Hantaviruses at an inflection point: scientific evidence, spillover risk, and One Health approach

Introduction

Hantaviruses are zoonotic pathogens that represent one of the most significant rodent-borne viral threats to human health. They are distributed worldwide and are associated with two major clinical syndromes: hemorrhagic fever with renal syndrome (HFRS), predominantly observed in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS), mainly reported in the Americas. These diseases differ in clinical presentation and mortality but share common virological and ecological characteristics (1, 2).

The discovery of hantaviruses dates back to the Korean War during the early 1950s, when thousands of United Nations soldiers developed a severe febrile illness later identified as Korean hemorrhagic fever. The causative agent, Hantaan virus, was isolated in 1978 near the Hantan River in South Korea, giving rise to the name “hantavirus.” Since then, numerous hantavirus species have been identified globally, each associated with a specific rodent or small mammal reservoir.

The global importance of hantaviruses has increased substantially during the last two decades. Ecological disturbances, deforestation, climate fluctuations, agricultural expansion, and increasing human encroachment into wildlife habitats have enhanced opportunities for rodent-human interactions. Concurrently, improved molecular surveillance has revealed previously unrecognized hantavirus diversity and geographic expansion (3–5).

Recent outbreaks linked to Andes virus in South America and a multi-country cruise ship-associated cluster in 2026 have once again highlighted the epidemic potential of hantaviruses and the importance of international preparedness (6–8).

This narrative review was conducted through a comprehensive search of PubMed, Scopus, Web of Science, Google Scholar, WHO reports, CDC resources, ECDC reports, and official public health documents published up to May 2026. Search terms included “hantavirus”, “orthohantavirus”, “HFRS”, “HCPS”, “Andes virus”, “Dobrava-Belgrade virus”, “zoonotic transmission”, “rodent reservoirs”, “viral evolution”, “diagnosis”, “treatment”, “vaccines”, and “One Health”. Priority was given to peer-reviewed articles, systematic reviews, surveillance reports, and official outbreak communications. Studies lacking scientific validation, duplicate reports, and non-relevant publications were excluded.

Epidemiology and global distribution of hantaviruses

Hantaviruses demonstrate a wide but geographically structured global distribution, with distinct viral species and associated clinical syndromes predominating in different regions. The epidemiology is largely shaped by the distribution of rodent reservoirs, environmental conditions, and human exposure patterns. Two major clinical syndromes define the global burden of disease: HFRS, predominantly seen in Eurasia, and HCPS, mainly reported in the Americas (9, 10).

In Asia, China represents the country with the highest global burden of HFRS, accounting for thousands of reported cases annually. The disease remains endemic in multiple provinces, largely driven by rodent species such as Apodemus agrarius and Rattus norvegicus, which serve as natural reservoirs. South Korea and parts of the Russian Federation also remain important endemic zones, where seasonal outbreaks are frequently reported, often associated with agricultural activities and increased human–rodent contact in rural environments (11).

In Europe, hantavirus infections are primarily caused by Puumala virus, which is responsible for a milder form of HFRS known as nephropathia epidemica. This virus is widely distributed across Northern and Central Europe, with recurrent outbreaks documented in countries such as Finland, Sweden, Germany, and France. These outbreaks are often cyclical and strongly influenced by ecological factors, particularly fluctuations in bank vole populations (Myodes glareolus), which serve as the principal reservoir (12–17). In southeastern Europe, Bulgaria represents an important endemic area for hantavirus infections, particularly those associated with Dobrava–Belgrade virus (DOBV). Molecular and epidemiological studies have demonstrated circulation of hantaviruses in both human patients and rodent reservoirs, emphasizing their continued public health relevance in the region (18–21).

In the Americas, hantavirus infections manifest predominantly as HCPS, a severe respiratory disease associated with high case-fatality rates. Reported cases are concentrated in North, Central, and South America, with significant disease burden in the United States, Argentina, Chile, Brazil, and Paraguay. Among the circulating species, Andes virus is of particular epidemiological concern due to its unique ability to transmit between humans under specific conditions, a feature not commonly observed in most other hantaviruses. This characteristic has contributed to notable outbreaks in South America and remains a focal point of public health surveillance (22). These epidemiological observations have direct implications for prevention. Regions experiencing increased rodent abundance following climatic events should strengthen rodent surveillance, reinforce public education, and enhance clinical awareness during seasonal peaks. Likewise, international travel-associated clusters highlight the need for cross-border surveillance and rapid case notification.

Despite considerable advances in global surveillance, the true epidemiological burden of hantavirus infections remains uncertain. Underdiagnosis is likely substantial, particularly in Africa and many low- and middle-income countries, where limited diagnostic capacity, inadequate surveillance systems, and overlap with other febrile illnesses may obscure disease recognition. Moreover, surveillance methodologies vary considerably between countries, limiting the comparability of incidence estimates and hindering the establishment of standardized global risk assessments. Another major challenge concerns the impact of climate change on hantavirus emergence. Although ecological studies suggest that changing temperature, precipitation patterns, and land-use modifications influence rodent population dynamics and spillover risk, the magnitude and consistency of these associations remain incompletely understood. Future epidemiological research should prioritize harmonized surveillance protocols, expanded genomic surveillance, and long-term ecological studies integrating climatic, environmental, and epidemiological data to improve outbreak prediction and preparedness.

Current outbreaks and public health concerns

Recent epidemiological observations highlight ongoing concerns regarding hantavirus emergence and re-emergence in multiple regions. WHO-reported clusters have raised attention toward potential multi-country exposure events, including those associated with international travel, where suspected Andes virus infections have been investigated in the context of severe respiratory illness and fatal outcomes. Although such reports remain under investigation, they emphasize the importance of global surveillance in detecting cross-border transmission events (8).

In parallel, an increasing number of hantavirus cases has been reported in Argentina during the 2025–2026 period; however, the factors contributing to this trend remain under investigation. These trends have been discussed in the context of broader ecological and climatic shifts that may influence rodent population dynamics and human exposure risk (23, 24). Factors such as deforestation, agricultural expansion, urban encroachment into wildlife habitats, and climate variability are considered key drivers that may facilitate future spillover events.

Despite public and media concern, current scientific evidence consistently indicates that hantaviruses do not possess efficient airborne transmission capabilities comparable to respiratory viruses such as influenza or SARS-CoV-2. Human-to-human transmission remains rare and is largely restricted to specific strains, most notably Andes virus, and typically requires prolonged close contact. This epidemiological constraint is a critical factor limiting widespread global dissemination (25–27).

Public health surveillance and One Health perspectives

Effective control and prevention of hantavirus infections require an integrated One Health approach that acknowledges the interconnectedness of human, animal, and environmental health (Figure 1). Surveillance strategies must simultaneously target human clinical cases, rodent reservoir populations, and environmental conditions that influence viral maintenance and spillover risk.

Modern public health frameworks increasingly incorporate wildlife monitoring systems to track reservoir abundance and viral prevalence, alongside environmental management strategies aimed at reducing human exposure. In addition, genomic surveillance has become a powerful tool for understanding viral evolution, transmission pathways, and phylogeographic patterns, enabling more precise outbreak reconstruction and risk assessment (28).

Advances in molecular epidemiology, particularly high-throughput sequencing technologies, have significantly improved the ability to detect viral variants and trace interregional spread. When combined with climate modeling and ecological forecasting, these approaches allow for more predictive and proactive outbreak preparedness strategies (29).

Ultimately, addressing hantavirus threats requires sustained interdisciplinary collaboration among virologists, epidemiologists, ecologists, clinicians, and public health authorities. Such coordination is essential to strengthen early warning systems, improve outbreak response capacity, and mitigate the impact of future zoonotic emergence events.

Taxonomy and classification of hantaviruses

Hantaviruses are classified within the order Bunyavirales and the family Hantaviridae, representing a distinct lineage of enveloped, negative-sense single-stranded RNA viruses. Historically, hantaviruses were grouped within the broader family Bunyaviridae; however, advances in molecular phylogenetics, genome sequencing, and evolutionary analysis have led to a major taxonomic revision. This restructuring resulted in the establishment of Hantaviridae as a separate family, reflecting the unique genetic and biological characteristics of hantaviruses compared to other bunyaviruses (30, 31).

Within this family, the genus Orthohantavirus includes the majority of species that are pathogenic to humans. Members of this genus are responsible for the two principal clinical syndromes associated with hantavirus infection: HFRS and HCPS. Several medically significant species have been identified, including Hantaan virus (HTNV), Seoul virus (SEOV), Puumala virus (PUUV), Dobrava–Belgrade virus (DOBV), Sin Nombre virus (SNV), and Andes virus (ANDV). These viruses differ in their geographic distribution, clinical severity, and epidemiological behavior, but share common structural and genomic features characteristic of the genus (30–33).

A defining feature of hantavirus biology is the strong association between each viral species and a specific rodent reservoir host. This host specificity reflects a long evolutionary history of virus–host coevolution, resulting in highly adapted and often asymptomatic infections in natural rodent populations. The maintenance of hantaviruses in nature is therefore primarily dependent on persistent infection within these reservoir species, with human infection occurring as an incidental spillover event rather than as part of the natural transmission cycle. This ecological and evolutionary relationship is central to understanding hantavirus emergence and persistence across different geographic regions.(30, 34)

Viral structure and genome organization

Hantaviruses are enveloped, spherical virions typically measuring approximately 80–120 nm in diameter. Their structural organization is characteristic of members of the family Hantaviridae, with a lipid envelope derived from the host cell membrane. Embedded within this envelope are viral glycoprotein spikes that play a crucial role in host cell recognition, attachment, and subsequent membrane fusion, thereby initiating infection. These surface glycoproteins are essential determinants of viral tropism and pathogenicity (Figure 2) (36).

The hantavirus genome is composed of three segments of negative-sense, single-stranded RNA, designated as the large (L), medium (M), and small (S) segments. Each segment encodes specific viral proteins that are essential for the replication cycle and structural integrity of the virion. The L segment encodes the RNA-dependent RNA polymerase (RdRp), which is responsible for transcription and replication of the viral genome. The M segment encodes the precursor of the envelope glycoproteins Gn and Gc, which are later processed and incorporated into the viral envelope to mediate host cell entry. The S segment encodes the nucleocapsid (N) protein, which binds and encapsidates viral RNA, forming ribonucleoprotein complexes that protect the genome from degradation and are essential for replication and transcription (37).

Beyond its structural role, the nucleocapsid protein also contributes to immune evasion by interfering with host innate immune responses. Importantly, the segmented nature of the hantavirus genome allows for genetic reassortment when multiple strains co-infect the same host cell. This mechanism significantly enhances viral genetic diversity and plays a key role in the emergence of novel strains with altered virulence, host range, and epidemiological characteristics (36, 37).

Molecular biology and replication cycle

Viral attachment and entry

Hantaviruses exhibit a broad cellular tropism, with primary infection occurring in endothelial cells, macrophages, dendritic cells, and epithelial cells. This tropism is a key determinant of disease pathology, particularly the vascular dysfunction observed in hantavirus-associated syndromes. Viral entry is initiated through interactions between the viral surface glycoproteins (Gn and Gc) and specific host cell receptors. Several cellular receptors have been implicated in this process, including β3 integrins, β1 integrins, decay-accelerating factor (DAF/CD55), and protocadherin-1 (PCDH1). Among these, PCDH1 has been identified as a particularly critical entry receptor for New-World hantaviruses, including Andes virus, Sin Nombre virus, Laguna Negra virus (LANV), Black Creek Canal virus (BCCV) and New York virus (NYV) highlighting its importance in zoonotic transmission and human pathogenicity (35).

Following receptor engagement, hantaviruses enter host cells predominantly through clathrin-mediated endocytosis. Once internalized, the virions are transported into endosomal compartments, where progressive acidification of the endosomal environment triggers conformational changes in the viral glycoproteins. These changes facilitate fusion between the viral envelope and the endosomal membrane, leading to the release of viral ribonucleoprotein complexes into the cytoplasm, where subsequent stages of replication are initiated.

Replication and transcription

Hantavirus replication is entirely cytoplasmic, distinguishing it from many other RNA viruses that involve nuclear stages (Figure 3). The viral RNA-dependent RNA polymerase mediates both transcription and genome replication through a cap-snatching mechanism, whereby short capped RNA fragments are cleaved from host mRNAs and used to initiate viral mRNA synthesis. This strategy not only ensures efficient translation of viral proteins but also contributes to host protein synthesis shutoff and immune evasion (39).

Following translation, viral proteins are synthesized in the cytoplasm and subsequently directed to intracellular membrane compartments, particularly the Golgi apparatus, which serves as the primary site for virion assembly. The nucleocapsid proteins encapsidate newly synthesized viral RNA segments, forming ribonucleoprotein complexes that interact with glycoprotein-enriched membranes for assembly. Mature virions are then transported through the secretory pathway and released via exocytosis. Overall, the hantavirus replication cycle is highly dependent on host cellular machinery, intracellular trafficking systems, and membrane dynamics, underscoring the virus’s tight adaptation to its mammalian hosts.

Reservoir hosts and ecology

Rodents represent the primary natural reservoir hosts of hantaviruses and play a central role in maintaining viral circulation in nature. In contrast to humans, infected rodent hosts typically remain asymptomatic, despite sustaining persistent infections over long periods. This asymptomatic persistence facilitates continuous viral shedding into the environment, particularly through urine, feces, and saliva, thereby sustaining transmission within rodent populations and enabling occasional zoonotic spillover to humans (39).

Distinct hantavirus species are closely associated with specific rodent hosts, reflecting long-standing co-evolutionary relationships. For example, Sin Nombre virus is primarily maintained in deer mouse populations (Peromyscus maniculatus), while Hantaan virus is associated with the striped field mouse. Seoul virus is carried by the Norway rat (Rattus norvegicus), which has a cosmopolitan distribution and contributes to its global epidemiological relevance. Andes virus, one of the few hantaviruses capable of person-to-person transmission, is primarily associated with the long-tailed pygmy rice rat (Table 1). These host-specific associations are critical for understanding geographic distribution patterns and predicting outbreak risks (40).

Table 1. Distinct hantavirus species reservoirs.

Although rodents are widely recognized as the principal reservoirs of hantaviruses, several important questions remain unresolved regarding reservoir ecology and host competence. Not all rodent species carrying hantavirus RNA necessarily represent true maintenance reservoirs capable of sustaining long-term viral transmission within natural populations. The biological and immunological determinants that define reservoir competence remain poorly understood, including host genetics, immune tolerance, viral persistence mechanisms, and ecological interactions. Furthermore, distinguishing incidental spillover hosts from true maintenance hosts continues to be challenging, particularly as novel hantaviruses are increasingly identified in rodents, shrews, bats, and other small mammals through metagenomic surveillance. Improved longitudinal ecological studies integrating virology, wildlife ecology, and host immunology are needed to clarify reservoir dynamics and better predict the conditions favoring zoonotic spillover.

Transmission pathways

Transmission dynamics are strongly influenced by rodent population density, which in turn is regulated by environmental and ecological factors. Climatic fluctuations, particularly El Niño Southern Oscillation (ENSO) events, can increase precipitation and food availability, leading to rapid expansions in rodent populations. Such population booms are often correlated with increased viral circulation and elevated risk of human exposure. Additionally, anthropogenic environmental changes, including deforestation, urbanization, and agricultural intensification, have significantly altered rodent habitats and increased the frequency of human–rodent interactions. These ecological disruptions have been recognized as key drivers in the emergence and re-emergence of hantavirus outbreaks in both rural and peri-urban settings (41, 42).

Rodent-to-human transmission

Human hantavirus infections are primarily acquired through zoonotic spillover from infected rodent reservoirs. The dominant route of transmission is the inhalation of aerosolized viral particles originating from contaminated rodent excreta, including urine, feces, and saliva. In enclosed or poorly ventilated environments, these particles can remain suspended in the air, significantly increasing the likelihood of inhalation and subsequent infection. In addition to airborne transmission, infection may also occur through direct contact with contaminated surfaces (fomites), where viral particles are transferred to mucous membranes via hand-to-mouth, hand-to-nose, or hand-to-eye contact. Although considerably less frequent, rodent bites have also been reported as a potential route of transmission. Consumption of food or water contaminated by rodent excreta further represents an additional, albeit indirect, exposure pathway (43, 44).

Epidemiologically, hantavirus infection is strongly associated with occupational and environmental exposure. High-risk groups include farmers, forestry workers, military personnel engaged in field operations, laboratory workers handling infected materials, as well as campers and hikers exposed to natural rodent habitats. Environments characterized by poor sanitation, rodent infestation, and inadequate ventilation significantly amplify transmission risk, particularly during activities that disturb contaminated dust, such as cleaning enclosed spaces or agricultural work (43–45).

Human-to-human transmission

Unlike most hantaviruses, for which transmission occurs almost exclusively through exposure to infected rodent reservoirs, ANDV is the only hantavirus with well-documented evidence of human-to-human transmission. Epidemiological investigations conducted in South America have demonstrated secondary transmission primarily among individuals with close and prolonged contact with infected patients, including household members, sexual partners, caregivers, and, less frequently, healthcare workers. Available evidence suggests that transmission occurs mainly during the prodromal phase of illness, when infected individuals exhibit high viral loads but only non-specific symptoms, thereby increasing the likelihood of unrecognized exposure (46–48).

Although person-to-person transmission of Andes virus is well established, such events remain uncommon and have generally been limited to small transmission chains rather than sustained community spread. Nevertheless, recent outbreak investigations, including clusters reported in confined settings such as cruise ships, have renewed interest in understanding the transmission dynamics of Andes virus and underscore the importance of rapid case identification, contact tracing, and appropriate infection prevention measures to limit secondary transmission among high-risk contacts (49).

The biological basis underlying the unique transmissibility of Andes virus remains one of the most important unresolved questions in hantavirus research. While several hypotheses have been proposed—including differences in viral glycoprotein structure, tissue tropism, receptor usage, viral shedding dynamics, and host immune responses—the precise viral and host determinants responsible for person-to-person transmission have yet to be elucidated. Likewise, it remains unclear whether other hantavirus species possess a similar but as yet undetected transmission potential, as opportunities to detect such events are limited by the rarity of outbreaks and the relatively small number of detailed molecular and epidemiological investigations. Addressing these knowledge gaps through integrated comparative genomic, structural, experimental, and epidemiological studies will be critical for elucidating the mechanisms governing hantavirus transmissibility and strengthening preparedness for future outbreaks.

Pathogenesis and immune responses

Hantavirus disease is defined clinically by a profound increase in vascular permeability resulting from endothelial dysfunction rather than direct cytopathic injury to infected cells. Hantaviruses preferentially infect vascular endothelial cells and can persist without causing overt lysis, such that host immune responses—rather than viral-mediated cell death—are the primary drivers of tissue injury and clinical severity (Figure 4) (50).

Innate immune sensing and early responses. Hantaviral infection is detected by host pattern-recognition receptors (PRRs), including endosomal Toll-like receptors (TLR3 and TLR7) and cytosolic RNA sensors such as retinoic acid–inducible gene I (RIG-I) and melanoma differentiation–associated protein 5 (MDA5). Activation of these sensors initiates downstream signaling via MAVS and TRIF, resulting in type I interferon (IFN-I) production and induction of interferon-stimulated genes (ISGs) that constrain viral replication. Nevertheless, many hantaviruses encode mechanisms to blunt IFN-I signaling, delaying antiviral responses and permitting viral persistence in endothelial compartments. Concurrent activation of innate myeloid cells (monocytes, macrophages, and dendritic cells) and natural killer (NK) cells amplifies local inflammation through secretion of cytokines and chemokines (e.g., TNF-α, IL-6, CXCL10), recruiting effector leukocytes to infected vascular beds (51).

Adaptive immunity and immune effectors. Robust adaptive responses follow initial innate activation. CD8+ cytotoxic T lymphocytes (CTLs) expand and recognize hantavirus-derived peptides presented by infected endothelial and antigen-presenting cells, mediating antiviral cytotoxicity and cytokine production (notably IFN-γ). B cell responses generate neutralizing antibodies directed primarily against the viral glycoproteins (Gn/Gc), which correlate with viral clearance and protective immunity in convalescent patients and animal models. However, the timing, magnitude, and quality of T- and B-cell responses influence outcome; delayed neutralizing antibody production or dysregulated CTL activity can exacerbate tissue damage and vascular leakage (50–53).

Immune-mediated pathogenesis. The clinical manifestations of Hantavirus Cardiopulmonary Syndrome (HCPS) and Hemorrhagic Fever with Renal Syndrome (HFRS) reflect organ-specific consequences of systemic immune dysregulation. Excessive CTL activation and innate immune hyperactivation produce a cytokine milieu characterized by elevated TNF-α, IL-6, IFN-γ, and other proinflammatory mediators, contributing to endothelial barrier disruption and a “cytokine storm” phenotype (52, 53). Complement activation, platelet dysfunction, and coagulation abnormalities further potentiate vascular permeability, thrombocytopenia, and microvascular leakage. Endothelial cell signaling pathways—particularly those regulating adherens and tight junction integrity (VE-cadherin, junctional adhesion molecules) and cytoskeletal dynamics—are dysregulated by inflammatory mediators and direct virus–host interactions, leading to increased paracellular permeability without frank endothelial death. Organ tropism determines clinical presentation: pulmonary vascular leakage predominates in HCPS (non-cardiogenic pulmonary edema, hypoxemia, cardiogenic shock), whereas renal microvascular injury and hemorrhagic manifestations are more characteristic of HFRS (53, 54).

Immunopathology versus viral control: a delicate balance. Evidence from patient cohorts and experimental models indicates that disease severity is often linked to an imbalanced immune response: insufficient early antiviral signaling permits viral persistence, while subsequent overexuberant adaptive and innate effector responses drive pathology. Markers of immune activation (high cytokine levels, activated CTL phenotypes, elevated soluble endothelial activation markers) correlate with poor outcomes and increased vascular leak, underscoring the dual role of immunity in both viral control and tissue injury (54, 55).

Implications for therapeutics and vaccines. Understanding the immunological determinants of protection versus pathology guides translational strategies. Therapeutic approaches under investigation seek to restore antiviral control while limiting immune-mediated damage—examples include early administration of neutralizing antibodies or antiviral agents to reduce antigenic burden, and targeted immunomodulation (e.g., cytokine blockade, complement inhibitors) to temper hyperinflammation. Vaccine design efforts focus on eliciting rapid neutralizing antibody responses and balanced T-cell immunity, with attention to epitope selection and adjuvantation that minimize immunopathogenic profiles. Finally, biomarkers of immune activation (cytokine signatures, CTL activation markers, complement activation products) may stratify patients for immunomodulatory interventions and predict clinical trajectories.

Clinical manifestations

Incubation period

The incubation period of hantavirus infections typically ranges from 1 to 8 weeks, depending on the infecting viral species, inoculum size, and route of exposure. This relatively long and variable incubation period complicates early epidemiological tracing and contributes to delayed diagnosis, particularly in sporadic cases (56–59).

Hemorrhagic fever with renal syndrome

HFRS is primarily observed in Europe and Asia and is caused by Old-World hantaviruses eg. Hantaan virus (HTNV), Dobrava–Belgrade virus (DOBV), Puumala virus (PUUV), Seoul virus (SEOV), Amur virus (AMRV). The clinical course is classically divided into five distinct phases: febrile, hypotensive, oliguric, polyuric, and convalescent phases. The febrile phase is characterized by sudden onset of high fever, severe headache, myalgia, and malaise. As the disease progresses into the hypotensive phase, patients may develop vascular leakage and shock. The oliguric phase is marked by acute kidney injury, reduced urine output, and metabolic disturbances, followed by a polyuric phase during which renal function gradually recovers but fluid imbalance may occur. Finally, the convalescent phase reflects gradual restoration of physiological homeostasis. Clinically, HFRS presents with fever, headache, myalgia, hypotension, and varying degrees of hemorrhagic manifestations, including petechiae and internal bleeding in severe cases. Mortality rates vary significantly depending on the viral strain, ranging from less than 1% in milder infections to approximately 15% in more severe cases (57–66).

Hantavirus cardiopulmonary syndrome

HCPS, primarily associated with New-World hantaviruses, is characterized by rapid and often severe respiratory compromise. The early phase of HCPS is non-specific and includes symptoms such as fever, fatigue, myalgia, and gastrointestinal disturbances, which may lead to misdiagnosis during initial presentation. As the disease progresses, patients rapidly develop severe respiratory symptoms, including dyspnea, pulmonary edema, hypoxia, and ultimately cardiogenic shock. HCPS is distinguished by its fulminant progression and high case-fatality rate, which can reach 40–50% in severe cases despite intensive supportive care. The rapid deterioration underscores the importance of early recognition and supportive management in suspected cases (57–66).

Diagnosis

The diagnosis of hantavirus infection is based on a combination of clinical suspicion, epidemiological exposure history, and confirmatory laboratory testing. Given the non-specific early clinical presentation and overlap with other febrile and respiratory illnesses, laboratory confirmation is essential for accurate diagnosis (66–74). Although serological and molecular diagnostic techniques have substantially improved the detection of hantavirus infections, important diagnostic limitations persist. Early diagnosis remains difficult because initial clinical manifestations are non-specific and molecular detection is often limited to a relatively narrow window of viremia. Serological assays may also exhibit cross-reactivity among closely related hantavirus species, potentially complicating species identification in endemic regions. Furthermore, access to molecular diagnostics, including real-time RT-PCR and genomic sequencing, remains limited in many resource-constrained settings where surveillance infrastructure is insufficient. The development of rapid, highly sensitive point-of-care diagnostic assays capable of simultaneously differentiating clinically relevant hantavirus species represents an important priority for improving clinical management, surveillance, and outbreak response.

Serological methods

Serological assays represent the most widely used diagnostic approach in clinical settings. Detection of virus-specific immunoglobulin M (IgM) by enzyme-linked immunosorbent assay (ELISA) is commonly used for the diagnosis of acute infection. The presence of IgM antibodies indicates recent exposure and active or very recent infection. Immunoglobulin G (IgG) seroconversion or a significant rise in IgG titers between acute and convalescent samples provides further confirmation of infection and is particularly useful in retrospective diagnosis. Immunofluorescence assays also contribute to serological detection, offering an alternative method for identifying hantavirus-specific antibodies, particularly in resource-limited settings (67–70).

Molecular diagnostics

Molecular techniques have become increasingly important for early and precise detection of hantavirus infection. Reverse transcription polymerase chain reaction (RT-PCR) enables the detection of viral RNA during the acute phase of infection, often before the development of detectable antibody responses. Real-time quantitative PCR further allows for viral load estimation and improved sensitivity. In addition, viral genome sequencing provides valuable information for strain identification, molecular epidemiology, and tracking of viral evolution during outbreaks (71, 72).

Differential diagnosis

Due to its non-specific initial presentation, hantavirus infection must be differentiated from a range of other infectious diseases. These include influenza, COVID-19, dengue fever, leptospirosis, bacterial sepsis, and other causes of viral pneumonia. Careful evaluation of epidemiological exposure, clinical progression, and laboratory findings is therefore critical to avoid misdiagnosis and ensure appropriate clinical management (72–76).

Treatment strategies

Therapeutic options for hantavirus infections remain limited, and supportive care continues to represent the cornerstone of clinical management. Although ribavirin has demonstrated benefit against certain Old-World hantaviruses when administered early, clinical outcomes have been inconsistent across studies, and its efficacy in HCPS remains unproven. Similarly, promising antiviral candidates such as favipiravir, monoclonal antibodies, and immunomodulatory therapies are supported primarily by preclinical investigations or limited clinical evidence. A major barrier to therapeutic progress is the scarcity of adequately powered randomized controlled trials, largely due to the sporadic nature of outbreaks and relatively low case numbers in most endemic regions. International multicenter clinical collaborations will therefore be essential to establish evidence-based therapeutic recommendations and accelerate the development of effective antiviral interventions. Currently, there is no universally approved, virus-specific antiviral therapy for hantavirus infections, and management remains primarily supportive. Early recognition and timely admission to intensive care units are crucial factors in improving patient outcomes (38, 77–79).

Supportive care

Supportive management constitutes the cornerstone of treatment and includes oxygen supplementation and advanced respiratory support in cases of respiratory failure. In severe presentations such as HCPS, mechanical ventilation and extracorporeal membrane oxygenation (ECMO) may be required to manage refractory hypoxemia and cardiopulmonary collapse. Hemodynamic stabilization through fluid management and vasoactive support is essential in cases of shock. Additionally, renal replacement therapy may be necessary for patients with acute kidney injury, particularly in HFRS. Early and aggressive supportive care has been consistently associated with improved survival rates (38, 77).

Antiviral agents

Among antiviral compounds, ribavirin has demonstrated partial efficacy against certain Old-World hantaviruses, particularly when administered early in the course of infection. However, its effectiveness remains variable and is not universally established. Favipiravir has shown promising antiviral activity in experimental models, although clinical data remain limited and its use is still under investigation. In addition, monoclonal antibodies targeting hantavirus glycoproteins have emerged as a promising therapeutic strategy, offering the potential for highly specific neutralization of viral entry mechanisms (77–81).

Experimental nanomedicine approaches

Recent advances in nanotechnology have opened new avenues for antiviral intervention against hantaviruses. Nanoparticle-based drug delivery systems, liposomal formulations, and immunomodulatory nanocarriers are being explored to enhance targeted delivery, improve drug stability, and increase antiviral efficacy. These approaches may enable the development of inhalable or intranasal therapeutic platforms capable of directly targeting the respiratory tract, which is a primary site of viral entry and pathology (82–86).

Vaccines and prevention

Vaccines

Decades of intensive research notwithstanding, no universally approved vaccine providing broad protection against hantavirus infections is currently available. To date, licensed vaccines are limited to a few inactivated formulations used primarily in China and South Korea for the prevention of hemorrhagic fever with renal syndrome (HFRS) caused by selected Old-World hantaviruses. Although these vaccines have demonstrated protective efficacy against regionally circulating strains, their use remains geographically restricted and they provide limited protection against the diverse spectrum of hantaviruses, particularly the New-World species responsible for hantavirus cardiopulmonary syndrome (HCPS). The development of a universal hantavirus vaccine remains particularly challenging because of the extensive genetic and antigenic diversity among hantavirus species, which limits the induction of broad cross-protective immunity. In addition, the immunological correlates of durable protection are not yet fully understood, making it difficult to identify the most appropriate vaccine antigens, optimize immunization strategies, and establish reliable efficacy endpoints during clinical development. These challenges continue to hinder the translation of promising preclinical candidates into licensed vaccines.

To overcome these limitations, multiple next-generation vaccine platforms are currently under investigation. These include DNA vaccines, mRNA-based vaccines, recombinant viral vector vaccines, and virus-like particle (VLP)-based vaccines, all of which aim to induce robust humoral and cellular immune responses capable of preventing infection or mitigating disease severity (77, 87–92). Advances in structural biology, reverse vaccinology, and immunogen design have further accelerated the identification of conserved viral epitopes that may serve as targets for broadly protective vaccine candidates.

Future vaccine development should prioritize the identification of conserved protective epitopes shared across hantavirus species, the characterization of immune correlates associated with long-lasting protection, and the development of universal vaccine platforms capable of eliciting broad cross-protective immunity against both Old-World and New-World hantaviruses. Achieving these objectives will be essential for improving global preparedness against the expanding public health threat posed by emerging hantaviruses.

Prevention measures

Primary prevention

Primary prevention remains the cornerstone of hantavirus control, as no universally available vaccine or specific antiviral prophylaxis currently exists for most hantavirus infections. Because transmission to humans occurs predominantly through exposure to infected rodent reservoirs and their excreta, preventive strategies are primarily aimed at interrupting zoonotic spillover by reducing opportunities for human–rodent contact. Effective environmental management therefore constitutes the first line of defense against infection.

Key preventive measures include maintaining good environmental sanitation to eliminate potential rodent food sources and nesting sites, storing food and water in tightly sealed containers, and implementing rodent-proofing strategies in homes, workplaces, and storage facilities to prevent infestation. Regular waste disposal, sealing structural openings, and controlling rodent populations around residential and occupational settings further reduce the likelihood of human exposure. In addition, proper ventilation of enclosed, abandoned, or poorly ventilated spaces is essential before cleaning or entering these environments, as aerosolized viral particles released from contaminated urine, feces, or nesting materials can accumulate and become infectious when disturbed. Wet-cleaning and disinfection methods should be preferred over sweeping or vacuuming to minimize aerosol generation and reduce the risk of inhalational exposure (93, 94). Collectively, these measures substantially decrease the probability of primary zoonotic transmission.

Occupational prevention

Individuals with occupational or recreational exposure to rodent-infested environments require additional preventive measures due to their increased risk of infection. High-risk groups include agricultural workers, forestry personnel, wildlife and pest-control workers, military personnel, laboratory staff handling infected materials, and individuals involved in cleaning rodent-infested buildings. In these settings, the use of appropriate personal protective equipment (PPE), including respirators or well-fitted masks, disposable gloves, protective clothing, and eye protection when necessary, is recommended during activities that may disturb contaminated dust or rodent nesting materials. Adherence to established biosafety protocols, environmental decontamination procedures, and occupational health guidelines is essential to minimize exposure and prevent accidental infection (93–95).

Community-level prevention

Community-based prevention complements individual and occupational measures by promoting public awareness and strengthening local preparedness in endemic areas. Educational campaigns play a critical role in informing communities about the routes of hantavirus transmission, strategies for preventing rodent infestation, safe cleaning and disinfection practices, and the importance of avoiding direct contact with rodents or their excreta. Public health initiatives should also encourage early recognition of potential exposure events and prompt medical consultation when compatible symptoms develop following high-risk exposure. By improving risk perception and encouraging preventive behaviors, community education contributes significantly to reducing the incidence of hantavirus infections and limiting zoonotic transmission (93–96).

Viral evolution and genetic diversity

Hantaviruses exhibit considerable genetic diversity, which is shaped by multiple evolutionary mechanisms, including mutation, genomic reassortment, host adaptation, and geographic isolation. The segmented nature of the hantavirus genome facilitates reassortment events when distinct viral strains co-infect the same host, leading to the emergence of novel genotypes with potentially altered pathogenicity or host range. This genetic flexibility contributes significantly to the evolutionary success and epidemiological persistence of hantaviruses. Phylogenetic analyses provide strong evidence supporting long-term coevolution between hantaviruses and their specific rodent hosts, suggesting a relatively stable host–virus relationship over evolutionary timescales. However, environmental and ecological disturbances may disrupt this equilibrium. Climate-driven changes, including shifts in temperature and precipitation patterns, can alter rodent population dynamics and geographic distribution, potentially increasing interspecies transmission and facilitating the emergence of novel viral strains. Such ecological pressures may therefore act as catalysts for viral diversification and expansion into new ecological niches (97–101).

Outbreak risk and public health preparedness

The emergence of SARS-CoV-2 and the global spread of mpox have highlighted the growing importance of zoonotic viruses as public health threats. In this context, questions have emerged regarding whether hantaviruses possess the potential to trigger future large-scale epidemics or pandemics (102–108).

Currently, hantaviruses differ substantially from SARS-CoV-2 in their transmission dynamics. Most hantavirus species are primarily transmitted through exposure to infected rodent excreta rather than sustained human-to-human transmission, which significantly limits their pandemic potential. Nevertheless, certain species such as Andes virus have demonstrated limited interpersonal transmission, indicating that evolutionary adaptation cannot be entirely excluded.

Compared with mpox outbreaks, hantavirus infections are generally characterized by lower transmissibility but substantially higher case fatality rates in severe forms such as HPS. Consequently, while a COVID-19-like global pandemic caused by hantaviruses currently appears unlikely, localized outbreaks with serious clinical consequences remain a persistent concern, particularly in endemic regions and areas experiencing ecological disruption (106–110).

The lessons learned from both the COVID-19 pandemic and recent mpox outbreaks underscore the importance of proactive surveillance, rapid diagnostics, international collaboration, and preparedness strategies for emerging zoonotic pathogens, including hantaviruses.

Future perspectives

Regardless of the advances in virology and clinical management, several challenges continue to hinder effective control of hantavirus infections globally. These include the absence of widely available specific antiviral therapies, the lack of a universal vaccine, persistent underdiagnosis due to non-specific early symptoms, ecological unpredictability of rodent reservoirs, and incomplete surveillance systems in many endemic and resource-limited regions. Future control strategies should prioritize the development of pan-hantavirus vaccines capable of providing broad protection across multiple strains and geographic regions. In parallel, the discovery of broad-spectrum antiviral agents remains a critical research goal. Advances in diagnostic technologies, particularly rapid point-of-care assays, are also essential for improving early detection and outbreak containment. Emerging computational approaches, including artificial intelligence–assisted outbreak prediction models, may enhance surveillance capabilities by integrating ecological, climatic, and epidemiological data. In addition, expanding genomic surveillance will be crucial for monitoring viral evolution, tracking emerging strains, and understanding transmission dynamics, as demonstrated by the comprehensive, multifactorial approaches adopted during the SARS-CoV-2 pandemic, which integrated genomic, environmental, and demographic factors (111, 112). Novel therapeutic approaches, including immunotherapy, monoclonal antibody platforms, and nanotechnology-based drug delivery systems, represent promising avenues that may significantly improve future clinical management and reduce hantavirus-associated morbidity and mortality (113, 114).

Conclusion

Hantaviruses remain major emerging zoonotic pathogens with significant outbreak potential and considerable public-health impact. Their transmission is closely linked to rodent reservoirs, while environmental change and globalization continue to facilitate spillover and geographic expansion. Andes virus is especially important because it can also transmit between humans under limited but clinically significant circumstances.

The absence of widely approved antivirals and vaccines highlights the importance of prevention, early detection, and preparedness. Future work should focus on reservoir ecology, viral evolution, host–pathogen interactions, immunopathogenesis, and the translation of promising therapeutic and predictive approaches into evidence-based interventions.

Although hantaviruses are unlikely to cause a COVID-19-like pandemic under current evidence, increasing ecological disruption and global connectivity require sustained surveillance, interdisciplinary research, and coordinated One Health preparedness to prevent future high-consequence outbreaks.

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Footnotes

Edited by: Masako Nomaguchi, Tokushima University, Japan

Reviewed by: Kalimuthu Karuppanan, Sai University, India

Jessenia Sabrina Navas Castillo, Hospital Roosevelt, Guatemala