Biology subjects

Borisevich, V.

Publications and source records attributed to Borisevich, V..

13 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

Oral 4`fluorouridine provides postexposure protection against lethal Nipah virus infection

There are no approved medical countermeasures for combatting Nipah virus (NiV) which causes regular outbreaks in humans and animals in South and Southeast Asia with mortality rates in humans ranging from 40% to more than 90%. Recently, it was shown that 4-fluorouridine (4-FlU; EIDD-2749), an orally available ribonucleoside analog, protected guinea pigs and nonhuman primates from lethal challenge with Lassa virus and that 4-FlU has in vitro antiviral activity against NiV. Here, we assessed the postexposure protective efficacy of 4-FlU in a lethal hamster model of NiV infection. Daily treatment with 4-FlU beginning 3 days after exposure to NiV resulted in complete protection from lethal infection. Our findings support the further development of 4-FlU as a therapy for NiV disease.

microbiology↗

bioRxiv2022

A highly attenuated Vesiculovax vaccine rapidly protects nonhuman primates against lethal Marburg virus challenge

BackgroundMarburg virus (MARV), an Ebola-like virus, remains an eminent threat to public health as demonstrated by its high associated mortality rate (23-90%) and recent emergence in West Africa for the first time. Although a recombinant vesicular stomatitis virus (rVSV)-based vaccine (Ervebo) is licensed for Ebola virus disease (EVD), no approved countermeasures exist against MARV. Results from clinical trials indicate Ervebo prevents EVD in 97.5-100% of vaccinees 10 days onwards post-immunization. Methodology/FindingsGiven the rapid immunogenicity of the Ervebo platform against EVD, we tested whether a similar, but highly attenuated, rVSV-based Vesiculovax vector expressing the glycoprotein (GP) of MARV (rVSV-N4CT1-MARV-GP) could provide swift protection against Marburg virus disease (MVD). Here, groups of cynomolgus monkeys were vaccinated 7, 5, or 3 days before exposure to a lethal dose of MARV (Angola variant). All subjects (100%) immunized one week prior to challenge survived; 80% and 20% of subjects survived when vaccinated 5- and 3-days pre-exposure, respectively. Lethality was associated with higher viral load and aberrant innate immunity signaling, whereas survival correlated with development of MARV GP-specific antibodies and early expression of NK cell-, B-cell-, and cytotoxic T-cell-related transcriptional signatures. Conclusions/SignificanceThese results emphasize the utility of Vesiculovax vaccines for MVD outbreak management. The highly attenuated nature of rVSV-N4CT1 vaccines, which are clinically safe in humans, may be preferable to vaccines based on the same platform as Ervebo (rVSV "delta G" platform), which in some trial participants induced vaccine-related adverse events in association with viral replication including arthralgia/arthritis, dermatitis, and cutaneous vasculitis. Author SummaryMarburg virus (MARV) is one of the deadliest viruses known to man. One of the most effective vaccines against this pathogen uses a recombinant vesicular stomatitis virus (rVSV) platform to express MARV glycoprotein (GP) immunogen. As rVSV-based vaccines may be used as medical interventions to mitigate or prevent outbreaks of MARV, defining the time window needed to elicit protection is vital. Here, a rVSV vector expressing MARV glycoprotein (rVSV-N4CT1-MARV-GP) fully protected nonhuman primates from lethality and disease when given as soon as 1 week prior to exposure. At 5- and 3-days pre-exposure, partial protection (80% and 20% survival, respectively) was achieved. Vaccination with rVSV-N4CT1-MARV-GP appears to "jump-start" the immune system to allow sufficient time for MARV-specific adaptive responses to form. This fast- acting vaccine is based on a similar platform as Ervebo, the only FDA- and EU-approved vaccine for preventing Ebola virus infection. The rVSV-N4CT1-MARV-GP vaccine features additional attenuations in the rVSV backbone that may contribute to a more acceptable safety profile in vaccinees, as Ervebo in some recipients induced vaccine- related adverse events including rashes and joint pain.

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↗

bioRxiv2021

Natural history of nonhuman primates after conjunctival exposure to Ebola virus

Transmission of Ebola virus (EBOV) primarily occurs via contact exposure of mucosal surfaces with infected body fluids. Historically, nonhuman primate (NHP) challenge studies have employed intramuscular or small particle aerosol exposure, which are uniformly lethal routes of infection, but mimic worst-case scenarios such as a needlestick. When exposed by more likely routes of natural infection, limited NHP studies have shown delayed onset of disease and reduced mortality. Here we performed a series of systematic natural history studies in cynomolgus macaques with a range of conjunctival exposure doses. Challenge with 10,000 plaque forming units (PFU) of EBOV was uniformly lethal, whereas 5/6 subjects survived low and moderate dose challenges (100 or 500 PFU). Conjunctival challenge resulted in a protracted time-to death. Asymptomatic disease was observed in survivors with limited detection of EBOV replication. Inconsistent seropositivity in survivors may suggest physical or natural immunological barriers are sufficient to prevent widespread viral dissemination.

microbiology↗

bioRxiv2021

Protective pan-ebolavirus combination therapy by two multifunctional human antibodies

Ebolaviruses cause a severe and often fatal illness with the potential for global spread. Monoclonal antibody-based treatments that have become available recently have a narrow therapeutic spectrum and are ineffective against ebolaviruses other than Ebola virus (EBOV), including medically important Bundibugyo (BDBV) and Sudan (SUDV) viruses. Here we report the development of a therapeutic cocktail comprising two broadly neutralizing human antibodies rEBOV-515 and rEBOV-442 that recognize non-overlapping sites on the ebolavirus glycoprotein (GP). Antibodies in the cocktail exhibited synergistic neutralizing activity and resisted viral escape, and they were optimized for their Fc-mediated effector function activities. The cocktail protected non-human primates from ebolavirus disease caused by EBOV, BDBV, or SUDV with high therapeutic effectiveness. High-resolution structures of the cocktail antibodies in complex with GP revealed the molecular determinants for neutralization breadth and potency. This study provides advanced preclinical data to support clinical development of this cocktail for pan-ebolavirus therapy.

immunology↗

bioRxiv2021

Functional cooperativity mediated by rationally selected combinations of human monoclonal antibodies targeting the henipavirus receptor binding protein

Hendra virus (HeV) and Nipah virus (NiV), the prototypic members of the Henipavirus (HNV) genus, are emerging, zoonotic paramyxoviruses known to cause severe disease across six mammalian orders, including humans (Eaton et al., 2006). While several research groups have made strides in developing candidate vaccines and therapeutics against henipaviruses, such countermeasures have not been licensed for human use, and significant gaps in knowledge about the human immune response to these viruses exist. To address these gaps, we isolated a large panel of human monoclonal antibodies (mAbs) from the B cells of an individual with prior occupation-related exposure to the equine HeV vaccine (Equivac(R) HeV). Competition-binding and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies identified at least six distinct antigenic sites on the HeV/NiV receptor binding protein (RBP) that are recognized by human mAbs. Antibodies recognizing multiple antigenic sites potently neutralized NiV and/or HeV isolates in vitro. The most potent class of cross-reactive antibodies achieved neutralization by blocking viral attachment to the host cell receptors ephrin-B2 and ephrin-B3. Antibodies from this class mimic receptor binding by inducing a receptor-bound conformation to the HeV-RBP protein tetramer, exposing an epitope that appears to lie hidden in the interface between protomers within the HeV-RBP tetramer. Antibodies that recognize this cryptic epitope potently neutralized HeV and NiV. Flow cytometric studies using cell-surface-displayed HeV-RBP protein showed that cross-reactive, neutralizing mAbs from each of these classes cooperate for binding. In a highly stringent hamster model of NiVB infection, antibodies from both classes reduced morbidity and mortality and achieved synergistic protection in combination and provided therapeutic benefit when combined into two bispecific platforms. These studies identified multiple candidate mAbs that might be suitable for use in a cocktail therapeutic approach to achieve synergistic antiviral potency and reduce the risk of virus escape during treatment.

immunology↗

bioRxiv2020

Use of convalescent serum reduces severity of COVID-19 in nonhuman primates

Passive transfer of convalescent plasma or serum is a time-honored strategy for treating infectious diseases. Human convalescent plasma containing antibodies against SARS-CoV-2 is currently being used to treat COVID-19 patients. However, most patients have been treated outside of randomized clinical trials making it difficult to determine the efficacy of this approach. Here, we assessed the efficacy of convalescent sera in a newly developed African green monkey model of COVID-19. Groups of SARS-CoV-2-infected animals were treated with pooled convalescent sera containing either high or low to moderate anti-SARS-CoV-2 neutralizing antibody titers. Differences in viral load and disease pathology were minimal between monkeys that received the lower titer convalescent sera and untreated controls. However, and importantly, lower levels of SARS-CoV-2 in respiratory compartments, reduced gross and histopathological lesion severity in the lungs, and reductions in several parameters associated with coagulation and inflammatory processes were observed in monkeys that received convalescent sera versus untreated controls. Our data support human studies suggesting that convalescent plasma therapy is an effective strategy if donors with high level of antibodies against SARS-CoV-2 are employed and if recipients are at an early stage of disease.

microbiology↗

bioRxiv2020

LY-CoV555, a rapidly isolated potent neutralizing antibody, provides protection in a non-human primate model of SARS-CoV-2 infection

SARS-CoV-2 poses a public health threat for which therapeutic agents are urgently needed. Herein, we report that high-throughput microfluidic screening of antigen-specific B-cells led to the identification of LY-CoV555, a potent anti-spike neutralizing antibody from a convalescent COVID-19 patient. Biochemical, structural, and functional characterization revealed high-affinity binding to the receptor-binding domain, ACE2 binding inhibition, and potent neutralizing activity. In a rhesus macaque challenge model, prophylaxis doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract. These data demonstrate that high-throughput screening can lead to the identification of a potent antiviral antibody that protects against SARS-CoV-2 infection. One Sentence SummaryLY-CoV555, an anti-spike antibody derived from a convalescent COVID-19 patient, potently neutralizes SARS-CoV-2 and protects the upper and lower airways of non-human primates against SARS-CoV-2 infection.

immunology↗

bioRxiv2020

Establishment of an African green monkey model for COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an unprecedented global pandemic of COVID-19. Animal models are urgently needed to study the pathogenesis of COVID-19 and to screen candidate vaccines and treatments. Nonhuman primates (NHP) are considered the gold standard model for many infectious pathogens as they usually best reflect the human condition. Here, we show that African green monkeys support a high level of SARS-CoV-2 replication and develop pronounced respiratory disease that may be more substantial than reported for other NHP species including cynomolgus and rhesus macaques. In addition, SARS-CoV-2 was detected in mucosal samples of all animals including feces of several animals as late as 15 days after virus exposure. Importantly, we show that virus replication and respiratory disease can be produced in African green monkeys using a much lower and more natural dose of SARS-CoV-2 than has been employed in other NHP studies.

microbiology↗

bioRxiv2020

Prior vaccination with the rVSV-ZEBOV vaccine does not interfere with but improves the efficacy of postexposure antibody treatment in nonhuman primates exposed to Ebola virus

A replication-competent, vesicular stomatitis virus vaccine expressing the Ebola virus (EBOV) glycoprotein (GP) (rVSV-ZEBOV) was successfully used during the 2013-16 EBOV epidemic1. Additionally, chimeric and human monoclonal antibodies (mAb) against the EBOV GP showed promise in animals and EBOV patients when administered therapeutically2-6. Given the large number of at-risk humans being prophylactically vaccinated with rVSV-ZEBOV, there is uncertainty regarding whether vaccination would preclude use of antibody treatments in the event of a known exposure of a recent vaccinee. To model a worst-case scenario, we performed a study using rhesus monkeys vaccinated or unvaccinated with the rVSV-ZEBOV vaccine. One day after vaccination, animals were challenged with a uniformly lethal dose of EBOV. Five vaccinated animals and five unvaccinated animals were then treated with the anti-EBOV GP mAb-based therapeutic MIL77 starting 3 days postexposure. Additionally, five vaccinated macaques received no therapeutic intervention. All five macaques that were vaccinated and subsequently treated with MIL77 showed no evidence of clinical illness and survived challenge. In contrast, all five animals that only received the rVSV-ZEBOV vaccine became ill and 2/5 survived; all five macaques that only received MIL77 only also became ill and 4/5 survived. Enhanced efficacy of vaccinated animals that were treated with MIL77 was associated with delayed EBOV viremia attributed to the vaccine. These results suggest that rVSV-ZEBOV augments immunotherapy.

microbiology↗

bioRxiv2018

Two-antibody pan-ebolavirus cocktail confers broad therapeutic protection in ferrets and nonhuman primates

All available experimental vaccines and immunotherapeutics1,2 against Ebola virus (EBOV), including rVSV-ZEBOV3 and ZMappTM4, lack activity against other ebolaviruses associated with human disease outbreaks. This year, two separate outbreaks of EBOV in the Democratic Republic of Congo underscored the unpredictable nature of ebolavirus reemergence in a region that has historically experienced outbreaks of the divergent ebolaviruses Sudan virus (SUDV) and Bundibugyo virus (BDBV)5. Here we show that MBP134AF, a pan-ebolavirus therapeutic comprising two broadly neutralizing human antibodies (bNAbs)6,7(see companion manuscript, Wec et al.) could protect against lethal EBOV, SUDV, and BDBV infection in ferrets and nonhuman primates (NHPs). MBP134AF not only not only establishes a viable therapeutic countermeasure to outbreaks caused by antigenically diverse ebolaviruses but also affords unprecedented effectiveness and potency--a single 25-mg/kg dose was fully protective in NHPs. This best-in-class antibody cocktail is the culmination of an intensive collaboration spanning academia, industry and government in response to the 2013-2016 EBOV epidemic6,7 and provides a translational research model for the rapid development of immunotherapeutics targeting emerging infectious diseases.

microbiology↗