{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T22:58:46Z","timestamp":1781218726611,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,9]]},"group-title":"Microbiology","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Crimean-Congo hemorrhagic fever virus (CCHFV) is the etiologic agent of a lethal hemorrhagic disease spread by ticks throughout Europe, the Middle East, Africa and Asia. The lack of approved medical countermeasures and fundamental understanding of molecular mechanisms of viral assembly and egress have thus far curtailed disease prevention. Here, we identify and characterize key residues within the viral glycoprotein through forward and reverse genetics for vesicular stomatitis virus (VSV)-based vaccine candidates that are highly protective in animal models. These residues are broadly applicable across divergent CCHFV strains and lead to greater protection\n                  <jats:italic>in vivo<\/jats:italic>\n                  against heterologous challenge. We further characterize the essential role of proteolytic processing in the maintenance of a stable fusogenic state required for effective VSV-based CCHFV vaccines. This study establishes a toolkit for better understanding orthonairovirus glycoprotein processing and vaccine development.\n                <\/jats:p>","DOI":"10.64898\/2026.06.07.730762","type":"posted-content","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T15:35:15Z","timestamp":1781019315000},"source":"Crossref","is-referenced-by-count":0,"title":["Finding the Goldilocks zone: Modulating glycoprotein cleavage and fusogenicity optimizes the efficacy of a candidate Crimean-Congo hemorrhagic fever virus vaccine"],"prefix":"10.64898","author":[{"given":"Jacob","family":"Berrigan","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie R.","family":"Monticelli","sequence":"additional","affiliation":[{"name":"U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA"},{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"Spealman","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences at Merrimack College, North Andover, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney A.","family":"Cohen","sequence":"additional","affiliation":[{"name":"U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Batchelor","sequence":"additional","affiliation":[{"name":"U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA"},{"name":"Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"McFadden","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell R.","family":"Bakken","sequence":"additional","affiliation":[{"name":"U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan M.","family":"Slough","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel S.","family":"Wirchnianski","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA"},{"name":"Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceutical Inc., Ridgefield, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Mittler","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Cross","sequence":"additional","affiliation":[{"name":"Galveston National Laboratory, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0858-1877","authenticated-orcid":false,"given":"Thomas W.","family":"Geisbert","sequence":"additional","affiliation":[{"name":"Galveston National Laboratory, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse H.","family":"Erasmus","sequence":"additional","affiliation":[{"name":"HDT Bio, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Hawman","sequence":"additional","affiliation":[{"name":"HDT Bio, Seattle, WA 98109, USA"},{"name":"Laboratory of Viral Zoonoses, Integrated Research Facility, Division of Intramural Research, NIAID\/NIH, Frederick, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3991-542X","authenticated-orcid":false,"given":"Jason S.","family":"McLellan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S.","family":"Herbert","sequence":"additional","affiliation":[{"name":"U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kartik","family":"Chandran","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061115402269000_2026.06.07.730762v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2013.07.006"},{"key":"2026061115402269000_2026.06.07.730762v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2018.12.002"},{"key":"2026061115402269000_2026.06.07.730762v1.3","doi-asserted-by":"crossref","first-page":"150016","DOI":"10.1038\/sdata.2015.16","article-title":"A global compendium of human Crimean-Congo haemorrhagic fever virus occurrence","volume":"2","year":"2015","journal-title":"Sci Data"},{"key":"2026061115402269000_2026.06.07.730762v1.4","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.056374-0"},{"key":"2026061115402269000_2026.06.07.730762v1.5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0006248"},{"issue":"44","key":"2026061115402269000_2026.06.07.730762v1.6","doi-asserted-by":"crossref","first-page":"6015","DOI":"10.1016\/j.vaccine.2017.05.031","article-title":"Development of vaccines against Crimean-Congo haemorrhagic fever virus","volume":"35","year":"2017","journal-title":"Vaccine"},{"issue":"4","key":"2026061115402269000_2026.06.07.730762v1.7","first-page":"421","article-title":"Crimean-Congo haemorrhagic fever (CCHF): present and future therapeutic armamentarium","volume":"32","year":"2024","journal-title":"Infez Med"},{"key":"2026061115402269000_2026.06.07.730762v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2018.09.009"},{"key":"2026061115402269000_2026.06.07.730762v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-023-00871-9"},{"key":"2026061115402269000_2026.06.07.730762v1.10","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.80.1.514-525.2006"},{"key":"2026061115402269000_2026.06.07.730762v1.11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008850"},{"key":"2026061115402269000_2026.06.07.730762v1.12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703200200"},{"key":"2026061115402269000_2026.06.07.730762v1.13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004879"},{"key":"2026061115402269000_2026.06.07.730762v1.14","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02730-06"},{"key":"2026061115402269000_2026.06.07.730762v1.15","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01647-07"},{"issue":"2","key":"2026061115402269000_2026.06.07.730762v1.16","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.cell.2024.11.008","article-title":"Engineering and structures of Crimean-Congo hemorrhagic fever virus glycoprotein complexes","volume":"188","year":"2025","journal-title":"Cell"},{"key":"2026061115402269000_2026.06.07.730762v1.17","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adq5928"},{"issue":"11","key":"2026061115402269000_2026.06.07.730762v1.18","doi-asserted-by":"crossref","first-page":"e0008834","DOI":"10.1371\/journal.pntd.0008834","article-title":"Evaluation of the cell culture based and the mouse brain derived inactivated vaccines against Crimean-Congo hemorrhagic fever virus in transiently immune-suppressed (IS) mouse model","volume":"14","year":"2020","journal-title":"PLoS Negl Trop Dis"},{"key":"2026061115402269000_2026.06.07.730762v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-44210-6"},{"key":"2026061115402269000_2026.06.07.730762v1.20","doi-asserted-by":"crossref","first-page":"104523","DOI":"10.1016\/j.ebiom.2023.104523","article-title":"Adenoviral vectored vaccination protects against Crimean-Congo Haemorrhagic Fever disease in a lethal challenge model","volume":"90","year":"2023","journal-title":"EBioMedicine"},{"issue":"1","key":"2026061115402269000_2026.06.07.730762v1.21","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/s41541-024-00877-1","article-title":"Replicon particle vaccination induces non-neutralizing anti-nucleoprotein antibody-mediated control of Crimean-Congo hemorrhagic fever virus","volume":"9","year":"2024","journal-title":"NPJ Vaccines"},{"key":"2026061115402269000_2026.06.07.730762v1.22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005908"},{"issue":"1","key":"2026061115402269000_2026.06.07.730762v1.23","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41541-024-00931-y","article-title":"Crimean Congo hemorrhagic fever virus nucleoprotein and GP38 subunit vaccine combination prevents morbidity in mice","volume":"9","year":"2024","journal-title":"NPJ Vaccines"},{"key":"2026061115402269000_2026.06.07.730762v1.24","doi-asserted-by":"crossref","first-page":"105698","DOI":"10.1016\/j.ebiom.2025.105698","article-title":"A replicating RNA vaccine confers protection against Crimean-Congo hemorrhagic fever in cynomolgus macaques","volume":"115","year":"2025","journal-title":"EBioMedicine"},{"issue":"1","key":"2026061115402269000_2026.06.07.730762v1.25","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41541-025-01164-3","article-title":"Single dose VSV-based vaccine protects mice against lethal heterologous Crimean-Congo hemorrhagic fever virus challenge","volume":"10","year":"2025","journal-title":"NPJ Vaccines"},{"key":"2026061115402269000_2026.06.07.730762v1.26","doi-asserted-by":"crossref","unstructured":"Mittler, E. , et al., Direct Intracellular Visualization of Ebola Virus-Receptor Interaction by. mBio, 2021. 12(1).","DOI":"10.1128\/mBio.03100-20"},{"key":"2026061115402269000_2026.06.07.730762v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.05.001"},{"issue":"7","key":"2026061115402269000_2026.06.07.730762v1.28","doi-asserted-by":"crossref","first-page":"114502","DOI":"10.1016\/j.celrep.2024.114502","article-title":"Crimean-Congo hemorrhagic fever survivors elicit protective non-neutralizing antibodies that target 11 overlapping regions on glycoprotein GP38","volume":"43","year":"2024","journal-title":"Cell Rep"},{"key":"2026061115402269000_2026.06.07.730762v1.29","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl6502"},{"key":"2026061115402269000_2026.06.07.730762v1.30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.18.8388"},{"issue":"1","key":"2026061115402269000_2026.06.07.730762v1.31","doi-asserted-by":"crossref","first-page":"2348508","DOI":"10.1080\/22221751.2024.2348508","article-title":"The PACS-2 protein and trafficking motifs in CCHFV Gn and Gc cytoplasmic domains govern CCHFV assembly","volume":"13","year":"2024","journal-title":"Emerg Microbes Infect"},{"key":"2026061115402269000_2026.06.07.730762v1.32","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-5-7"},{"issue":"6","key":"2026061115402269000_2026.06.07.730762v1.33","doi-asserted-by":"crossref","first-page":"e70457","DOI":"10.1002\/jmv.70457","article-title":"The Single Amino Acid Change of R516K Enables Efficient Generation of Vesicular Stomatitis Virus-Based Crimean-Congo Hemorrhagic Fever Reporter Virus","volume":"97","year":"2025","journal-title":"J Med Virol"},{"key":"2026061115402269000_2026.06.07.730762v1.34","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.23.11418-11421.2000"},{"key":"2026061115402269000_2026.06.07.730762v1.35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004259"},{"key":"2026061115402269000_2026.06.07.730762v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1326"},{"key":"2026061115402269000_2026.06.07.730762v1.37","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03310-12"},{"key":"2026061115402269000_2026.06.07.730762v1.38","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.256248"},{"key":"2026061115402269000_2026.06.07.730762v1.39","doi-asserted-by":"crossref","unstructured":"Ebel, H. , T. Benecke , and B. Vollmer , Stabilisation of Viral Membrane Fusion Proteins in Prefusion Conformation by Structure-Based Design for Structure Determination and Vaccine Development. Viruses, 2022. 14(8).","DOI":"10.3390\/v14081816"},{"key":"2026061115402269000_2026.06.07.730762v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2013.05.030"},{"key":"2026061115402269000_2026.06.07.730762v1.41","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.006387-0"},{"issue":"5","key":"2026061115402269000_2026.06.07.730762v1.42","doi-asserted-by":"crossref","first-page":"e0320224","DOI":"10.1128\/mbio.03202-24","article-title":"Avidity and variable domain spacing strongly influence the therapeutic potency of bispecific antibodies against Crimean-Congo hemorrhagic fever virus","volume":"16","year":"2025","journal-title":"mBio"},{"issue":"21","key":"2026061115402269000_2026.06.07.730762v1.43","doi-asserted-by":"crossref","first-page":"5789","DOI":"10.1002\/j.1460-2075.1996.tb00965.x","article-title":"Sequence requirements for the recognition of tyrosine-based endocytic signals by clathrin AP-2 complexes","volume":"15","year":"1996","journal-title":"EMBO J"},{"key":"2026061115402269000_2026.06.07.730762v1.44","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5392.1327"},{"key":"2026061115402269000_2026.06.07.730762v1.45","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.14109"},{"key":"2026061115402269000_2026.06.07.730762v1.46","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-016-2803-1"},{"key":"2026061115402269000_2026.06.07.730762v1.47","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.16.8640-8649.2003"},{"key":"2026061115402269000_2026.06.07.730762v1.48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.221447598"},{"key":"2026061115402269000_2026.06.07.730762v1.49","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.116.2.349"},{"key":"2026061115402269000_2026.06.07.730762v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(01)02495-4"},{"key":"2026061115402269000_2026.06.07.730762v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2005.07.025"},{"key":"2026061115402269000_2026.06.07.730762v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2015.08.028"},{"key":"2026061115402269000_2026.06.07.730762v1.53","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00005.2004"},{"key":"2026061115402269000_2026.06.07.730762v1.54","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.16.7392-7398.2001"},{"key":"2026061115402269000_2026.06.07.730762v1.55","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01507-13"},{"issue":"8","key":"2026061115402269000_2026.06.07.730762v1.56","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1002\/j.1460-2075.1986.tb04444.x","article-title":"The budding mechanism of spikeless vesicular stomatitis virus particles","volume":"5","year":"1986","journal-title":"EMBO J"},{"key":"2026061115402269000_2026.06.07.730762v1.57","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.1031355"},{"key":"2026061115402269000_2026.06.07.730762v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-02024-y"},{"key":"2026061115402269000_2026.06.07.730762v1.59","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-021-02472-2"},{"key":"2026061115402269000_2026.06.07.730762v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0072-8"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.07.730762","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T22:40:31Z","timestamp":1781217631000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.07.730762"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,9]]},"references-count":60,"URL":"https:\/\/doi.org\/10.64898\/2026.06.07.730762","relation":{},"subject":[],"published":{"date-parts":[[2026,6,9]]},"subtype":"preprint"}}