Biology subjects

Geisbert, T.

Publications and source records attributed to Geisbert, T..

4 recordsLinked to original sources

bioRxiv2026

A single-dose recombinant rVSVΔG-CCHFV-GPC vaccine protects nonhuman primates against heterologous Crimean-Congo hemorrhagic fever virus challenge

Crimean-Congo hemorrhagic fever virus (CCHFV) is a widespread tickborne virus with potential to cause lethal disease in humans. Countermeasure research for CCHFV has been hindered by the lack of a preclinical model that closely recapitulates human disease in an immunocompetent species. Recent reports of experimental CCHFV infection of cynomolgus macaques indicate these animals exhibit disease reflective of that observed in humans. Here, we assessed the ability of a replication competent, recombinant vesicular stomatitis virus (rVSV) vector encoding CCHFV structural glycoproteins (rVSV-CCHFV-GPC) from a Clade III isolate to prevent disease in cynomolgus macaques after challenge with a Clade V isolate of CCHFV and demonstrate that a single vaccination dose is potently immunogenic and reduced viremia and inflammatory biomarker circulation when compared with unvaccinated controls. Importantly, humoral responses to CCHFV glycoproteins in vaccinated macaques were similar to those observed in human CCHF survivors. This study further supports that a rVSV expressing only the CCHFV-GPC has the potential to serve as a vaccine platform against CCHFV infections.

microbiology↗

bioRxiv2026

Pathogenesis and natural history of the Bundibugyo species of Orthoebolavirus in nonhuman primates

The current outbreak of Bundibugyo virus (BDBV) in Africa is a global public health concern particularly as there are no licensed medical countermeasures (MCM). Well characterized animal models that accurately replicate human BDBV infection are needed to develop effective MCM. We exposed 21 cynomolgus monkeys (CM) to BDBV to examine the progression and natural history of BDBV disease (BVD). BVD was more protracted than reported for Ebola and Sudan infection in CM with a lower lethality rate of 67% consistent with lower human BVD mortality rates. IHC and spatial proteomics identified CD209+, CD68+, and/or HLA-DR+ macrophages and dendritic cells as early targets of BDBV. These infected cells frequently colocalized with fibrin and infiltrating MPO+ neutrophils and S100A9+ myeloid-derived suppressor cells, consistent with the development of an active inflammatory response and early coagulopathy. Transcriptomic and proteomic analyses of the circulating immune response correspondingly reflected a cytokine-driven hyperinflammatory state in CM that succumbed to disease. Surviving animals resolved systemic inflammation by the study endpoint; however, BDBV antigen was identified in immune privileged tissues with lesion-associated inflammation aligning with known post-Ebola sequela in humans. This data should assist in identifying weaknesses in the disease course that can be exploited to develop new MCM.

microbiology↗

bioRxiv2026

Finding the Goldilocks zone: Modulating glycoprotein cleavage and fusogenicity optimizes the efficacy of a candidate Crimean-Congo hemorrhagic fever virus vaccine

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 in vivo 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.

microbiology↗

bioRxiv2022

Reversion of Ebolavirus Disease from a Single Intramuscular Injection of a pan-Ebolavirus Immunotherapeutic

Intravenous administration (IV) of antiviral monoclonal antibodies (mAbs) is challenging due to limited resources for performing infusions during an ongoing epidemic. An ebolavirus therapeutic administered via intramuscular (IM) injection would reduce these burdens and allow rapid treatment of exposed individuals during an outbreak. Here, we demonstrate how MBP134, a two mAb pan-ebolavirus cocktail, reverses the course of Sudan ebolavirus (SUDV/Gulu) disease with a single IV or IM dose in non-human primates (NHPs) as far as five days post-exposure. Furthermore, we investigated the utility of adding half-life extension mutations to the MBP134 mAbs, ultimately creating a half-life extended cocktail designated MBP431. MBP431 demonstrated an extended serum half-life in vivo and offered complete or significant protection with a single IM dose delivered as a post-exposure prophylactic (PEP) or therapeutic in NHPs challenged with EBOV. These results support the use of MBP431 as a rapidly deployable IM medical countermeasure against every known ebolavirus.

microbiology↗