RARE DISEASE
Hantavirus pulmonary syndrome
Hantavirus pulmonary syndrome
Hantavirus pulmonary syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Hantavirus Pulmonary Syndrome (HPS) is a severe respiratory illness caused by New World hantaviruses, primarily transmitted via inhalation of aerosolized rodent excreta. Initial flu-like symptoms (fever, myalgia, gastrointestinal distress) progress rapidly to cardiopulmonary failure due to vascular leakage and non-cardiogenic pulmonary edema. Case fatality rates reach 38–40% despite aggressive care [1][4][17]. Diagnosis relies on clinical suspicion, serology, and PCR. Early ICU admission for hemodynamic and respiratory support is critical [1][6].
Burden
Global: ~200,000 annual hantavirus infections (HPS and HFRS) [9][12]; U.S. averages 30 HPS cases/year [17].
Mortality: 38–40% in HPS, with 90% of deaths occurring within 48 hours of cardiopulmonary phase onset [4][17][18].
Long-term morbidity: Survivors often experience residual fatigue, exertional dyspnea, and renal impairment for months [4][16].
Therapies
Supportive care: Mechanical ventilation (50% of cases), vasopressors, and cautious fluid management to prevent pulmonary edema [1][6][16].
ECMO: Early initiation improves survival to 80% in severe cardiopulmonary collapse [1][4].
No antivirals: Ribavirin ineffective in late-stage HPS; investigational therapies include neutralizing antibodies and siRNA [3][8][16].
Categories: rare infectious diseases
Research Papers
318 drug discovery papers about Hantavirus pulmonary syndrome, with 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
318 drug discovery papers about Hantavirus pulmonary syndrome, with 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-03 | Angiopoietin-1/Tie2 Activation as a Therapeutic Hypothesis for Hantavirus-Induced Vascular Permeability
Severe hantavirus infection produces extensive vascular leakage, driven by a combination of endothelial dysfunction, dysregulated inflammation, VEGF-mediated hyperpermeability, angiopoietin imbalance, and degradation of the endothelial glycocalyx. This narrative review draws on the peer-reviewed literature, with particular attention to work published between 2016 and 2026, to examine how hantavirus-induced vascular permeability arises in hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), and how Angiopoietin-1 (Ang-1)/Tie2 signaling and glycocalyx injury contribute to endothelial barrier failure. Direct hantavirus evidence shows that Ang-1 inhibits hantavirus-directed endothelial permeability in vitro and that angiopoietin dysregulation tracks with disease severity in patients; findings that Tie2 activation curbs vascular leakage in sepsis and other non-hantavirus models are mechanistically suggestive but remain inferential rather than hantavirus-specific. No hantavirus animal model or clinical trial has yet evaluated Ang-1/Tie2-directed therapy, so this review treats the approach as a testable hypothesis rather than an established or recommended treatment; confirming its therapeutic value will require dedicated hantavirus-specific animal and clinical studies.
2026-05-19 | Cytokine storm dynamics in hantavirus pulmonary syndrome: a multiscale ODE model with Wasserstein early-warning score and application to the 2026 Andes virus outbreak
Abstract Background The ongoing Andes hantavirus outbreak linked to the cruise ship MV Hondius (April−May 2026, seven confirmed cases, three deaths, patients hospitalised across six countries including France) highlights the urgent need for mechanistic tools to predict which hantavirus pulmonary syndrome (HPS) patients will progress to fatal cytokine storm. Methods We present a 14-variable antigen-gated ordinary differential equation (ODE) model integrating viral dynamics, CD8 + cytotoxic T lymphocyte (CTL) expansion, four cytokines (TNF-α, IFN-γ, IL-6, IL-10), VEGF-mediated vascular permeability, and platelets. We derive two reproduction numbers: the viral invasion number ℛ 0 and the immunopathological loop gain ℛ ip . We apply Villani’s hypocoercivity theory and the HWI optimal transport inequality to prove that the spectral gap of the CTL-IFN-γ feedback loop collapses to zero at a critical infected endothelial cell count , providing a computable early-warning threshold. We define a Wasserstein patient stratification score from six clinically observable variables. Results At default parameters ( ℛ 0 = 0.396, ℛ ip = 1.875): (1) the DFE is locally asymptotically stable—the virus self-limits—but the CTL-IFN-γ loop has sufficient gain to amplify autonomously once established; (2) the storm-block spectral gap collapses exactly to zero at cells μ L −1 —a threshold attained within hours of infection onset, confirming that immunopathological amplification is essentially unavoidable; (3) rises 1-2 days before P ( t ) reaches clinical threshold, providing an early-warning window; (4) exogenous IL-10 supplementation is the single most effective intervention (predicted 40% reduction in peak permeability), outperforming corticosteroid immunosuppression and ECMO; the combination of all three applied at day 7 reduces peak permeability below the fatal threshold. Conclusions This framework predicts that HPS cytokine storm is a structural consequence of ℛ ip > 1 rather than excessive viral load, explaining death after viral clearance. For clinicians managing MV Hondius Andes virus patients today, the model identifies a six-variable triage score and a day-7 IL-10-centred therapeutic window as the highest-priority clinical targets. Full code is open source.
2026-05-17 | THE RODENT RECEPTOR CODE: A HOST-ENCODED Β3- INTEGRIN DECOY DOMAIN DICTATES HANTAVIRUS PATHOGENICITY
ABSTRACTHantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome(HPS) in humans, with case-fatality rates reaching 10-15% for HFRS and 40-60% for HPS, yet remaincompletely asymptomatic in their reservoir rodent hosts. The molecular basis of this host-specificpathogenicity has remained one of the most enigmatic questions in hantavirology.Here, we demonstrate that a single amino acid polymorphism at position 39 of the β3-integrin plexinsemaphorin-integrin (PSI) domain — Aspartate in humans versus Asparagine in all eight major reservoirspecies — functions as a molecular switch that couples hantavirus glycoprotein binding to downstream propermeability signaling. We cloned β3-integrin PSI domains from all eight reservoir species (Apodemusagrarius, A. flavicollis, Rattus norvegicus, Myodes glareolus, Microtus arvalis, Peromyscus maniculatus,Oligoryzomys longicaudatus, and Homo sapiens) and showed that rodent PSI peptides bind hantavirus Gn/Gc envelope glycoproteins with high affinity but fail to activate the FAK/Src/PI3K/Akt/VEGF-mTORpermeability axis. In contrast, human β3-integrin engagement by Gn/Gc triggers robust signaling, adherensjunction disruption, and vascular leakage.Leveraging this mechanistic insight, we designed soluble "decoy" peptides mimicking the rodent Asn-39PSI domain that competitively inhibit hantavirus entry into human endothelial cells with IC50 values of0.5-1.2 μg/ml and selectivity indices exceeding 500x. In the Syrian hamster model of lethal Andes virus(ANDV) infection, prophylactic administration of Decoy-2 (derived from M. glareolus) conferred 70%survival versus 0% in vehicle controls (p < 0.001), reduced tissue viral loads by >3 log10 copies/g,suppressed cytokine storm, and preserved pulmonary and renal histopathology. These findings identify thefirst host-encoded viral entry decoy, establish the "rodent receptor code" as the mechanistic basis ofreservoir asymptomaticity, and provide a first-in-class hantavirus-specific therapeutic candidate currentlyabsent from the clinical armamentarium.Keywords: hantavirus, β3-integrin, PSI domain, decoy peptide, vascular permeability, host-pathogen evolution,translational therapeutics
2024-08-01 | Innate lymphoid cells are activated in HFRS, and their function can be modulated by hantavirus-induced type I interferons.
Hantaviruses cause the acute zoonotic diseases hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Infected patients show strong systemic inflammation and immune cell activation. NK cells are highly activated in HFRS, suggesting that also other innate lymphoid cells (ILCs) might be responding to infection. Here, we characterized peripheral ILC responses, and measured plasma levels of soluble factors and plasma viral load, in 17 Puumala virus (PUUV)-infected HFRS patients. This revealed an increased frequency of ILC2 in patients, in particular the ILC2 lineage-committed c-Kitlo ILC2 subset. Patients' ILCs showed an activated profile with increased proliferation and displayed altered expression of several homing markers. How ILCs are activated during viral infection is largely unknown. When analyzing PUUV-mediated activation of ILCs in vitro we observed that this was dependent on type I interferons, suggesting a role for type I interferons-produced in response to virus infection-in the activation of ILCs. Further, stimulation of naïve ILC2s with IFN-β affected ILC2 cytokine responses in vitro, causing decreased IL-5 and IL-13, and increased IL-10, CXCL10, and GM-CSF secretion. These results show that ILCs are activated in HFRS patients and suggest that the classical antiviral type I IFNs are involved in shaping ILC functions.
2024-02-07 | Production and Purification of Hantavirus Glycoproteins in Drosophila melanogaster S2 Cells.
Hantaviruses, are rodent-borne viruses found worldwide that are transmitted to humans through inhalation of contaminated excreta. They can cause a renal or a pulmonary syndrome, depending on the virus, and no effective treatment is currently available for either of these diseases. Hantaviral particles are covered by a protein lattice composed of two glycoproteins (Gn and Gc) that mediate adsorption to target cells and fusion with endosomal membranes, making them prime targets for neutralizing antibodies. Here we present the methodology to produce soluble recombinant glycoproteins in different conformations, either alone or as a stabilized Gn/Gc complex, using stably transfected Drosophila S2 cells.
antibodies
2026-09-21 | Immunopathogenesis of vascular leakage in hantavirus infections: a systematic review of mechanisms underlying HPS and HFRS
Hantavirus infections manifest as Hantavirus Pulmonary Syndrome (HPS) and Hemorrhagic Fever with Renal Syndrome (HFRS), both associated with increased vascular permeability despite the lack of direct cytopathic injury to endothelial cells. A systematic search of PubMed, Scopus, and Web of Science (January 2020–May 2026) identified human studies investigating immunopathogenic mechanisms in HPS or HFRS. Due to substantial heterogeneity across study designs, findings were synthesized descriptively. Forty-one studies (39 cohorts, 2 case–control) were included, predominantly on HFRS-associated hantaviruses (HTNV, PUUV, DOBV); only one study evaluated HPS-associated ANDV. The reviewed literature revealed elevated inflammatory cytokines (IL-6, IL-18, CXCL10, CX3CL1), depletion of Mucosal-Associated Invariant T (MAIT) cells linked to IRE1αdependent pyroptosis, disruption of the endothelial glycocalyx, and coagulation disturbances with platelet dysfunction. Biomarkers of glycocalyx injury (heparan sulfate, chondroitin sulfate, and soluble thrombomodulin) were associated with increased mortality risk (AUC 0.87–0.93). No human mechanistic studies on Sin Nombre virus (SNV) were identified. Hantavirus-induced vascular leakage is driven by cytokine-mediated endothelial dysfunction, MAIT cell pyroptosis, glycocalyx degradation, and immunothrombosis. While HFRS mechanisms are now well-characterized, the absence of human mechanistic data for HPS—particularly for SNV—remains a critical gap.
2026-08-01 | Hantavirus Disease in the Emergency Department: Evidence-Informed Nursing Priorities for Recognition, Stabilization, and Infection Prevention
Hantavirus disease is an uncommon zoonotic infection that can progress rapidly from a nonspecific febrile illness to life-threatening cardiopulmonary or renal dysfunction. In the Americas, hantavirus cardiopulmonary syndrome (HCPS), also termed hantavirus pulmonary syndrome (HPS), is characterized by increased vascular permeability, pulmonary edema, hypoxemia, and circulatory failure, whereas hemorrhagic fever with renal syndrome (HFRS), encountered predominantly in Europe and Asia, is distinguished by acute kidney injury, thrombocytopenia, and variable hemorrhagic manifestations (1-3). The emergency department is an important point of recognition because patients may initially present with fever, myalgia, gastrointestinal symptoms, or headache before respiratory or hemodynamic deterioration becomes apparent. Emergency nurses participate in exposure assessment, serial physiologic observation, implementation of supportive-care protocols, fluid-balance surveillance, recognition of respiratory and circulatory deterioration, and infection-prevention measures. However, nursing-specific outcome evidence identified by the targeted search used for this mini-review is limited; the nursing role should therefore be derived cautiously from established clinical-management principles rather than presented as independently proven to improve survival. This mini-review examines evidence relevant to emergency nursing practice, including 2026 publications on critical-care management, prognosis, outbreak response, and healthcare-worker exposure. It emphasizes early recognition of HCPS, monitoring during the transition to cardiopulmonary failure, careful fluid and hemodynamic management, escalation to critical care, renal surveillance in HFRS, and infection prevention in suspected Andes virus infection. The multinational Andes virus outbreak linked to expedition cruise travel in 2026 was declared contained by WHO on 2 July 2026; nevertheless, the event illustrates the need for emergency departments to maintain operational readiness for an uncommon but potentially severe infection in which limited person-to-person transmission is operationally relevant (7,21).
2026-07-31 | The Changing Landscape of Hantavirus Infections: A Narrative Review of Epidemiology, Pathogenesis, and Countermeasures.
Hantaviruses are emerging zoonotic pathogens of increasing global public health significance. Their epidemiological landscape is rapidly changing due to ecological disruption, climate variability, urbanisation, and evolving human-animal interfaces. This narrative review synthesises current knowledge on hantavirus virology, epidemiology, pathogenesis, clinical management, and emerging countermeasures, with a focus on developments from the past 5 years. Traditionally classified into Old World viruses causing haemorrhagic fever with renal syndrome (HFRS) and New World viruses causing hantavirus cardiopulmonary syndrome (HCPS), this dichotomy has become increasingly blurred, with overlapping renal and pulmonary manifestations now recognized. Among the most consequential recent advances is the consolidated evidence for person-to-person transmission of Andes virus, documented among household contacts and during the prodromal phase, with viral shedding in respiratory secretions. Endothelial dysfunction remains the pathological hallmark of severe disease, driven by VEGF sensitisation, Src kinase and RhoA pathway activation, pericyte infection, and dysregulated inflammatory responses including IL-6 trans-signalling. Concurrently, environmental and ecological studies have linked climate change, rodent population dynamics, land-use modification, and urbanisation to increased human disease risk across multiple continents. Diagnostic strategies continue to rely on serology and molecular testing, while management remains predominantly supportive, with extracorporeal membrane oxygenation (ECMO) improving survival in fulminant HCPS. Importantly, recent structural virology advances have enabled the development of broadly neutralising monoclonal antibodies targeting conserved quaternary epitopes, as well as next-generation vaccine platforms including DNA, mRNA, and prefusion-stabilised glycoprotein candidates. Hantaviruses represent a paradigmatic One Health challenge at the intersection of environmental change, viral evolution, and global interconnectedness. Despite major progress in understanding transmission dynamics and endothelial pathogenesis, critical gaps remain regarding determinants of person-to-person spread, long-term post-infection sequelae, and the absence of licenced broadly protective vaccines or specific antiviral therapies. Future preparedness will require integrated surveillance frameworks combining ecological monitoring, genomic epidemiology, and clinical readiness within coordinated international public health strategies.
2026-07-25 | Hantavirus: A Comprehensive Narrative Review of Virology, Epidemiology, Pathogenesis, Clinical Manifestations, Diagnostics, and Emerging Therapeutic Strategies.
Hantaviruses are a genus of negative-sense, single-stranded, tri-segmented RNA viruses that are distributed worldwide. They cause two severe zoonotic diseases in humans: haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), also known as hantavirus cardiopulmonary syndrome (HCPS). Hantaviruses are primarily spread by inhaling aerosolised excreta from infected rodent reservoirs. Over 50 rodent species on six continents have been found to carry hantaviruses, with only one reported case of human-to-human transmission, involving the Andes virus (ANDV) in South America. HFRS is estimated to cause 100,000-150,000 cases worldwide annually, mainly in Asia and Europe. HPS/HCPS is far less common, with case fatality rates of 25%-40%, predominantly in the Americas. The pathogenesis of hantaviral disease is characterised by viral infection of endothelial cells, dysregulation of vascular permeability, and dysregulated innate and adaptive immune responses, leading to cytokine storm physiology. Diagnosis relies on enzyme-linked immunosorbent assay (ELISA)-based serology and reverse transcription polymerase chain reaction (RT-PCR). Strain characterisation and outbreak investigations are increasingly being performed using next-generation sequencing. No hantavirus species has a licenced vaccine outside of HTNV and SEOV, for which inactivated rodent-brain-derived vaccines remain in limited regional use in Korea and China. Regulatory-agency-approved antiviral therapy is similarly lacking worldwide, and management remains largely supportive. Ribavirin has shown benefit in reducing mortality and renal morbidity in HFRS when initiated early, but has not demonstrated efficacy in HPS/HCPS in controlled trials. Recent advancements include the development of monoclonal antibodies, candidate mRNA and subunit vaccines, and an improved understanding of the mechanisms of immune evasion. This review synthesises the latest information on hantavirus biology, clinical medicine and public health. This highlights the critical gaps that must be addressed to counter the growing threat posed by this pathogen in an era of climate change and global ecological transformation.
2026-07-16 | Hantavirus cardiopulmonary syndrome in children: a systematic scoping review of presentation, critical care management, and outcomes.
Pediatric hantavirus cardiopulmonary syndrome/hantavirus pulmonary syndrome (HCPS/HPS) is rare but can progress rapidly from a nonspecific febrile prodrome to respiratory failure, shock, and multiorgan dysfunction. Pediatric-specific evidence is limited, and a comprehensive map of the clinical literature is lacking. We conducted a systematic scoping review per Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidance (protocol registered at DOI:10.17605/OSF.IO/MZDN4). PubMed/MEDLINE, Embase, Scopus, Web of Science, and Cochrane CENTRAL were searched from inception to May 2026. Eligible reports described children or adolescents (age ≤18 years) with HCPS/HPS and extractable pediatric clinical data. Two reviewers independently screened records, assessed overlap, extracted data, and appraised reporting quality using Joanna Briggs Institute tools. Of 2208 database records, 20 reports were included in the core pediatric synthesis after removal of 976 duplicates and screening. Reports were concentrated in the Americas. Recurrent features included fever, gastrointestinal symptoms, myalgia, thrombocytopenia, hemoconcentration, pulmonary edema, respiratory failure, and shock. Severe cases required mechanical ventilation, vasoactive support, extracorporeal membrane oxygenation, and in some cases renal replacement therapy. Larger pediatric case series and surveillance-level reports reported mortality of approximately 33% to 37%. Evidence was predominantly case-based with variable reporting completeness. Pediatric HCPS/HPS is rare but potentially rapidly fatal. Early suspicion in endemic regions or after rodent exposure, with prompt supportive critical care and timely consideration of advanced cardiopulmonary support, is central to management.
vaccines
2026-08-13 | Broad-Spectrum Multi-Epitope Design Targeting Conserved Hantavirus Glycoproteins (Gn/Gc): Chimeric Antigen Engineering and Structural Mapping.
Hantaviruses, the etiological agents of hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), represent a high-risk zoonotic threat with substantial global health impact. Currently, there is no FDA-approved vaccine. The viral surface glycoprotein (GP) is crucial for host cell entry and is regarded as a key target for vaccine development. However, its variability among hantavirus species limits the effectiveness of conventional vaccine strategies. Epitope-based vaccines offer a promising alternative by enabling the design of broadly protective constructs. In this study, we applied immunoinformatics approaches to design a universal multi-epitope vaccine candidate targeting both HFRS- and HPS-associated hantaviruses through a multi-layered workflow integrating B-cell and T-cell epitope prediction, antigenicity scoring, IFN-γ induction potential, conservation analysis, and population coverage assessment. Viral GPs from SEOV, PUUV, SNV, and ANDV were analyzed using algorithms for B-cell and T-cell epitope prediction. Predicted epitopes were assessed for allergenicity, toxicity, conservation, and population coverage. Two vaccine constructs incorporating β-defensin or 50S ribosomal protein L7/L12 as adjuvants were assessed for physicochemical properties, structural stability and immunogenic potential. Molecular docking analyses provided exploratory ectodomain-compatibility screening, suggesting potential interactions with TLR4 that require future experimental confirmation. The in silico immune simulations suggested potential robust and long-lasting responses with memory cell persistence exceeding one year. Simulations also indicated balanced humoral and cellular responses, robust antibody production, and long-term memory formation suggestive of durable protective immunity. These findings support the rational design of broad-spectrum multi-epitope vaccines against genetically diverse hantaviruses, offering a rational framework for preclinical development of next-generation universal vaccines against hantavirus-associated diseases.
2026-01-01 | The Use of Artificial Intelligence to Create a Model for the Vaccine Against the Hantavirus
The Use of Artificial Intelligence to Create a Model for the Vaccine Against the Hantavirus Carlo Lazzari1*, Marco Rabottini1 1Department of Experimental Pharmacology, International Centre for Healthcare and Medical Education (ICHME), London, United Kingdom *Correspondence: Carlo Lazzari, email: carlolazzari2015@gmail.com Abstract Background — Hantaviruses are globally distributed zoonotic pathogens responsible for Hemorrhagic Fever with Renal Syndrome (HFRS) and Hantavirus Pulmonary Syndrome (HPS). Maintained in rodent reservoirs and transmitted through aerosolised excreta, they remain a persistent public health threat. Their enveloped structure, incorporating Gn/Gc glycoproteins and ribonucleoprotein complexes, complicates traditional vaccine development. Recent advances in AI driven vaccinology offer new strategies for identifying antigenic determinants and designing safer, more immunogenic constructs. Methods — An integrated AI computational pipeline combined structural modelling, reverse vaccinology, and immunoinformatics. Glycoprotein sequences from representative hantaviruses were modelled to predict conformational features. Deep learning algorithms identified high affinity B cell epitopes and T cell epitopes, which were assembled into a multi epitope construct. Allergenicity, toxicity, and population coverage were computationally screened, and immune simulations assessed predicted host responses. Results — The AI generated construct demonstrated high predicted antigenicity, favourable physicochemical stability, and non allergenic, non toxic profiles. Structural modelling confirmed appropriate folding and solvent exposure of key epitopes. Immune simulations suggested strong induction of humoral and cellular responses, including memory cell formation. Conclusions — AI enabled vaccine design provides a rapid, rational framework for developing next generation hantavirus vaccines. By integrating molecular virology with machine learning, this approach accelerates antigen discovery and construct optimisation. The findings support AI as a transformative tool for emerging pathogen vaccine development and highlight its potential to overcome longstanding barriers in hantavirus prevention.
2025-02-26 | Achievement and Challenges in Orthohantavirus Vaccines.
Orthohantaviruses (also known as hantaviruses) are pathogens that cause two distinct, yet related forms of severe human disease: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). These diseases pose a significant threat to global public health due to their high case fatality rates, which can range from 1% to 50%. In recent years, an increasing number of countries and regions have reported human cases, underscoring the urgent need for improved understanding, prevention, and treatment strategies. Given the severity of these diseases and the lack of specific post-exposure antiviral treatments, preventive measures are critical. For several decades, substantial efforts have been dedicated to developing orthohantavirus vaccines, leading to significant advancements. The first large-scale deployment involved inactivated vaccines, which played a crucial role in reducing HFRS incidence in South Korea and China. Subunit vaccines, viral vector vaccines, and virus-like particle (VLP) vaccines have also been extensively researched. Nucleic acid vaccines, including both mRNA and DNA vaccines, hold the greatest potential for future development due to their rapid design and production cycles, ability to elicit robust immune responses, ease of storage and transportation, and adaptable production platforms. Ongoing advancements in computer technology and artificial intelligence promise to further enhance the development of more effective orthohantavirus vaccines.
2024-10-11 | Recombinant Production and Functional Characterization of Andes Virus Gn and Gc in Pichia pastoris: A Path Towards Subunit Vaccine Development
Hantavirus Pulmonary Syndrome (HPS), caused by the Andes virus (ANDV), is a significant public health concern in South America, with no available vaccines or specific treatments. Neutralizing antibodies targeting ANDV glycoproteins Gn and Gc have shown protective effects in animal models, making them promising vaccine candidates. This study reports the recombinant expression, purification, and immunogenicity evaluation of sGn and sGc glycoproteins produced in the methylotrophic yeast Pichia pastoris. Initially, sGn was expressed as a secretable protein, but it formed aggregates once accumulated in the culture medium. To address this, the same strain was transformed with a vector expressing Gc, based on the hypothesis that Gn folding depends on Gc presence. However, co-expression of Gn and Gc in Pichia resulted in both proteins becoming trapped as insoluble aggregates inside the yeast, resembling inclusion bodies seen in E. coli. The recombinant proteins were solubilized and purified using metal ion affinity chromatography, followed by a refolding step before being used for immunization. The purified sGn and sGc antigens, formulated with aluminum hydroxide (AlOH), were tested in Syrian hamsters. The immunization results showed that the sGn-sGc formulation induced a strong Th1-biased immune response, characterized by high levels of IFN-γ, IL-12, and IL-6 cytokines, along with a specific antibody response against both Gn and Gc, with titers exceeding 1:10,000. These findings suggest the potential of these antigens as promising candidates for a subunit vaccine against HPS.
2024-04-25 | Design and validation of a novel multi-epitopes vaccine against hantavirus.
Hantavirus is a member of the order Bunyavirales and an emerging global pathogen. Hantavirus infections have affected millions of people globally based on available epidemiological data and research studies. Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) are the two main human diseases associated with hantavirus infections. Hence, efforts are required to develop a potent vaccine against the pathogen. The only vaccine that is in use for hantavirus is an inactivated virus vaccine, "Hantavax", but it failed to produce neutralizing antibodies. Vaccine development is of much importance in dealing with the surge of hantavirus globally. In this study, hantavirus five proteins (N protein, G1 and G2, L protein, and non-structural proteins) were used in NetCTL 1.2 program to predict T-cell epitopes. To predict major histocompatibility complex (MHC) binding alleles, an immune epitope database (IEDB) was used. All predicted epitopes were then investigated for different immunoinformatics analyses such as antigenicity and toxicity analyses. The good water-soluble, non-toxic, probable antigenic, and DRB*0101 binder was selected. A multi-epitopes-based vaccine designing was then done where linkers were used to connect the shortlisted epitopes. In addition, an adjuvant molecule was supplementary to the multi-epitopes peptide to improve the vaccine's immunogenic potential. The final vaccine construct's three-dimensional structure was modeled by ab initio method. The vaccine molecule was then evaluated for its binding potential with TLR-3 immune receptor, which is key for its recognition and processing by the host immune system. Docking studies were performed using HADDOCK software. The best-docked complex was selected and visualized for intermolecular binding and interactions using UCSF Chimera 1.16 software. The findings revealed that the designed vaccine might be a potential vaccine against hantavirus and can be used in experimental animal model testings.Communicated by Ramaswamy H. Sarma.
small molecules
2026-08-31 | Nucleoside analogues in etiotropic therapy of hantavirus fevers
Hantavirus fevers (HF) are caused by pathogenic orthohantaviruses and are classified into two clinical forms: hemorrhagic fever with renal syndrome (HFRS), reported in Eurasia, and hantavirus pulmonary syndrome (HPS), reported in the Americas. HF are characterised by an acute course with predominant involvement of internal organs: HFRS is mainly associated with kidney damage, while HPS is characterised by severe lung injury. Both diseases may also affect the central nervous and endocrine systems. In addition, hantavirus fevers are marked by severe complications during the acute phase and a prolonged recovery period. Currently, there is neither a WHO-approved vaccine nor any effective etiotropic anti-hantavirus therapy. The development of antiviral treatment strategies focuses on preventing orthohantavirus entry into cells or suppressing their intracellular replication. One of the main directions in the search for effective anti-hantavirus therapy is the low-molecular-weight compounds development and testing, many of which have demonstrated pronounced antiviral activity against orthohantaviruses through direct or indirect effects on viral RNA polymerase function. The review shows that new antiviral nucleoside compounds development and study has promising potential, as well as their combined use for effective etiotropic, pathogenetic and symptomatic treatment of hantavirus fevers.
2026-06-26 | A drug repurposing screen identifies antiviral compounds against Puumala Orthohantavirus.
Hantaviruses are zoonotic negative-sense RNA viruses that cause haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), yet no approved antiviral therapies are available. To identify host-directed modulators of hantavirus infection we performed a drug repurposing screen using live Puumala virus (PUUV). We identified and validated 70 drugs with antiviral activity in A549 cells and primary human endothelial cells. Functional clustering confirmed the known infection-inhibitory effect of several groups of compounds, including inhibitors of heat shock proteins, mTOR pathway and nucleotide synthesis. Our screen also identified compounds yet unexplored as antivirals against Hantaviruses, such as certain antibiotics. Our dataset provides a systematic map of host pathways influencing PUUV infection and highlights candidate compounds and cellular processes that can modulate this process.
2026-06-19 | Potent in vitro antiviral activity of 4'-Fluorouridine against diverse orthohantaviruses including Andes virus.
Hantaviruses are emerging pathogens responsible for severe and often fatal diseases, including hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), for which no FDA-approved antivirals currently exist. Using a Seoul virus minigenome system, we first confirmed that the ribonucleoside analog 4'-fluorouridine (EIDD-2749) effectively targets the hantavirus polymerase complex, inhibiting viral RNA transcription and replication. We subsequently evaluated its antiviral activity against a comprehensive panel of 16 hantaviruses representing both Old and New World lineages including both the Chilean and Argentinian strains of Andes virus. 4'-fluorouridine demonstrated potent, dose-dependent inhibition across all viruses tested, with EC50 values uniformly in the low-to sub-micromolar range. Collectively, these findings establish 4'-fluorouridine as a highly potent, pan-hantavirus inhibitor and a promising candidate for further preclinical development.
2026-05-29 | Kinin Dysregulation in Hantavirus Cardiopulmonary Syndrome and Possible Treatment Targets
Hantavirus cardiopulmonary syndrome (HCPS) is characterized by endothelial dysfunction and sudden vascular collapse, with a stereotyped biphasic course: a prodromal febrile phase with thrombocytopenia, followed in severe cases by explosive non-cardiogenic pulmonary oedema, shock and death (case-fatality 30–45% for HCPS causing species). We propose that HCPS is fundamentally a disease of kinin dysregulation, in which an endothelial IL-18/IFN-γ autoinflammatory loop predisposes to uncontrolled contact-system activation and bradykinin-driven capillary leak.Pathogenic hantaviruses can inhibit endothelial cell death pathways, maintaining long-lived endothelial “viral factories” that continue to trigger type I interferon and non-canonical caspase-4 activation. This pathway could drive selective IL-18 release (without IL-1β surge), which in concert with IL-12 licenses an NK/CD8 IFN-γ response. IFN-γ signals back on the endothelium in a self-sustaining loop that has no intrinsic off-switch because the virus maintains endothelial persistence without triggering cell death pathways. This loop's primary effect is not acute lethality but dysregulation of the kinin system resulting in chronic IFN-γ signalling that remodels the kinin-receptor repertoire in the inflammatory environment, with upregulation of the inducible B1 receptor (BKB1R) that can act as a synergistic receptor for B2 receptor (BKB2R). The clinical fingerprint is rising ferritin with disproportionately low CRP.Around day 7–10, antibody-mediated changes in viral-endothelial-platelet interactions may unmask a procoagulant endothelial surface, triggering FXII autoactivation and a bradykinin burst. On an endothelium already dysregulated by chronic IFN-γ, the newly induced BKB1R amplifies the BKB2R-mediated permeability response, precipitating explosive capillary leak. These inflammatory events inevitably produce TNF/IL-1/IL-6, that will happen in any antimicrobial response that normally aid immune recruitment and tissue repair. However, when standing IFN-γ remains elevated and compensatory mechanisms (IL-1Ra, IL-10) fail to contain these innate signals, TNF/IL-1/IL-6 potentiate endothelial dysfunction and risk amplification toward systemic shock. Critically, icatibant (a selective B2R antagonist) is sufficient to arrest progression, a clinical observation that unifies hantavirus pathogenesis with the bradykinin-dysregulation framework previously established for severe COVID-19.This model identifies kinin-system antagonism (icatibant) as the rational primary intervention, with short-acting JAK inhibition as supportive but balanced modulators of the inflammatory dysregulation driver. Here, the balance is critical, while JAK/IFN-γ blockade reduces the dysregulation substrate, excessive suppression of type I/II IFN impairs antiviral immunity and risks enabling viral persistence. The predictions are testable with existing assays and drugs, the time to test them is now.
2026-05-17 | THE CAP-BINDING DOMAIN OF THE HANTAVIRUS L PROTEIN: A PAN-HANTAVIRUS DRUG TARGET ENABLED BY COMPARATIVE GENOMICS A Novel Therapeutic Strategy for Hemorrhagic Fever with Renal Syndrome and Hantavirus Pulmonary Syndrome
ABSTRACT Hantaviruses cause two distinct human diseases — hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) — with case fatality rates ranging from <1% to 40%. No approved antivirals or vaccines exist outside of Korea and China. Here, we present a comparative genomic analysis of the L segment (RNA-dependent RNA polymerase) across eight pathogenic hantavirus species, revealing that the C-terminal cap-binding domain (aa 1851-2153) is the most conserved region (90-93% amino acid identity) and is structurally distinct from human cap-binding proteins (eIF4E/eIF4G). We propose that this domain represents a pan-hantavirus drug target, enabling the development of a single antiviral effective against all hantaviruses. Using fragment-based drug design, we identify six absolutely conserved pocket residues (W1872, F1895, Y1920, K1955, E1980, R2010) that coordinate the m⁷G cap. Molecular modeling predicts that small-molecule inhibitors can occupy this pocket with >1,000-fold selectivity over human eIF4E. This work establishes the first rational drug target for pan-hantavirus therapy and provides a roadmap from genomic conservation to clinical translation. KEYWORDS: hantavirus, L protein, cap-binding domain, pan-antiviral, fragment-based drug discovery, hemorrhagic fever, pulmonary syndrome, comparative genomics
other
2024-01-10 | Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents
Abstract Hantaan virus (HTNV) is asymptomatically carried by rodents, yet causes lethal hemorrhagic fever with renal syndrome in humans, the underlying mechanisms of which remain to be elucidated. Here, we show that differential macrophage responses may determine disparate infection outcomes. In mice, late-phase inactivation of inflammatory macrophage prevents cytokine storm syndrome that usually occurs in HTNV-infected patients. This is attained by elaborate crosstalk between Notch and NF-κB pathways. Mechanistically, Notch receptors activated by HTNV enhance NF-κB signaling by recruiting IKKβ and p65, promoting inflammatory macrophage polarization in both species. However, in mice rather than humans, Notch-mediated inflammation is timely restrained by a series of murine-specific long noncoding RNAs transcribed by the Notch pathway in a negative feedback manner. Among them, the lnc-ip65 detaches p65 from the Notch receptor and inhibits p65 phosphorylation, rewiring macrophages from the pro-inflammation to the pro-resolution phenotype. Genetic ablation of lnc-ip65 leads to destructive HTNV infection in mice. Thus, our findings reveal an immune-braking function of murine noncoding RNAs, offering a special therapeutic strategy for HTNV infection.
2023-10-12 | Hantavirus: an overview and advancements in therapeutic approaches for infection
Hantaviruses are a significant and emerging global public health threat, impacting more than 200,000 individuals worldwide each year. The single-stranded RNA viruses belong to the Hantaviridae family and are responsible for causing two acute febrile diseases in humans: Hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS). Currently, there are no licensed treatments or vaccines available globally for HTNV infection. Various candidate drugs have shown efficacy in increasing survival rates during the early stages of HTNV infection. Some of these drugs include lactoferrin, ribavirin, ETAR, favipiravir and vandetanib. Immunotherapy utilizing neutralizing antibodies (NAbs) generated from Hantavirus convalescent patients show efficacy against HTNV. Monoclonal antibodies such as MIB22 and JL16 have demonstrated effectiveness in protecting against HTNV infection. The development of vaccines and antivirals, used independently and/or in combination, is critical for elucidating hantaviral infections and the impact on public health. RNA interference (RNAi) arised as an emerging antiviral therapy, is a highly specific degrades RNA, with post-transcriptional mechanism using eukaryotic cells platform. That has demonstrated efficacy against a wide range of viruses, both in vitro and in vivo . Recent antiviral methods involve using small interfering RNA (siRNA) and other, immune-based therapies to target specific gene segments (S, M, or L) of the Hantavirus. This therapeutic approach enhances viral RNA clearance through the RNA interference process in Vero E6 cells or human lung microvascular endothelial cells. However, the use of siRNAs faces challenges due to their low biological stability and limited in vivo targeting ability. Despite their successful inhibition of Hantavirus replication in host cells, their antiviral efficacy may be hindered. In the current review, we focus on advances in therapeutic strategies, as antiviral medications, immune-based therapies and vaccine candidates aimed at enhancing the body’s ability to control the progression of Hantavirus infections, with the potential to reduce the risk of severe disease.
2022-01-06 | Differential Macrophage Phenotype Rewired by Hantaan Virus Constrains the Magnitude of Inflammatory Responses in Murine versus Humans
Abstract Hantaan virus (HTNV) is principally maintained and transmitted by rodents in nature, the infection of which is non-pathogenic in the field or laboratory mouse, but can cause hemorrhagic fever with renal syndrome (HFRS) in human beings, a severe systemic inflammatory disease with high mortality. It remains obscure how HTNV infection leads to disparate outcomes in distinct species. Here, we revealed a differential immune status in murine versus humans post HTNV infection, which was orchestrated by the macrophage reprogramming process and characterized by late-phase inactivation of NF-κB signaling. In HFRS patients, the immoderate and continuous activation of inflammatory monocyte/macrophage (M1) launched TNFα-centered cytokine storm and aggravated host immunopathologic injury, which can be life-threatening; however, in field or laboratory mice, the M1 activation and TNFα release were significantly suppressed at the late infection stage of HTNV, restricting excessive inflammation and blocking viral disease process, which also protected mice from secondary LPS challenge or polymicrobial sepsis. Mechanistically, we found that murine macrophage phenotype was dynamically manipulated by HTNV via the Notch-lncRNA-p65 axis. At the early stage of HTNV infection, the intracellular domain of Notch receptor (NICD) was activated by viral nucleocapsid (NP) stimulation and potentiated the NF-κB pathway by associating with and facilitating the interaction between IKKβ and p65. At the late stage, Notch signaling launched the expression of diverse murine-specific long non-coding RNAs (lncRNAs) and attenuated M1 polarization. Among them, lncRNA 30740.1 (termed as lnc-ip65, an inhibitor of p65) bound to p65 and hindered its phosphorylation, exerting negative feedback on the NF-κB pathway. Genetic ablation of lnc-ip65 shifted the balance of macrophage polarization from a pro-resolution to an inflammatory phenotype, leading to superabundant production of pro-inflammatory cytokines and increasing mice susceptibility to HTNV infection or bacterial sepsis. Collectively, our findings identify an immune braking function and mechanism for murine lncRNAs in inhibiting p65-mediated M1 activation, opening a novel therapeutic avenue of controlling the magnitude of immune responses for HFRS and other inflammatory diseases.
2021-08-27 | Defibrotide: potential for treating endothelial dysfunction related to viral and post-infectious syndromes.
Defibrotide (DF) is a polyribonucleotide with antithrombotic, pro-fibrinolytic, and anti-inflammatory effects on endothelium. These effects and the established safety of DF present DF as a strong candidate to treat viral and post-infectious syndromes involving endothelial dysfunction. We discuss DF and other therapeutic agents that have the potential to target endothelial components of pathogenesis in viral and post-infectious syndromes. We introduce defibrotide (DF), describe its mechanisms of action, and explore its established pleiotropic effects on the endothelium. We describe the established pathophysiology of Coronavirus Disease 2019 (COVID-19) and highlight the processes specific to COVID-19 potentially modulated by DF. We also present influenza A and viral hemorrhagic fevers, especially those caused by hantavirus, Ebola virus, and dengue virus, as viral syndromes in which DF might serve therapeutic benefit. Finally, we offer our opinion on novel treatment strategies targeting endothelial dysfunction in viral infections and their severe manifestations. Given the critical role of endothelial dysfunction in numerous infectious syndromes, in particular COVID-19, therapeutic pharmacology for these conditions should increasingly prioritize endothelial stabilization. Several agents with endothelial protective properties should be further studied as treatments for severe viral infections and vasculitides, especially where other therapeutic modalities have failed.
2020-11-09 | Small Animal Jet Injection Technique Results in Enhanced Immunogenicity of Hantavirus DNA Vaccines
Abstract DNA vaccine evaluation in small animals is hampered by low immunogenicity when the vaccines are delivered using a needle and syringe. To overcome this technical hurdle we tested the possibility that a device developed for human intradermal medicine delivery might be adapted to successfully deliver a DNA vaccine to small animals. The PharmaJet ® Tropis device is a FDA 510(k)-cleared disposable syringe, needle-free jet injection device designed to administer medicines to the human dermis in a 0.1 mL volume. Here, we found that hantavirus DNA vaccines administered to Syrian hamsters using Tropis were substantially more immunogenic than the same vaccines delivered by needle/syringe or particle mediated epidermal delivery (gene gun) vaccination. By adjusting how the device was used we could deliver vaccine to either subcutaneous tissues, or through the skin into the muscle. RNA and/or antigen expression was detected in epidermal, subepidermal and fibroblast cells. We directly compared six optimized and non-optimized hantavirus DNA vaccines in hamsters. Optimization, including codon-usage and mRNA stability, did not necessarily result in increased immunogenicity for all vaccines tested; however, optimization of the Andes virus (ANDV) DNA vaccine protected vaccinated hamsters from lethal disease. This is the first time active vaccination with an ANDV DNA vaccine has shown protective efficacy in the hamster model. The adaptation of a human intradermal jet injection device for use as a method of subcutaneous and intramuscular jet injection of DNA vaccines will advance the development of nucleic acid based medical countermeasures for diseases modeled in hamsters.
proteins
2026-08-03 | Angiopoietin-1/Tie2 Activation as a Therapeutic Hypothesis for Hantavirus-Induced Vascular Permeability
Severe hantavirus infection produces extensive vascular leakage, driven by a combination of endothelial dysfunction, dysregulated inflammation, VEGF-mediated hyperpermeability, angiopoietin imbalance, and degradation of the endothelial glycocalyx. This narrative review draws on the peer-reviewed literature, with particular attention to work published between 2016 and 2026, to examine how hantavirus-induced vascular permeability arises in hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), and how Angiopoietin-1 (Ang-1)/Tie2 signaling and glycocalyx injury contribute to endothelial barrier failure. Direct hantavirus evidence shows that Ang-1 inhibits hantavirus-directed endothelial permeability in vitro and that angiopoietin dysregulation tracks with disease severity in patients; findings that Tie2 activation curbs vascular leakage in sepsis and other non-hantavirus models are mechanistically suggestive but remain inferential rather than hantavirus-specific. No hantavirus animal model or clinical trial has yet evaluated Ang-1/Tie2-directed therapy, so this review treats the approach as a testable hypothesis rather than an established or recommended treatment; confirming its therapeutic value will require dedicated hantavirus-specific animal and clinical studies.
2026-05-19 | Cytokine storm dynamics in hantavirus pulmonary syndrome: a multiscale ODE model with Wasserstein early-warning score and application to the 2026 Andes virus outbreak
Abstract Background The ongoing Andes hantavirus outbreak linked to the cruise ship MV Hondius (April−May 2026, seven confirmed cases, three deaths, patients hospitalised across six countries including France) highlights the urgent need for mechanistic tools to predict which hantavirus pulmonary syndrome (HPS) patients will progress to fatal cytokine storm. Methods We present a 14-variable antigen-gated ordinary differential equation (ODE) model integrating viral dynamics, CD8 + cytotoxic T lymphocyte (CTL) expansion, four cytokines (TNF-α, IFN-γ, IL-6, IL-10), VEGF-mediated vascular permeability, and platelets. We derive two reproduction numbers: the viral invasion number ℛ 0 and the immunopathological loop gain ℛ ip . We apply Villani’s hypocoercivity theory and the HWI optimal transport inequality to prove that the spectral gap of the CTL-IFN-γ feedback loop collapses to zero at a critical infected endothelial cell count , providing a computable early-warning threshold. We define a Wasserstein patient stratification score from six clinically observable variables. Results At default parameters ( ℛ 0 = 0.396, ℛ ip = 1.875): (1) the DFE is locally asymptotically stable—the virus self-limits—but the CTL-IFN-γ loop has sufficient gain to amplify autonomously once established; (2) the storm-block spectral gap collapses exactly to zero at cells μ L −1 —a threshold attained within hours of infection onset, confirming that immunopathological amplification is essentially unavoidable; (3) rises 1-2 days before P ( t ) reaches clinical threshold, providing an early-warning window; (4) exogenous IL-10 supplementation is the single most effective intervention (predicted 40% reduction in peak permeability), outperforming corticosteroid immunosuppression and ECMO; the combination of all three applied at day 7 reduces peak permeability below the fatal threshold. Conclusions This framework predicts that HPS cytokine storm is a structural consequence of ℛ ip > 1 rather than excessive viral load, explaining death after viral clearance. For clinicians managing MV Hondius Andes virus patients today, the model identifies a six-variable triage score and a day-7 IL-10-centred therapeutic window as the highest-priority clinical targets. Full code is open source.
2026-05-17 | THE RODENT RECEPTOR CODE: A HOST-ENCODED Β3- INTEGRIN DECOY DOMAIN DICTATES HANTAVIRUS PATHOGENICITY
ABSTRACTHantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome(HPS) in humans, with case-fatality rates reaching 10-15% for HFRS and 40-60% for HPS, yet remaincompletely asymptomatic in their reservoir rodent hosts. The molecular basis of this host-specificpathogenicity has remained one of the most enigmatic questions in hantavirology.Here, we demonstrate that a single amino acid polymorphism at position 39 of the β3-integrin plexinsemaphorin-integrin (PSI) domain — Aspartate in humans versus Asparagine in all eight major reservoirspecies — functions as a molecular switch that couples hantavirus glycoprotein binding to downstream propermeability signaling. We cloned β3-integrin PSI domains from all eight reservoir species (Apodemusagrarius, A. flavicollis, Rattus norvegicus, Myodes glareolus, Microtus arvalis, Peromyscus maniculatus,Oligoryzomys longicaudatus, and Homo sapiens) and showed that rodent PSI peptides bind hantavirus Gn/Gc envelope glycoproteins with high affinity but fail to activate the FAK/Src/PI3K/Akt/VEGF-mTORpermeability axis. In contrast, human β3-integrin engagement by Gn/Gc triggers robust signaling, adherensjunction disruption, and vascular leakage.Leveraging this mechanistic insight, we designed soluble "decoy" peptides mimicking the rodent Asn-39PSI domain that competitively inhibit hantavirus entry into human endothelial cells with IC50 values of0.5-1.2 μg/ml and selectivity indices exceeding 500x. In the Syrian hamster model of lethal Andes virus(ANDV) infection, prophylactic administration of Decoy-2 (derived from M. glareolus) conferred 70%survival versus 0% in vehicle controls (p < 0.001), reduced tissue viral loads by >3 log10 copies/g,suppressed cytokine storm, and preserved pulmonary and renal histopathology. These findings identify thefirst host-encoded viral entry decoy, establish the "rodent receptor code" as the mechanistic basis ofreservoir asymptomaticity, and provide a first-in-class hantavirus-specific therapeutic candidate currentlyabsent from the clinical armamentarium.Keywords: hantavirus, β3-integrin, PSI domain, decoy peptide, vascular permeability, host-pathogen evolution,translational therapeutics
2024-08-01 | Innate lymphoid cells are activated in HFRS, and their function can be modulated by hantavirus-induced type I interferons.
Hantaviruses cause the acute zoonotic diseases hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Infected patients show strong systemic inflammation and immune cell activation. NK cells are highly activated in HFRS, suggesting that also other innate lymphoid cells (ILCs) might be responding to infection. Here, we characterized peripheral ILC responses, and measured plasma levels of soluble factors and plasma viral load, in 17 Puumala virus (PUUV)-infected HFRS patients. This revealed an increased frequency of ILC2 in patients, in particular the ILC2 lineage-committed c-Kitlo ILC2 subset. Patients' ILCs showed an activated profile with increased proliferation and displayed altered expression of several homing markers. How ILCs are activated during viral infection is largely unknown. When analyzing PUUV-mediated activation of ILCs in vitro we observed that this was dependent on type I interferons, suggesting a role for type I interferons-produced in response to virus infection-in the activation of ILCs. Further, stimulation of naïve ILC2s with IFN-β affected ILC2 cytokine responses in vitro, causing decreased IL-5 and IL-13, and increased IL-10, CXCL10, and GM-CSF secretion. These results show that ILCs are activated in HFRS patients and suggest that the classical antiviral type I IFNs are involved in shaping ILC functions.
2024-02-07 | Production and Purification of Hantavirus Glycoproteins in Drosophila melanogaster S2 Cells.
Hantaviruses, are rodent-borne viruses found worldwide that are transmitted to humans through inhalation of contaminated excreta. They can cause a renal or a pulmonary syndrome, depending on the virus, and no effective treatment is currently available for either of these diseases. Hantaviral particles are covered by a protein lattice composed of two glycoproteins (Gn and Gc) that mediate adsorption to target cells and fusion with endosomal membranes, making them prime targets for neutralizing antibodies. Here we present the methodology to produce soluble recombinant glycoproteins in different conformations, either alone or as a stabilized Gn/Gc complex, using stably transfected Drosophila S2 cells.
antibodies
2026-09-21 | Immunopathogenesis of vascular leakage in hantavirus infections: a systematic review of mechanisms underlying HPS and HFRS
Hantavirus infections manifest as Hantavirus Pulmonary Syndrome (HPS) and Hemorrhagic Fever with Renal Syndrome (HFRS), both associated with increased vascular permeability despite the lack of direct cytopathic injury to endothelial cells. A systematic search of PubMed, Scopus, and Web of Science (January 2020–May 2026) identified human studies investigating immunopathogenic mechanisms in HPS or HFRS. Due to substantial heterogeneity across study designs, findings were synthesized descriptively. Forty-one studies (39 cohorts, 2 case–control) were included, predominantly on HFRS-associated hantaviruses (HTNV, PUUV, DOBV); only one study evaluated HPS-associated ANDV. The reviewed literature revealed elevated inflammatory cytokines (IL-6, IL-18, CXCL10, CX3CL1), depletion of Mucosal-Associated Invariant T (MAIT) cells linked to IRE1αdependent pyroptosis, disruption of the endothelial glycocalyx, and coagulation disturbances with platelet dysfunction. Biomarkers of glycocalyx injury (heparan sulfate, chondroitin sulfate, and soluble thrombomodulin) were associated with increased mortality risk (AUC 0.87–0.93). No human mechanistic studies on Sin Nombre virus (SNV) were identified. Hantavirus-induced vascular leakage is driven by cytokine-mediated endothelial dysfunction, MAIT cell pyroptosis, glycocalyx degradation, and immunothrombosis. While HFRS mechanisms are now well-characterized, the absence of human mechanistic data for HPS—particularly for SNV—remains a critical gap.
2026-08-01 | Hantavirus Disease in the Emergency Department: Evidence-Informed Nursing Priorities for Recognition, Stabilization, and Infection Prevention
Hantavirus disease is an uncommon zoonotic infection that can progress rapidly from a nonspecific febrile illness to life-threatening cardiopulmonary or renal dysfunction. In the Americas, hantavirus cardiopulmonary syndrome (HCPS), also termed hantavirus pulmonary syndrome (HPS), is characterized by increased vascular permeability, pulmonary edema, hypoxemia, and circulatory failure, whereas hemorrhagic fever with renal syndrome (HFRS), encountered predominantly in Europe and Asia, is distinguished by acute kidney injury, thrombocytopenia, and variable hemorrhagic manifestations (1-3). The emergency department is an important point of recognition because patients may initially present with fever, myalgia, gastrointestinal symptoms, or headache before respiratory or hemodynamic deterioration becomes apparent. Emergency nurses participate in exposure assessment, serial physiologic observation, implementation of supportive-care protocols, fluid-balance surveillance, recognition of respiratory and circulatory deterioration, and infection-prevention measures. However, nursing-specific outcome evidence identified by the targeted search used for this mini-review is limited; the nursing role should therefore be derived cautiously from established clinical-management principles rather than presented as independently proven to improve survival. This mini-review examines evidence relevant to emergency nursing practice, including 2026 publications on critical-care management, prognosis, outbreak response, and healthcare-worker exposure. It emphasizes early recognition of HCPS, monitoring during the transition to cardiopulmonary failure, careful fluid and hemodynamic management, escalation to critical care, renal surveillance in HFRS, and infection prevention in suspected Andes virus infection. The multinational Andes virus outbreak linked to expedition cruise travel in 2026 was declared contained by WHO on 2 July 2026; nevertheless, the event illustrates the need for emergency departments to maintain operational readiness for an uncommon but potentially severe infection in which limited person-to-person transmission is operationally relevant (7,21).
2026-07-31 | The Changing Landscape of Hantavirus Infections: A Narrative Review of Epidemiology, Pathogenesis, and Countermeasures.
Hantaviruses are emerging zoonotic pathogens of increasing global public health significance. Their epidemiological landscape is rapidly changing due to ecological disruption, climate variability, urbanisation, and evolving human-animal interfaces. This narrative review synthesises current knowledge on hantavirus virology, epidemiology, pathogenesis, clinical management, and emerging countermeasures, with a focus on developments from the past 5 years. Traditionally classified into Old World viruses causing haemorrhagic fever with renal syndrome (HFRS) and New World viruses causing hantavirus cardiopulmonary syndrome (HCPS), this dichotomy has become increasingly blurred, with overlapping renal and pulmonary manifestations now recognized. Among the most consequential recent advances is the consolidated evidence for person-to-person transmission of Andes virus, documented among household contacts and during the prodromal phase, with viral shedding in respiratory secretions. Endothelial dysfunction remains the pathological hallmark of severe disease, driven by VEGF sensitisation, Src kinase and RhoA pathway activation, pericyte infection, and dysregulated inflammatory responses including IL-6 trans-signalling. Concurrently, environmental and ecological studies have linked climate change, rodent population dynamics, land-use modification, and urbanisation to increased human disease risk across multiple continents. Diagnostic strategies continue to rely on serology and molecular testing, while management remains predominantly supportive, with extracorporeal membrane oxygenation (ECMO) improving survival in fulminant HCPS. Importantly, recent structural virology advances have enabled the development of broadly neutralising monoclonal antibodies targeting conserved quaternary epitopes, as well as next-generation vaccine platforms including DNA, mRNA, and prefusion-stabilised glycoprotein candidates. Hantaviruses represent a paradigmatic One Health challenge at the intersection of environmental change, viral evolution, and global interconnectedness. Despite major progress in understanding transmission dynamics and endothelial pathogenesis, critical gaps remain regarding determinants of person-to-person spread, long-term post-infection sequelae, and the absence of licenced broadly protective vaccines or specific antiviral therapies. Future preparedness will require integrated surveillance frameworks combining ecological monitoring, genomic epidemiology, and clinical readiness within coordinated international public health strategies.
2026-07-25 | Hantavirus: A Comprehensive Narrative Review of Virology, Epidemiology, Pathogenesis, Clinical Manifestations, Diagnostics, and Emerging Therapeutic Strategies.
Hantaviruses are a genus of negative-sense, single-stranded, tri-segmented RNA viruses that are distributed worldwide. They cause two severe zoonotic diseases in humans: haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), also known as hantavirus cardiopulmonary syndrome (HCPS). Hantaviruses are primarily spread by inhaling aerosolised excreta from infected rodent reservoirs. Over 50 rodent species on six continents have been found to carry hantaviruses, with only one reported case of human-to-human transmission, involving the Andes virus (ANDV) in South America. HFRS is estimated to cause 100,000-150,000 cases worldwide annually, mainly in Asia and Europe. HPS/HCPS is far less common, with case fatality rates of 25%-40%, predominantly in the Americas. The pathogenesis of hantaviral disease is characterised by viral infection of endothelial cells, dysregulation of vascular permeability, and dysregulated innate and adaptive immune responses, leading to cytokine storm physiology. Diagnosis relies on enzyme-linked immunosorbent assay (ELISA)-based serology and reverse transcription polymerase chain reaction (RT-PCR). Strain characterisation and outbreak investigations are increasingly being performed using next-generation sequencing. No hantavirus species has a licenced vaccine outside of HTNV and SEOV, for which inactivated rodent-brain-derived vaccines remain in limited regional use in Korea and China. Regulatory-agency-approved antiviral therapy is similarly lacking worldwide, and management remains largely supportive. Ribavirin has shown benefit in reducing mortality and renal morbidity in HFRS when initiated early, but has not demonstrated efficacy in HPS/HCPS in controlled trials. Recent advancements include the development of monoclonal antibodies, candidate mRNA and subunit vaccines, and an improved understanding of the mechanisms of immune evasion. This review synthesises the latest information on hantavirus biology, clinical medicine and public health. This highlights the critical gaps that must be addressed to counter the growing threat posed by this pathogen in an era of climate change and global ecological transformation.
2026-07-16 | Hantavirus cardiopulmonary syndrome in children: a systematic scoping review of presentation, critical care management, and outcomes.
Pediatric hantavirus cardiopulmonary syndrome/hantavirus pulmonary syndrome (HCPS/HPS) is rare but can progress rapidly from a nonspecific febrile prodrome to respiratory failure, shock, and multiorgan dysfunction. Pediatric-specific evidence is limited, and a comprehensive map of the clinical literature is lacking. We conducted a systematic scoping review per Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidance (protocol registered at DOI:10.17605/OSF.IO/MZDN4). PubMed/MEDLINE, Embase, Scopus, Web of Science, and Cochrane CENTRAL were searched from inception to May 2026. Eligible reports described children or adolescents (age ≤18 years) with HCPS/HPS and extractable pediatric clinical data. Two reviewers independently screened records, assessed overlap, extracted data, and appraised reporting quality using Joanna Briggs Institute tools. Of 2208 database records, 20 reports were included in the core pediatric synthesis after removal of 976 duplicates and screening. Reports were concentrated in the Americas. Recurrent features included fever, gastrointestinal symptoms, myalgia, thrombocytopenia, hemoconcentration, pulmonary edema, respiratory failure, and shock. Severe cases required mechanical ventilation, vasoactive support, extracorporeal membrane oxygenation, and in some cases renal replacement therapy. Larger pediatric case series and surveillance-level reports reported mortality of approximately 33% to 37%. Evidence was predominantly case-based with variable reporting completeness. Pediatric HCPS/HPS is rare but potentially rapidly fatal. Early suspicion in endemic regions or after rodent exposure, with prompt supportive critical care and timely consideration of advanced cardiopulmonary support, is central to management.
vaccines
2026-08-13 | Broad-Spectrum Multi-Epitope Design Targeting Conserved Hantavirus Glycoproteins (Gn/Gc): Chimeric Antigen Engineering and Structural Mapping.
Hantaviruses, the etiological agents of hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), represent a high-risk zoonotic threat with substantial global health impact. Currently, there is no FDA-approved vaccine. The viral surface glycoprotein (GP) is crucial for host cell entry and is regarded as a key target for vaccine development. However, its variability among hantavirus species limits the effectiveness of conventional vaccine strategies. Epitope-based vaccines offer a promising alternative by enabling the design of broadly protective constructs. In this study, we applied immunoinformatics approaches to design a universal multi-epitope vaccine candidate targeting both HFRS- and HPS-associated hantaviruses through a multi-layered workflow integrating B-cell and T-cell epitope prediction, antigenicity scoring, IFN-γ induction potential, conservation analysis, and population coverage assessment. Viral GPs from SEOV, PUUV, SNV, and ANDV were analyzed using algorithms for B-cell and T-cell epitope prediction. Predicted epitopes were assessed for allergenicity, toxicity, conservation, and population coverage. Two vaccine constructs incorporating β-defensin or 50S ribosomal protein L7/L12 as adjuvants were assessed for physicochemical properties, structural stability and immunogenic potential. Molecular docking analyses provided exploratory ectodomain-compatibility screening, suggesting potential interactions with TLR4 that require future experimental confirmation. The in silico immune simulations suggested potential robust and long-lasting responses with memory cell persistence exceeding one year. Simulations also indicated balanced humoral and cellular responses, robust antibody production, and long-term memory formation suggestive of durable protective immunity. These findings support the rational design of broad-spectrum multi-epitope vaccines against genetically diverse hantaviruses, offering a rational framework for preclinical development of next-generation universal vaccines against hantavirus-associated diseases.
2026-01-01 | The Use of Artificial Intelligence to Create a Model for the Vaccine Against the Hantavirus
The Use of Artificial Intelligence to Create a Model for the Vaccine Against the Hantavirus Carlo Lazzari1*, Marco Rabottini1 1Department of Experimental Pharmacology, International Centre for Healthcare and Medical Education (ICHME), London, United Kingdom *Correspondence: Carlo Lazzari, email: carlolazzari2015@gmail.com Abstract Background — Hantaviruses are globally distributed zoonotic pathogens responsible for Hemorrhagic Fever with Renal Syndrome (HFRS) and Hantavirus Pulmonary Syndrome (HPS). Maintained in rodent reservoirs and transmitted through aerosolised excreta, they remain a persistent public health threat. Their enveloped structure, incorporating Gn/Gc glycoproteins and ribonucleoprotein complexes, complicates traditional vaccine development. Recent advances in AI driven vaccinology offer new strategies for identifying antigenic determinants and designing safer, more immunogenic constructs. Methods — An integrated AI computational pipeline combined structural modelling, reverse vaccinology, and immunoinformatics. Glycoprotein sequences from representative hantaviruses were modelled to predict conformational features. Deep learning algorithms identified high affinity B cell epitopes and T cell epitopes, which were assembled into a multi epitope construct. Allergenicity, toxicity, and population coverage were computationally screened, and immune simulations assessed predicted host responses. Results — The AI generated construct demonstrated high predicted antigenicity, favourable physicochemical stability, and non allergenic, non toxic profiles. Structural modelling confirmed appropriate folding and solvent exposure of key epitopes. Immune simulations suggested strong induction of humoral and cellular responses, including memory cell formation. Conclusions — AI enabled vaccine design provides a rapid, rational framework for developing next generation hantavirus vaccines. By integrating molecular virology with machine learning, this approach accelerates antigen discovery and construct optimisation. The findings support AI as a transformative tool for emerging pathogen vaccine development and highlight its potential to overcome longstanding barriers in hantavirus prevention.
2025-02-26 | Achievement and Challenges in Orthohantavirus Vaccines.
Orthohantaviruses (also known as hantaviruses) are pathogens that cause two distinct, yet related forms of severe human disease: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). These diseases pose a significant threat to global public health due to their high case fatality rates, which can range from 1% to 50%. In recent years, an increasing number of countries and regions have reported human cases, underscoring the urgent need for improved understanding, prevention, and treatment strategies. Given the severity of these diseases and the lack of specific post-exposure antiviral treatments, preventive measures are critical. For several decades, substantial efforts have been dedicated to developing orthohantavirus vaccines, leading to significant advancements. The first large-scale deployment involved inactivated vaccines, which played a crucial role in reducing HFRS incidence in South Korea and China. Subunit vaccines, viral vector vaccines, and virus-like particle (VLP) vaccines have also been extensively researched. Nucleic acid vaccines, including both mRNA and DNA vaccines, hold the greatest potential for future development due to their rapid design and production cycles, ability to elicit robust immune responses, ease of storage and transportation, and adaptable production platforms. Ongoing advancements in computer technology and artificial intelligence promise to further enhance the development of more effective orthohantavirus vaccines.
2024-10-11 | Recombinant Production and Functional Characterization of Andes Virus Gn and Gc in Pichia pastoris: A Path Towards Subunit Vaccine Development
Hantavirus Pulmonary Syndrome (HPS), caused by the Andes virus (ANDV), is a significant public health concern in South America, with no available vaccines or specific treatments. Neutralizing antibodies targeting ANDV glycoproteins Gn and Gc have shown protective effects in animal models, making them promising vaccine candidates. This study reports the recombinant expression, purification, and immunogenicity evaluation of sGn and sGc glycoproteins produced in the methylotrophic yeast Pichia pastoris. Initially, sGn was expressed as a secretable protein, but it formed aggregates once accumulated in the culture medium. To address this, the same strain was transformed with a vector expressing Gc, based on the hypothesis that Gn folding depends on Gc presence. However, co-expression of Gn and Gc in Pichia resulted in both proteins becoming trapped as insoluble aggregates inside the yeast, resembling inclusion bodies seen in E. coli. The recombinant proteins were solubilized and purified using metal ion affinity chromatography, followed by a refolding step before being used for immunization. The purified sGn and sGc antigens, formulated with aluminum hydroxide (AlOH), were tested in Syrian hamsters. The immunization results showed that the sGn-sGc formulation induced a strong Th1-biased immune response, characterized by high levels of IFN-γ, IL-12, and IL-6 cytokines, along with a specific antibody response against both Gn and Gc, with titers exceeding 1:10,000. These findings suggest the potential of these antigens as promising candidates for a subunit vaccine against HPS.
2024-04-25 | Design and validation of a novel multi-epitopes vaccine against hantavirus.
Hantavirus is a member of the order Bunyavirales and an emerging global pathogen. Hantavirus infections have affected millions of people globally based on available epidemiological data and research studies. Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) are the two main human diseases associated with hantavirus infections. Hence, efforts are required to develop a potent vaccine against the pathogen. The only vaccine that is in use for hantavirus is an inactivated virus vaccine, "Hantavax", but it failed to produce neutralizing antibodies. Vaccine development is of much importance in dealing with the surge of hantavirus globally. In this study, hantavirus five proteins (N protein, G1 and G2, L protein, and non-structural proteins) were used in NetCTL 1.2 program to predict T-cell epitopes. To predict major histocompatibility complex (MHC) binding alleles, an immune epitope database (IEDB) was used. All predicted epitopes were then investigated for different immunoinformatics analyses such as antigenicity and toxicity analyses. The good water-soluble, non-toxic, probable antigenic, and DRB*0101 binder was selected. A multi-epitopes-based vaccine designing was then done where linkers were used to connect the shortlisted epitopes. In addition, an adjuvant molecule was supplementary to the multi-epitopes peptide to improve the vaccine's immunogenic potential. The final vaccine construct's three-dimensional structure was modeled by ab initio method. The vaccine molecule was then evaluated for its binding potential with TLR-3 immune receptor, which is key for its recognition and processing by the host immune system. Docking studies were performed using HADDOCK software. The best-docked complex was selected and visualized for intermolecular binding and interactions using UCSF Chimera 1.16 software. The findings revealed that the designed vaccine might be a potential vaccine against hantavirus and can be used in experimental animal model testings.Communicated by Ramaswamy H. Sarma.
small molecules
2026-08-31 | Nucleoside analogues in etiotropic therapy of hantavirus fevers
Hantavirus fevers (HF) are caused by pathogenic orthohantaviruses and are classified into two clinical forms: hemorrhagic fever with renal syndrome (HFRS), reported in Eurasia, and hantavirus pulmonary syndrome (HPS), reported in the Americas. HF are characterised by an acute course with predominant involvement of internal organs: HFRS is mainly associated with kidney damage, while HPS is characterised by severe lung injury. Both diseases may also affect the central nervous and endocrine systems. In addition, hantavirus fevers are marked by severe complications during the acute phase and a prolonged recovery period. Currently, there is neither a WHO-approved vaccine nor any effective etiotropic anti-hantavirus therapy. The development of antiviral treatment strategies focuses on preventing orthohantavirus entry into cells or suppressing their intracellular replication. One of the main directions in the search for effective anti-hantavirus therapy is the low-molecular-weight compounds development and testing, many of which have demonstrated pronounced antiviral activity against orthohantaviruses through direct or indirect effects on viral RNA polymerase function. The review shows that new antiviral nucleoside compounds development and study has promising potential, as well as their combined use for effective etiotropic, pathogenetic and symptomatic treatment of hantavirus fevers.
2026-06-26 | A drug repurposing screen identifies antiviral compounds against Puumala Orthohantavirus.
Hantaviruses are zoonotic negative-sense RNA viruses that cause haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), yet no approved antiviral therapies are available. To identify host-directed modulators of hantavirus infection we performed a drug repurposing screen using live Puumala virus (PUUV). We identified and validated 70 drugs with antiviral activity in A549 cells and primary human endothelial cells. Functional clustering confirmed the known infection-inhibitory effect of several groups of compounds, including inhibitors of heat shock proteins, mTOR pathway and nucleotide synthesis. Our screen also identified compounds yet unexplored as antivirals against Hantaviruses, such as certain antibiotics. Our dataset provides a systematic map of host pathways influencing PUUV infection and highlights candidate compounds and cellular processes that can modulate this process.
2026-06-19 | Potent in vitro antiviral activity of 4'-Fluorouridine against diverse orthohantaviruses including Andes virus.
Hantaviruses are emerging pathogens responsible for severe and often fatal diseases, including hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), for which no FDA-approved antivirals currently exist. Using a Seoul virus minigenome system, we first confirmed that the ribonucleoside analog 4'-fluorouridine (EIDD-2749) effectively targets the hantavirus polymerase complex, inhibiting viral RNA transcription and replication. We subsequently evaluated its antiviral activity against a comprehensive panel of 16 hantaviruses representing both Old and New World lineages including both the Chilean and Argentinian strains of Andes virus. 4'-fluorouridine demonstrated potent, dose-dependent inhibition across all viruses tested, with EC50 values uniformly in the low-to sub-micromolar range. Collectively, these findings establish 4'-fluorouridine as a highly potent, pan-hantavirus inhibitor and a promising candidate for further preclinical development.
2026-05-29 | Kinin Dysregulation in Hantavirus Cardiopulmonary Syndrome and Possible Treatment Targets
Hantavirus cardiopulmonary syndrome (HCPS) is characterized by endothelial dysfunction and sudden vascular collapse, with a stereotyped biphasic course: a prodromal febrile phase with thrombocytopenia, followed in severe cases by explosive non-cardiogenic pulmonary oedema, shock and death (case-fatality 30–45% for HCPS causing species). We propose that HCPS is fundamentally a disease of kinin dysregulation, in which an endothelial IL-18/IFN-γ autoinflammatory loop predisposes to uncontrolled contact-system activation and bradykinin-driven capillary leak.Pathogenic hantaviruses can inhibit endothelial cell death pathways, maintaining long-lived endothelial “viral factories” that continue to trigger type I interferon and non-canonical caspase-4 activation. This pathway could drive selective IL-18 release (without IL-1β surge), which in concert with IL-12 licenses an NK/CD8 IFN-γ response. IFN-γ signals back on the endothelium in a self-sustaining loop that has no intrinsic off-switch because the virus maintains endothelial persistence without triggering cell death pathways. This loop's primary effect is not acute lethality but dysregulation of the kinin system resulting in chronic IFN-γ signalling that remodels the kinin-receptor repertoire in the inflammatory environment, with upregulation of the inducible B1 receptor (BKB1R) that can act as a synergistic receptor for B2 receptor (BKB2R). The clinical fingerprint is rising ferritin with disproportionately low CRP.Around day 7–10, antibody-mediated changes in viral-endothelial-platelet interactions may unmask a procoagulant endothelial surface, triggering FXII autoactivation and a bradykinin burst. On an endothelium already dysregulated by chronic IFN-γ, the newly induced BKB1R amplifies the BKB2R-mediated permeability response, precipitating explosive capillary leak. These inflammatory events inevitably produce TNF/IL-1/IL-6, that will happen in any antimicrobial response that normally aid immune recruitment and tissue repair. However, when standing IFN-γ remains elevated and compensatory mechanisms (IL-1Ra, IL-10) fail to contain these innate signals, TNF/IL-1/IL-6 potentiate endothelial dysfunction and risk amplification toward systemic shock. Critically, icatibant (a selective B2R antagonist) is sufficient to arrest progression, a clinical observation that unifies hantavirus pathogenesis with the bradykinin-dysregulation framework previously established for severe COVID-19.This model identifies kinin-system antagonism (icatibant) as the rational primary intervention, with short-acting JAK inhibition as supportive but balanced modulators of the inflammatory dysregulation driver. Here, the balance is critical, while JAK/IFN-γ blockade reduces the dysregulation substrate, excessive suppression of type I/II IFN impairs antiviral immunity and risks enabling viral persistence. The predictions are testable with existing assays and drugs, the time to test them is now.
2026-05-17 | THE CAP-BINDING DOMAIN OF THE HANTAVIRUS L PROTEIN: A PAN-HANTAVIRUS DRUG TARGET ENABLED BY COMPARATIVE GENOMICS A Novel Therapeutic Strategy for Hemorrhagic Fever with Renal Syndrome and Hantavirus Pulmonary Syndrome
ABSTRACT Hantaviruses cause two distinct human diseases — hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) — with case fatality rates ranging from <1% to 40%. No approved antivirals or vaccines exist outside of Korea and China. Here, we present a comparative genomic analysis of the L segment (RNA-dependent RNA polymerase) across eight pathogenic hantavirus species, revealing that the C-terminal cap-binding domain (aa 1851-2153) is the most conserved region (90-93% amino acid identity) and is structurally distinct from human cap-binding proteins (eIF4E/eIF4G). We propose that this domain represents a pan-hantavirus drug target, enabling the development of a single antiviral effective against all hantaviruses. Using fragment-based drug design, we identify six absolutely conserved pocket residues (W1872, F1895, Y1920, K1955, E1980, R2010) that coordinate the m⁷G cap. Molecular modeling predicts that small-molecule inhibitors can occupy this pocket with >1,000-fold selectivity over human eIF4E. This work establishes the first rational drug target for pan-hantavirus therapy and provides a roadmap from genomic conservation to clinical translation. KEYWORDS: hantavirus, L protein, cap-binding domain, pan-antiviral, fragment-based drug discovery, hemorrhagic fever, pulmonary syndrome, comparative genomics
other
2024-01-10 | Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents
Abstract Hantaan virus (HTNV) is asymptomatically carried by rodents, yet causes lethal hemorrhagic fever with renal syndrome in humans, the underlying mechanisms of which remain to be elucidated. Here, we show that differential macrophage responses may determine disparate infection outcomes. In mice, late-phase inactivation of inflammatory macrophage prevents cytokine storm syndrome that usually occurs in HTNV-infected patients. This is attained by elaborate crosstalk between Notch and NF-κB pathways. Mechanistically, Notch receptors activated by HTNV enhance NF-κB signaling by recruiting IKKβ and p65, promoting inflammatory macrophage polarization in both species. However, in mice rather than humans, Notch-mediated inflammation is timely restrained by a series of murine-specific long noncoding RNAs transcribed by the Notch pathway in a negative feedback manner. Among them, the lnc-ip65 detaches p65 from the Notch receptor and inhibits p65 phosphorylation, rewiring macrophages from the pro-inflammation to the pro-resolution phenotype. Genetic ablation of lnc-ip65 leads to destructive HTNV infection in mice. Thus, our findings reveal an immune-braking function of murine noncoding RNAs, offering a special therapeutic strategy for HTNV infection.
2023-10-12 | Hantavirus: an overview and advancements in therapeutic approaches for infection
Hantaviruses are a significant and emerging global public health threat, impacting more than 200,000 individuals worldwide each year. The single-stranded RNA viruses belong to the Hantaviridae family and are responsible for causing two acute febrile diseases in humans: Hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS). Currently, there are no licensed treatments or vaccines available globally for HTNV infection. Various candidate drugs have shown efficacy in increasing survival rates during the early stages of HTNV infection. Some of these drugs include lactoferrin, ribavirin, ETAR, favipiravir and vandetanib. Immunotherapy utilizing neutralizing antibodies (NAbs) generated from Hantavirus convalescent patients show efficacy against HTNV. Monoclonal antibodies such as MIB22 and JL16 have demonstrated effectiveness in protecting against HTNV infection. The development of vaccines and antivirals, used independently and/or in combination, is critical for elucidating hantaviral infections and the impact on public health. RNA interference (RNAi) arised as an emerging antiviral therapy, is a highly specific degrades RNA, with post-transcriptional mechanism using eukaryotic cells platform. That has demonstrated efficacy against a wide range of viruses, both in vitro and in vivo . Recent antiviral methods involve using small interfering RNA (siRNA) and other, immune-based therapies to target specific gene segments (S, M, or L) of the Hantavirus. This therapeutic approach enhances viral RNA clearance through the RNA interference process in Vero E6 cells or human lung microvascular endothelial cells. However, the use of siRNAs faces challenges due to their low biological stability and limited in vivo targeting ability. Despite their successful inhibition of Hantavirus replication in host cells, their antiviral efficacy may be hindered. In the current review, we focus on advances in therapeutic strategies, as antiviral medications, immune-based therapies and vaccine candidates aimed at enhancing the body’s ability to control the progression of Hantavirus infections, with the potential to reduce the risk of severe disease.
2022-01-06 | Differential Macrophage Phenotype Rewired by Hantaan Virus Constrains the Magnitude of Inflammatory Responses in Murine versus Humans
Abstract Hantaan virus (HTNV) is principally maintained and transmitted by rodents in nature, the infection of which is non-pathogenic in the field or laboratory mouse, but can cause hemorrhagic fever with renal syndrome (HFRS) in human beings, a severe systemic inflammatory disease with high mortality. It remains obscure how HTNV infection leads to disparate outcomes in distinct species. Here, we revealed a differential immune status in murine versus humans post HTNV infection, which was orchestrated by the macrophage reprogramming process and characterized by late-phase inactivation of NF-κB signaling. In HFRS patients, the immoderate and continuous activation of inflammatory monocyte/macrophage (M1) launched TNFα-centered cytokine storm and aggravated host immunopathologic injury, which can be life-threatening; however, in field or laboratory mice, the M1 activation and TNFα release were significantly suppressed at the late infection stage of HTNV, restricting excessive inflammation and blocking viral disease process, which also protected mice from secondary LPS challenge or polymicrobial sepsis. Mechanistically, we found that murine macrophage phenotype was dynamically manipulated by HTNV via the Notch-lncRNA-p65 axis. At the early stage of HTNV infection, the intracellular domain of Notch receptor (NICD) was activated by viral nucleocapsid (NP) stimulation and potentiated the NF-κB pathway by associating with and facilitating the interaction between IKKβ and p65. At the late stage, Notch signaling launched the expression of diverse murine-specific long non-coding RNAs (lncRNAs) and attenuated M1 polarization. Among them, lncRNA 30740.1 (termed as lnc-ip65, an inhibitor of p65) bound to p65 and hindered its phosphorylation, exerting negative feedback on the NF-κB pathway. Genetic ablation of lnc-ip65 shifted the balance of macrophage polarization from a pro-resolution to an inflammatory phenotype, leading to superabundant production of pro-inflammatory cytokines and increasing mice susceptibility to HTNV infection or bacterial sepsis. Collectively, our findings identify an immune braking function and mechanism for murine lncRNAs in inhibiting p65-mediated M1 activation, opening a novel therapeutic avenue of controlling the magnitude of immune responses for HFRS and other inflammatory diseases.
2021-08-27 | Defibrotide: potential for treating endothelial dysfunction related to viral and post-infectious syndromes.
Defibrotide (DF) is a polyribonucleotide with antithrombotic, pro-fibrinolytic, and anti-inflammatory effects on endothelium. These effects and the established safety of DF present DF as a strong candidate to treat viral and post-infectious syndromes involving endothelial dysfunction. We discuss DF and other therapeutic agents that have the potential to target endothelial components of pathogenesis in viral and post-infectious syndromes. We introduce defibrotide (DF), describe its mechanisms of action, and explore its established pleiotropic effects on the endothelium. We describe the established pathophysiology of Coronavirus Disease 2019 (COVID-19) and highlight the processes specific to COVID-19 potentially modulated by DF. We also present influenza A and viral hemorrhagic fevers, especially those caused by hantavirus, Ebola virus, and dengue virus, as viral syndromes in which DF might serve therapeutic benefit. Finally, we offer our opinion on novel treatment strategies targeting endothelial dysfunction in viral infections and their severe manifestations. Given the critical role of endothelial dysfunction in numerous infectious syndromes, in particular COVID-19, therapeutic pharmacology for these conditions should increasingly prioritize endothelial stabilization. Several agents with endothelial protective properties should be further studied as treatments for severe viral infections and vasculitides, especially where other therapeutic modalities have failed.
2020-11-09 | Small Animal Jet Injection Technique Results in Enhanced Immunogenicity of Hantavirus DNA Vaccines
Abstract DNA vaccine evaluation in small animals is hampered by low immunogenicity when the vaccines are delivered using a needle and syringe. To overcome this technical hurdle we tested the possibility that a device developed for human intradermal medicine delivery might be adapted to successfully deliver a DNA vaccine to small animals. The PharmaJet ® Tropis device is a FDA 510(k)-cleared disposable syringe, needle-free jet injection device designed to administer medicines to the human dermis in a 0.1 mL volume. Here, we found that hantavirus DNA vaccines administered to Syrian hamsters using Tropis were substantially more immunogenic than the same vaccines delivered by needle/syringe or particle mediated epidermal delivery (gene gun) vaccination. By adjusting how the device was used we could deliver vaccine to either subcutaneous tissues, or through the skin into the muscle. RNA and/or antigen expression was detected in epidermal, subepidermal and fibroblast cells. We directly compared six optimized and non-optimized hantavirus DNA vaccines in hamsters. Optimization, including codon-usage and mRNA stability, did not necessarily result in increased immunogenicity for all vaccines tested; however, optimization of the Andes virus (ANDV) DNA vaccine protected vaccinated hamsters from lethal disease. This is the first time active vaccination with an ANDV DNA vaccine has shown protective efficacy in the hamster model. The adaptation of a human intradermal jet injection device for use as a method of subcutaneous and intramuscular jet injection of DNA vaccines will advance the development of nucleic acid based medical countermeasures for diseases modeled in hamsters.
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Drug Discovery Landscape
2 orphan drug designations for Hantavirus pulmonary syndrome.
2 orphan drug designations for Hantavirus pulmonary syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
zapnometinib (proposed) | small molecules | FDA | — | Mithrilium Therapeutics B.V. |
a recombinant human monoclonal antibody targeting hantavirus | antibodies | FDA | — | Ichor Biologics |
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