Mouse models of Japanese encephalitis virus infection: A systematic review and meta-analysis using a meta-regression approach

Background: Japanese encephalitis (JE) virus (JEV) remains a leading cause of neurological infection across Asia. The high lethality of disease and absence of effective therapies mean that standardised animal models will be crucial in developing therapeutics. However, published mouse models are heterogeneous. We performed a systematic review, meta-analysis and meta-regression of published JEV mouse experiments to investigate the variation in model parameters, assess homogeneity and test the relationship of key variables against mortality. Methodology/ Principal findings: A PubMed search was performed up to August 2020. 1991 publications were identified, of which 127 met inclusion criteria, with data for 5026 individual mice across 487 experimental groups. Quality assessment was performed using a modified CAMARADES criteria and demonstrated incomplete reporting with a median quality score of 10/17. The pooled estimate of mortality in mice after JEV challenge was 64.7% (95% confidence interval 60.9 to 68.3) with substantial heterogeneity between experimental groups (I^2 70.1%, df 486). Using meta-regression to identify key moderators, a refined dataset was used to model outcome dependent on five variables: mouse age, mouse strain, virus strain, virus dose (in log10PFU) and route of inoculation. The final model reduced the heterogeneity substantially (I^2 38.9, df 265%, df 241), explaining 54% of the variability. Conclusion/ Significance: This is the first systematic review of mouse models of JEV infection. Better adherence to CAMARADES guidelines may reduce bias and variability of reporting. In particular, sample size calculations were notably absent. We report that mouse age, mouse strain, virus strain, virus dose and route of inoculation account for much, though not all, of the variation in mortality. This dataset is available for researchers to access and use as a guideline for JEV mouse experiments. Author summary: Japanese encephalitis (JE) virus (JEV) remains a leading cause of brain infection across Asia, resulting in considerable death and disability. No effective treatment exists. Mouse models are fundamental to evaluate novel treatments. We aimed to perform the first systematic literature review and data synthesis of JEV infection in mouse models. We identified an abundance of experimental data in the field, with 127 studies meeting the inclusion criteria involving a total of 5026 individual mice. Overall, 64.7% of mice died after JEV infection. However, there was incomplete reporting in publications and considerable variability in the results. In summary, the findings support the ongoing use of mouse models of JEV infection and inform researchers in the field in refining their experiments. Key factors affecting variation in mortality across studies that need to be carefully considered in study design are mouse age, mouse strain, virus strain, virus dose and route of inoculation. We highlight the need for researchers to adhere to reporting guidelines in preparing manuscripts for publication.