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Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus.

ABSTRACT: Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.

SUBMITTER: Koenig MR

PROVIDER: S-EPMC7580995 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus.

Koenig Michelle R MR Razo Elaina E Mitzey Ann A Newman Christina M CM Dudley Dawn M DM Breitbach Meghan E ME Semler Matthew R MR Stewart Laurel M LM Weiler Andrea M AM Rybarczyk Sierra S Bach Kathryn M KM Mohns Mariel S MS Simmons Heather A HA Mejia Andres A Fritsch Michael M Dennis Maria M Teixeira Leandro B C LBC Schotzko Michele L ML Nork T Michael TM Rasmussen Carol A CA Katz Alex A Nair Veena V Hou Jiancheng J Hartman Amy A Ver Hoeve James J Kim Charlene C Schneider Mary L ML Ausderau Karla K Kohn Sarah S Jaeger Anna S AS Aliota Matthew T MT Hayes Jennifer M JM Schultz-Darken Nancy N Eickhoff Jens J Antony Kathleen M KM Noguchi Kevin K Zeng Xiankun X Permar Sallie S Prabhakaran Vivek V Capuano Saverio S Friedrich Thomas C TC Golos Thaddeus G TG O'Connor David H DH Mohr Emma L EL

PloS one 20201022 10

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inocula ...[more]

PMID: 33091010

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Project description:BackgroundZika virus (ZIKV), a mosquito-borne flavivirus, is a re-emerging virus that constitutes a public health threat due to its recent global spread, recurrent outbreaks, and infections that are associated with neurological abnormalities in developing fetuses and Guillain-Barré syndrome in adults. To date, there are no approved vaccines against ZIKV infection. Various preclinical and clinical development programs are currently ongoing in an effort to bring forward a vaccine for ZIKV.Methodology/principle findingsWe have developed a ZIKV vaccine candidate based on Virus-Like-Particles (VLPs) produced in HEK293 mammalian cells using the prM (a precursor to M protein) and envelope (E) structural protein genes from ZIKV. Transient transfection of cells via plasmid and electroporation produced VLPs which were subsequently purified by column chromatography yielding approximately 2mg/L. Initially, immunogenicity and efficacy were evaluated in AG129 mice using a dose titration of VLP with and without Alhydrogel 2% (alum) adjuvant. We found that VLP with and without alum elicited ZIKV-specific serum neutralizing antibodies (nAbs) and that titers correlated with protection. A follow-up immunogenicity and efficacy study in rhesus macaques was performed using VLP formulated with alum. Multiple neutralization assay methods were performed on immune sera including a plaque reduction neutralization test, a microneutralization assay, and a Zika virus Renilla luciferase neutralization assay. All of these assays indicate that following immunization, VLP induces high titer nAbs which correlate with protection against ZIKV challenge.Conclusions/significanceThese studies confirm that ZIKV VLPs could be efficiently generated and purified. Upon VLP immunization, in both mice and NHPs, nAb was induced that correlate with protection against ZIKV challenge. These studies support translational efforts in developing a ZIKV VLP vaccine for evaluation in human clinical trials.

Dataset Information

Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus.

Publications

Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus.

Similar Datasets

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