Bivalent single domain antibody constructs for effective neutralization of Venezuelan equine encephalitis

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dc.contributor.authorLiu, Jinny L.en
dc.contributor.authorZabetakis, Danen
dc.contributor.authorGardner, Christina L.en
dc.contributor.authorBurke, Crystal W.en
dc.contributor.authorGlass, Pamela J.en
dc.contributor.authorWebb, Emily M.en
dc.contributor.authorShriver-Lake, Lisa C.en
dc.contributor.authorAnderson, George P.en
dc.contributor.authorWeger-Lucarelli, Jamesen
dc.contributor.authorGoldman, Ellen R.en
dc.date.accessioned2022-08-05T18:07:54Zen
dc.date.available2022-08-05T18:07:54Zen
dc.date.issued2022-01-13en
dc.description.abstractVenezuelan equine encephalitis virus (VEEV) is a mosquito borne alphavirus which leads to high viremia in equines followed by lethal encephalitis and lateral spread to humans. In addition to naturally occurring outbreaks, VEEV is a potential biothreat agent with no approved human vaccine or therapeutic currently available. Single domain antibodies (sdAb), also known as nanobodies, have the potential to be effective therapeutic agents. Using an immune phage display library derived from a llama immunized with an equine vaccine that included inactivated VEEV, five sdAb sequence families were identified that showed varying ability to neutralize VEEV. One of the sequence families had been identified previously in selections against chikungunya virus, a related alphavirus of public health concern. A key advantage of sdAb is the ability to optimize properties such as neutralization capacity through protein engineering. Neutralization of VEEV was improved by two orders of magnitude by genetically linking sdAb. One of the bivalent constructs showed effective neutralization of both VEEV and chikungunya virus. Several of the bivalent constructs neutralized VEEV in cell-based assays with reductions in the number of plaques by 50% at protein concentrations of 1 ng/mL or lower, making future evaluation of their therapeutic potential compelling.en
dc.description.notesThis research was supported by the Defense Threat Reduction Agency (DTRA) Project CB10487. The research conducted at VT was performed while EW held a doctoral fellowship through the Institute for Critical Technology and Applied Science (ICTAS). The following reagent was obtained through the NIH Biodefense and Emerging Infections Research Resources Repository, NIAID, NIH: Venezuelan Equine Encephalitis Virus, TC-83, NR-63. The opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the U.S. Army or the US Navy. Finally, we publish this paper in memory of Jay Jorgensen of Triple J farms, whom we have partnered with for llama immunizations over many years.en
dc.description.sponsorshipDefense Threat Reduction Agency (DTRA) [CB10487]; Institute for Critical Technology and Applied Science (ICTAS)en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41598-021-04434-xen
dc.identifier.issn2045-2322en
dc.identifier.issue1en
dc.identifier.other700en
dc.identifier.pmid35027600en
dc.identifier.urihttp://hdl.handle.net/10919/111480en
dc.identifier.volume12en
dc.language.isoenen
dc.publisherNature Portfolioen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectvirusen
dc.subjectbindingen
dc.titleBivalent single domain antibody constructs for effective neutralization of Venezuelan equine encephalitisen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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