AUTHOR=Lizárraga David , Timms Peter , Quigley Bonnie L. , Hanger Jon , Carver Scott 

TITLE=Capturing Complex Vaccine-Immune-Disease Relationships for Free-Ranging Koalas: Higher Chlamydial Loads Are Associated With Less IL17 Expression and More Chlamydial Disease

JOURNAL=Frontiers in Veterinary Science

VOLUME=7

YEAR=2020

URL=https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2020.530686

DOI=10.3389/fvets.2020.530686

ISSN=2297-1769

ABSTRACT=<p><bold>Background:</bold> Chlamydial disease is a major factor negatively affecting koala populations. Vaccination is a promising management option that would result in immune-mediated protection against disease. Measuring and assessing vaccine efficacy can be challenging owing to both direct and indirect interactions caused by vaccination. In this study, we investigate vaccine-immune-chlamydial load-disease relationships from MOMP (major outer membrane protein) vaccine trials to protect healthy free-ranging koalas against <italic>Chlamydia</italic>-related diseases.</p><p><bold>Methods:</bold> We created <italic>a priori</italic> hypotheses based on data sources and perceived direct and indirect interactions from koalas vaccinated 6 months prior. Each hypothesis was tested as a structural equation model separately for either the urogenital or the ocular site to evaluate possible causality among measured variables. Model averaging was used as multiple models fit the data, and the strength of relationships was examined through averaged coefficients and the raw data.</p><p><bold>Results:</bold> We found more relationships in urogenital models as compared to ocular models, particularly those with interleukin 17 (IL17) mRNA expression compared to models with interferon gamma (IFNγ) expression. In the averaged model with IL17, urogenital chlamydial load was positively associated with disease and negatively associated with IL17 expression. MOMP vaccination had a trending effect for reducing urogenital chlamydial load and also had a strong effect on increasing IL17 expression. Not surprisingly, urogenital chlamydial load was a positive predictor for the development of urogenital disease at 6 months post-vaccination.</p><p><bold>Conclusions:</bold> Despite multiple potential sources of variation owing to the koalas in this study being free-ranging, our analyses provide unique insights into the effects of vaccinating against <italic>Chlamydia</italic>. Using structural equation modeling, this study has helped illuminate that the expression of the immune cytokine IL17 is linked to MOMP vaccination, and animals with a high urogenital chlamydial load expressed less IL17 and were more likely to develop disease, enhancing previous investigations. Going beyond univariate statistics, the methods used in this study can be applied to other preclinical vaccination experiments to identify important direct and indirect factors underpinning the effects of a vaccine.</p>