A Yellow Fever Virus 17D Infection and Disease Mouse Model Used to Evaluate a Chimeric Binjari-Yellow Fever Virus Vaccine

Abstract

<jats:p>Despite the availability of an effective, live attenuated yellow fever virus (YFV) vaccine (YFV 17D), this flavivirus still causes up to ≈60,000 deaths annually. A number of new approaches are seeking to address vaccine supply issues and improve safety for the immunocompromised vaccine recipients. Herein we describe an adult female IFNAR-/- mouse model of YFV 17D infection and disease that recapitulates many features of infection and disease in humans. We used this model to evaluate a new YFV vaccine that is based on a recently described chimeric Binjari virus (BinJV) vaccine technology. BinJV is an insect-specific flavivirus and the chimeric YFV vaccine (BinJ/YFV-prME) was generated by replacing the prME genes of BinJV with the prME genes of YFV 17D. Such BinJV chimeras retain their ability to replicate to high titers in C6/36 mosquito cells (allowing vaccine production), but are unable to replicate in vertebrate cells. Vaccination with adjuvanted BinJ/YFV-prME induced neutralizing antibodies and protected mice against infection, weight loss and liver pathology after YFV 17D challenge.</jats:p>

A Zika Vaccine Generated Using the Chimeric Insect-Specific Binjari Virus Platform Protects against Fetal Brain Infection in Pregnant Mice

“…Vaccine-induced T cell responses likely also contribute to protection against transplacental infection, although the required phenotypes and their contributions in different model systems remain to be fully elucidated [ 48 ]. Induction of T cell responses by the chimeric BinJV vaccines also remains to be characterized, although wild-type mice rather than IFNAR −/− mice are being used for these studies, given the roles of type I IFNs in T cell biology [ 12 , 49 , 50 ].…”

“…The mice were then euthanized using CO 2 , and placenta and fetal heads were harvested and stored at −80 °C (for viral titrations) or RNAlater (Qiagen, Hilden, Germany) for qRT-PCR. ZIKV titers in sera and tissues were determined by CCID 50 assay as described previously using titration on C6/36 cells and virus detection by cytopathic effects in Vero E6 cells [ 12 , 14 , 34 ], with one modification; supernatants from homogenized tissues were titered using five-fold serial dilutions.…”

“…Tissues were transferred from RNAlater to TRIzol (Life Technologies, Carlsbad, CA, USA) with subsequent homogenization of tissue, RNA extractions, and cDNA synthesis undertaken as described previously [ 12 ]. qRT PCR was performed on cDNA from maternal placenta, fetal brain, and deformed fetal tissue as described [ 14 ] with minor modifications.…”

“…The resulting chimeras have potential utility as vaccines as they retained their ability to replicate in insect cells (allowing vaccine manufacture), but are unable to replicate in vertebrate cells (providing complete attenuation in the vaccine recipient) [ 10 ]. The BinJV platform has now been used to generate a number of flavivirus vaccines that have induced protective immunity in mouse models; these include a chimeric Yellow fever (YF) virus vaccine, BinJ/YF-prME [ 12 ]; a chimeric West Nile (WN) virus vaccine, Binj/WN-prME [ 13 ]; and a chimeric ZIKV vaccine, BinJ/ZIKA-prME [ 10 ].…”

A Novel Strategy for the Development of Vaccines for SARS-CoV-2 (COVID-19) and Other Viruses Using AI and Viral Shell Disorder

“…Further details pertaining to the correlations between virulence and inner shell disorder among the mentioned viruses can be found in previous papers. 10 , 17 − 19 , 43 − 45 The CFRs of the viruses have been well-studied and documented. 46 − 48…”