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Development of Rationally Designed Live Attenuated Vaccines for Lassa Fever and Venezuelan Equine Encephalitis

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Development of Rationally Designed Live Attenuated Vaccines for Lassa Fever and Venezuelan Equine Encephalitis University of Louisville ThinkIR: The University of Louisville's Institutional Repository Electronic Theses and Dissertations 5-2020 Development of rationally designed live attenuated vaccines for Lassa fever and Venezuelan equine encephalitis. Dylan MacGregor Johnson University of Louisville Follow this and additional works at: https://ir.library.louisville.edu/etd Part of the Virus Diseases Commons Recommended Citation Johnson, Dylan MacGregor, "Development of rationally designed live attenuated vaccines for Lassa fever and Venezuelan equine encephalitis." (2020). Electronic Theses and Dissertations. Paper 3393. Retrieved from https://ir.library.louisville.edu/etd/3393 This Doctoral Dissertation is brought to you for free and open access by ThinkIR: The University of Louisville's Institutional Repository. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of ThinkIR: The University of Louisville's Institutional Repository. This title appears here courtesy of the author, who has retained all other copyrights. For more information, please contact [email protected]. DEVELOPMENT OF RATIONALLY DESIGNED LIVE ATTENUATED VACCINES FOR LASSA FEVER AND VENEZUELAN EQUINE ENCEPHALITIS By Dylan MacGregor Johnson B.S., University of Hawaii 2008 M.S., Indiana State University 2014 M.S., University of Louisville, 2018 A Dissertation Submitted to the Faculty of the School of Medicine of the University of Louisville in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Microbiology and Immunology Department of Microbiology and Immunology University of Louisville Louisville, Kentucky May 2020 DEVELOPMENT OF RATIONALLY DESIGNED LIVE ATTENUATED VACCINES FOR LASSA FEVER AND VENEZUELAN EQUINE ENCEPHALITIS By Dylan MacGregor Johnson B.S., University of Hawaii 2008 M.S., Indiana State University 2014 M.S., University of Louisville 2018 A Dissertation Approved on March 3, 2020 By the following Dissertation Committee: ___________________________________________ Igor S. Lukashevich, MD,PhD, DSc ___________________________________________ Thomas C. Mitchell, PhD ___________________________________________ Donghoon Chung, PhD ___________________________________________ Jill M. Steinbach-Rankins, PhD ___________________________________________ Kenneth E. Palmer, PhD ii DEDICATION I dedicate this dissertation to the memory of my grandmothers, Sylvia “Grams” Coleman and Margaret F Johnson who always provided unconditional love and support, and to the memory of Alex Johnson who always reminded me to enjoy life. iii ACKNOWLEDGEMENTS I would like to express my deepest appreciation for the guidance and mentorship of Dr. Igor S Lukashevich. I would also like to thank my committee members, Dr. Donghoon Chung, Dr. Kevin Sokoloski, Dr. Thomas Mitchell, Dr. Jill Steinbach-Rankins, and Dr. Kenneth Palmer for their input and support. This work would not have been possible without the assistance of my collaborators, Dr. Juan Carlos de la Torre, Dr. Peter Pushko, Dr. Slobodan Paessler, and Dr. Irina Tretyakova. I am very grateful to Jenny D. Jokinen and Beatrice Cubitt for the excellent laboratory training they provided. I am also thankful for the research support I received from the of the University of Louisville Center for Predictive Medicine, particularly Dr. William Severson, Dr. Jon Gabbard, Marlene Steffen, Dr. Torsten Hopp, Dr. Dan Cramer, Tia Pfeffer, Clarissa Cowen, Dr. Yong-Kyu Chu, Dr. Julie Stotsky, and Robert Scott Adcock; from the University of Louisville Research Resource Facilities, especially Dr. Karen Powell and Jennifer Kraenzel; and from the faculty of the University of Louisville Department of Microbiology and Immunology, especially Dr. Pascale Alard, Dr. Michelle Kosiewicz, Dr. Matthew Lawrenz, Dr. Russell Salter, Dr. Haval Shirwan, and Dr. Esma Shirwan Yolcu. I am also thankful for the training that provided a wonderful foundation from Dr. Swapan K Ghosh, Dr. Joy O’Keefe, Dr. Kand McQueen, Dr. Richard Fitch, Dr. William L Gosnell, Dr. Sandra Chang, Dr. Abby Collier, Dr. Alan Katz, Dr. Paul Patek, Mike Remer, Glen Cook, Mike McPheeters, Frank Holley, Dan Shortenhaus, Barbra Denny, and Patrick Russi. I would also like to express my thanks to my loving wife, Emily, for being my cornerstone. Also, my gratitude to my family: Mary Ellen, Russ and Mark Thurow; Carrie, John and Jacob Gillette; and Carl, Connie, Maggie, and Preston Johnson, and Melvin Roth. iv ABSTRACT DEVELOPMENT OF RATIONALLY DESIGNED LIVE ATTENUATED VACCINES FOR LASSA FEVER AND VENEZUELAN EQUINE ENCEPHALITIS Dylan M Johnson May 9, 2020 Lassa Virus (LASV) and Venezuelan Equine Encephalitis Virus (VEEV) are two single stranded RNA viruses belonging to the Arenavirus and Alphavirus families, respectively. Both are emerging pathogens without approved vaccines or treatments. VEEV is an important biothreat pathogen because it has been weaponized and is extremely infectious as an aerosol. VEEV causes biphasic febrile illness that can progress to a viral encephalitis with low mortality, but high morbidity. LASV causes a viral hemorrhagic fever, Lassa Fever (LF), which is endemic in West Africa, and responsible for between 100-500k annual infections with a 1-2% overall mortality rate. ML29 and VEEV TC-83 are well-described live attenuated vaccines based on LASV and VEEV, respectively. This work describes strategies to further attenuate and enhance the safety of ML29 and TC-83, an important step in preclinical development. VEEV V4020 was designed based on the stabilization of an E2 mutation, and rearrangement of the structural genes of TC-83. Here, VEEV V4020 is shown to be more attenuated than TC-83 based on IC inoculation in mice, and more phenotypically stable, in terms of pathogenicity, during serial passaging. ML29 is a reassortant virus combining the immune dominant glycoprotein (GPC) and nucleoprotein (NP) of LASV with the replicative machinery of to Mopeia virus (MOPV), a nonpathogenic relative of LASV. We provide evidence ML29 is safer and more immunogenic v than MOPV in STAT-1 deficient (STAT-1-/-) mice and Hartley guinea pigs. Additionally, Defective Interfering Particles (DIPs) from ML29 enhance vaccine immunity and attenuation in STAT-1-/- mice, and in intracranial inoculations of CBA/J mice. A potential mechanism of attenuation for ML29 is presented based on small RNAs detected from the ML29 L-segment by Northern Blot (NB). Furthermore, a unique RNA band was associated with DIP enriched ML29 was detected. A L-segment based Minigenome System (MG) for arenaviruses is described, which can be used for future analysis of the mechanism of replication for reassortant arenaviruses. The advanced safety data for both ML29 and VEEV V4020, described in this dissertation, combined with non-human primate efficacy studies described elsewhere, supports the advancement of both of these experimental vaccines to human clinical trials. vi TABLE OF CONTENTS PAGE DEDICATION ……………………………………………………………………………………………………………………. iii ACKNOWLEDGEMENTS …………………………………………………………………………………………………… iv ABSTRACT ………………………………………………………………………………………………………………………. v LIST OF FIGURES ……………………………………………………………………………………………………………… viii INTRODUCTION ………………………………………………………………………………………………………………. 1 NEW CHALLENGES FOR DEVELOPMENT OF A LASSA FEVER VACCINE WITH FULL COVERAGE………………………………………………………………………………………………………………………. 6 ATTENUATED REPLICATION OF LASSA VIRUS VACCINE CANDIDATE ML29 IN STAT-1-/- MICE …………………………………………………………………………………………………………………. 30 SAFETY AND IMMUNOGENICITY OF A DEFECTIVE INTERFERING PARTICLE ENHANCED LASSA VIRUS VACCINE CANDIDATE IN STAT-1-/- MICE, CBA MICE, AND GUINEA PIGS ……… 55 ADVANCED SAFETY AND GENETIC STABILITY IN MICE OF A NOVEL DNA-LAUNCHED VENEZUELAN EQUINE ENCEPHALITIS VIRUS VACCINE WITH REARRANGED STRUCTURAL GENES …………………………………………………………………………………………………………….………………. 80 DISCUSSION AND CONCLUSIONS……………………………………………………………………................... 111 REFERENCES……………………………………………………………………………………………………………………. 116 CURRICULUM VITA………………………………………………………………………………………………………….. 134 vii LIST OF FIGURES FIGURE PAGE 1. Evidence for ML29 defective interfering particles……………………………………………….. 47 2. ML29 and ML29P50 attenuation in STAT-1-/- mice…………………………………………… 48 3. Histology showing attenuated ML29 and ML29P50 in STAT-1-/- .……………………. 50 4. Immunogenicity of ML29, ML29P50, and MOPV in STAT-1-/- …………………………… 51 5. Cytokine responses to ML29, ML29P50, and MOPV in STAT-1-/- mice………………… 51 6. Protein expression of passaged ML29………………………………………………………………… 52 7. ML29 and ML29P50 attenuation in 129S6 mice…………………………………………………. 53 8. Cytokine responses to ML29, ML29P50, and MOPV in 192S6 mice…………………….. 53 9. Passaged ML29 interferes with LCMV-Arm-GFP/GFP reporter expression…………. 75 10. Northern blots of ML29, ML29P28, ML29P53, LASV, and MOPV………………………… 75 11. L-Segment LCMV minigenome system………………………………………………………………. 76 12. Attenuation of ML29 and ML29P50 in STAT-1-/- and CBA/J mice………………………… 77 13. Immunogenicity and safety of ML29 and ML29P50 in Hartley guinea pigs…………. 78 14. VEEV V4020 and VEEV TC-83 design and titers after mouse IC inoculation…………. 100 15. Histological kinetics of VEEV V4020 compared to TC-83 brain infection……………… 102 16. NanoString immunogenicity of VEEV V4020 compared to VEEV TC-83………………. 103 17. Passaging of attenuated VEEV in mouse brain……………………………………………………. 105 18. Next Generation Sequencing genetic variation of passaged attenuated VEEV……. 106 19. Mock IC inoculation control data……………………………………………………………………….. 107 20. Attenuated VEEV NanoString
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