Subtype Antibodies ........................................... 40 2.2.10 Protein Gel Electrophoresis and Staining ................................................................................. 41 2.2.11 Pharmacokinetic Study Design .................................................................................................... 41 2.2.12 Alpaca PcIgG Antibody Detection by ELISA ........................................................................ 42 2.2.13 Alpaca PcIgG Protection Study Design .................................................................................... 43 2.2.14 Viral RNA Detection in Tissues using qRT-PCR .................................................................. 44 iv 2.2.15 Statistical Analysis ........................................................................................................................... 45 Chapter 3. Results .................................................................................................................. 46 3.1 Development of
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