Assessing Epitope-Specific Antibody Responses to Two Novel Zika Vaccine Platforms Open Access

Abstract

There is an urgent need for vaccines to prevent disease caused by Zika virus (ZIKV) infection, particularly congenital anomalies, developmental delays, and pregnancy loss. However, the current understanding of humoral responses to ZIKV is incomplete, and tools to assess the immunogenicity of candidate vaccines are lacking. Moreover, ideal ZIKV vaccines need to be safe for use in pregnancy. We developed blockade of binding (BOB) assays employing monoclonal antibodies (mAbs) to assess epitope-specific ZIKV immunity induced by infection and vaccination. Validation of these BOB assays revealed quantitatively and qualitatively distinct antibody (Ab) responses between two leading ZIKV vaccines. To apply this approach to assess the immunogenicity of novel ZIKV vaccine platforms, we generated serologic data from pre-clinical development in a mouse model of a non-replicating ZIKV vaccine candidate, which leverages recombinant expression of ZIKV surface proteins within the backbone of the insect-only flavivirus Aripo virus (ARPV). ARPV/ZIKV vaccination of immunocompetent mice induced seroconversion in BOB assays across multiple distinct epitopes, even more effectively than wildtype ZIKV infection. We also further applied this approach to assess immunogenicity after vaccination of mRNA-1893 vaccination of humans participating in a phase 1 dose-ranging trial (NCT04064905). Early results indicate that this vaccine produces Abs to complex ZIKV-specific epitopes, an observation that holds true in flavivirus-naïve participants and those with pre-existing cross-reactive Abs to ZIKV due to prior dengue infection. This study indicates that these novel ZIKV vaccine candidate elicits Abs that compete with strongly-neutralizing ZIKV-specific mAb, which may predict protective immunity. Our findings also support the value of BOB assays in assessing immunogenicity of other vaccine candidates for ZIKV or other emerging viruses.

Table of Contents

1. Introduction –––––––––––––––––––––––– 1

1.1 Zika Virus: A Global Health Challenge –––––––––––––––––––––––– 1

1.2 Virology and Serologic Approaches for Epitope-Specific Immunity to ZIKV –––––––––––––––––––––––– 3

1.3 Zika Virus Vaccine Development: Progress and Potential Challenges –––––––––––––––––––––––– 5

1.4 Vaccine Considerations for Pregnant Individuals –––––––––––––––––––––––– 8

1.5 Novel Vaccine Platforms: mRNA & Insect-Specific Flavivirus Vaccines –––––––––––––––––––––––– 9

1.6 Research Objectives –––––––––––––––––––––––– 10

2. Materials & Methods –––––––––––––––––––––––– 12

2.1 Ethical Statement –––––––––––––––––––––––– 12

2.2 Biospecimens & Study Design –––––––––––––––––––––––– 12

2.3 Lab Experiments –––––––––––––––––––––––– 13

2.4 Statistical Analysis –––––––––––––––––––––––– 14

3. Results –––––––––––––––––––––––– 15

3.1 Binding Characteristics of Monoclonal Antibodies –––––––––––––––––––––––– 15

3.2 Epitope-Specific Responses to ZIKV in ARPV/ZIKV –––––––––––––––––––––––– 15

3.3 Epitope-Specific Responses to ZIKV in mRNA Vaccine –––––––––––––––––––––––– 16

3.4 Epitope-Specific Responses to DENV in mRNA Vaccine –––––––––––––––––––––––– 17

4. Discussion –––––––––––––––––––––––– 18

4.1 ARPV/ZIKV –––––––––––––––––––––––– 18

4.2 mRNA-1893 –––––––––––––––––––––––– 19

4.3 Flavivirus Immune Interactions –––––––––––––––––––––––– 21

4.4 Value of BOB Assay as a Serologic Tool –––––––––––––––––––––––– 23

4.5 Conclusion –––––––––––––––––––––––– 24

5. Appendix –––––––––––––––––––––––– 25

6. References –––––––––––––––––––––––– 36

About this Honors Thesis

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School	Emory College
Department	Human Health
Degree	B.A.
Submission	Honors Thesis
Language	English
Research Field	Health Sciences, Immunology Biology, Virology Health Sciences, Public Health
Keyword	Infectious Diseases Vaccine Zika virus Antibody Response
Committee Chair / Thesis Advisor	Matthew Collins, Emory University
Committee Members	Christina Gavegnano, Emory University Amanda Freeman, Emory University

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