Hantavirus infections: A growing global health concern

Abstract

Hantaviruses are increasingly regarded as an important emerging risk to global health, with an estimated annual impact on more than 200000 people worldwide. These pathogens are single-stranded RNA viruses belonging to the family Hantaviridae and are known to cause two major clinical syndromes in humans: Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The so-called old world hantaviruses, which are associated with HFRS, are predominantly distributed across Asia, Europe, and parts of Africa. In contrast, new world hantaviruses, responsible for HPS, are largely confined to North and South America. Each year, approximately 150000-200000 HFRS cases require hospitalization globally, with the greatest burden occurring in developing regions. The mortality rate of HFRS ranges from below 1% to about 12%, depending on the infecting strain. Both disease forms are characterized by increased capillary permeability, leading to clinical features such as hypotension, thrombocytopenia, and leukocytosis. While HFRS has a broader geographic distribution, HPS carries a higher risk of death. Moreover, the detection of new viral strains and the steady rise in reported cases have intensified global concern. Enhancing surveillance systems and expanding laboratory diagnostic capacity are therefore essential for effective monitoring and control of hantavirus diseases.

Key Words: Hantavirus infection; Hantaviridae; Hemorrhagic fever with renal syndrome; Hantavirus pulmonary syndrome; Global health threat; Leukocytosis

Core Tip: Hantavirus infections represent an expanding global zoonotic threat characterized by high mortality rates and limited therapeutic options. This article provides an updated and integrated overview of hantavirus biology, epidemiology, clinical manifestations, diagnostic strategies, and emerging therapeutic approaches. Particular emphasis is placed on recent advances in molecular virology, RNA-based antiviral technologies, monoclonal antibody therapy, and next-generation vaccine platforms, including mRNA and DNA vaccines. By combining classical clinical perspectives with contemporary translational research, this review identifies key gaps in current knowledge and proposes future directions for surveillance, therapeutic development, and global preparedness.

INTRODUCTION

Hantaviruses are rodent-borne, enveloped, negative-sense RNA viruses currently classified in the family Hantaviridae, order Bunyavirales. Historically, they were grouped under the family Bunyaviridae, but current International Committee on Taxonomy of Viruses taxonomy recognizes Hantaviridae as a distinct family and are most commonly associated with reservoir hosts such as rats, mice, and voles. In humans, these viruses are responsible for two major clinical syndromes: Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). HFRS is linked to old world hantaviruses that circulate predominantly in Asia, Europe, and parts of Africa, whereas HPS is caused by new world hantaviruses and is mainly reported in North and South America[1].

Both conditions share a key pathological feature - enhanced vascular permeability -which leads to manifestations such as hypotension, thrombocytopenia, and leukocytosis. Although HFRS occurs more frequently, HPS is associated with a substantially higher mortality rate due to severe pulmonary involvement. At present, management of both syndromes is largely supportive, as no specific antiviral therapy has been universally approved for hantavirus infection. It is also important to note that not all hantaviruses are pathogenic in humans; certain species, including Prospect Hill orthohantavirus, have not been linked to human disease[2].

HFRS

HFRS is primarily associated with hantavirus infections occurring in Asia and Europe. The severity of the disease ranges widely, from asymptomatic or mild cases to life-threatening illness, depending on the viral strain involved. Following an incubation period of approximately two weeks to four weeks, patients typically develop nonspecific symptoms such as high fever, chills, headache, back pain, abdominal discomfort, nausea, and vomiting. This initial febrile phase is often followed by the appearance of petechial hemorrhages and hypotension, which may progress to more extensive internal bleeding. Subsequently, renal impairment develops, leading to complications that can be fatal in severe cases. A milder European variant of HFRS, known as nephropathia epidemica, is characterized by less severe renal involvement and lower mortality. Historical accounts suggest that the condition referred to as “trench nephritis” during World War I was likely an early description of HFRS[3].

HPS

HPS, also referred to as hantavirus cardiopulmonary syndrome (HCPS), is most commonly reported in the Americas and is associated with new world hantaviruses. The incubation period generally ranges from about 16 days to 24 days. The early phase of the illness resembles that of HFRS, with nonspecific symptoms such as fever, myalgia, and malaise. Within a few days, patients develop a sudden onset of respiratory involvement characterized by cough, progressive dyspnea, and tachycardia, resulting from fluid accumulation in the lungs. These pulmonary manifestations are often accompanied by dysfunction of lymphoid tissues and rapid clinical deterioration. In severe cases, cardiovascular shock can develop quickly and may lead to death (Table 1). Although HCPS is predominantly linked to new world hantaviruses, rare instances of similar cardiopulmonary disease have been reported in Europe in association with Puumala orthohantavirus infection[4].

Table 1 Critical comparison of hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome pathogenesis and clinical outcomes.

Parameter	HFRS	HPS
Major viral group	Old World hantaviruses	New world hantaviruses
Main target organ	Kidney and vascular system	Lung and cardiovascular system
Key pathology	Increased vascular permeability with renal endothelial dysfunction	Pulmonary capillary leakage and myocardial depression
Dominant clinical feature	Fever, hemorrhage, thrombocytopenia, acute kidney injury	Fever, rapidly progressive pulmonary edema, shock
Mortality	Usually < 1%-12%, depending on strain	Often 30%-50%
Immune mechanism	Cytokine-mediated endothelial activation and renal inflammation	Strong inflammatory response causing pulmonary vascular leakage
Treatment response	Ribavirin may help if given early	Ribavirin benefit is limited or unclear
Main reason for difference	Longer disease evolution allows earlier antiviral intervention	Rapid cardiopulmonary phase occurs when immunopathology dominates

HFRS: Hemorrhagic fever with renal syndrome; HPS: Hantavirus pulmonary syndrome.

The specific “vector” or carrier depends on the region and the strain of the virus

Deer mouse (Peromyscus maniculatus): The primary carrier of the Sin Nombre virus in North America, which causes HPS.

Cotton rat (Sigmodon hispidus): A common carrier in the Southeastern United States.

Rice rat (Oryzomys palustris): Another key carrier found in the Southeastern United States.

White-footed mouse (Peromyscus leucopus): Found mainly in the Northeastern United States.

Bank vole (Myodes glareolus): The most common carrier in Europe, spreading the Puumala virus.

Norway rat (Rattus norvegicus): The worldwide host for the Seoul virus, which causes HFRS (Figure 1).

Figure 1 Major rodent reservoirs associated with human-pathogenic hantaviruses. Representative rodent reservoirs include rat. Human infection occurs mainly through inhalation of aerosolized virus from contaminated rodent urine, feces, or saliva.

Several investigational drugs have demonstrated the ability to improve survival when administered during the early phase of hantaan virus (HTNV) infection. Compounds such as lactoferrin, ribavirin, endothelin type-A receptor antagonist, favipiravir, and vandetanib have shown promising antiviral activity in experimental models. In addition to small-molecule agents, immunotherapeutic approaches using neutralizing antibodies derived from convalescent hantavirus patients have exhibited protective effects against HTNV. Specific monoclonal antibodies, including MIB22 and JL16, have been reported to confer significant protection in preclinical studies[5].

The continued development of both antiviral agents and vaccines - either as standalone therapies or in combination - remains essential for improving disease outcomes and reducing the public health burden of hantaviral infections. Among emerging strategies, RNA interference (RNAi) has gained attention as a highly targeted antiviral approach. This mechanism operates through post-transcriptional gene silencing in eukaryotic cells, leading to the degradation of viral RNA. RNAi-based methods, particularly those employing small interfering RNA (siRNA), have demonstrated the capacity to inhibit multiple viruses in both in vitro and in vivo systems[6].

In the context of hantavirus, siRNA molecules designed to target the small (S), medium (M), or large (L) genomic segments have been shown to enhance viral RNA clearance in cell culture models such as vero E6 cells and human lung microvascular endothelial cells. Despite these encouraging findings, several limitations remain, including poor biological stability, rapid degradation, and challenges in achieving efficient delivery to target tissues in vivo. Consequently, although siRNA can effectively suppress hantavirus replication at the cellular level, its therapeutic application may be constrained without further improvements in delivery systems and molecular stability[7].

ETIOLOGY AND VIROLOGY OF HANTAVIRUSES

Hantaviruses were first recognized during the early 1950s among United Nations soldiers stationed in Korea. The disease was later named after the Hantaan River, located near the area where many of the initial cases were reported. In North America, the most prevalent hantavirus is the Sin Nombre virus, which is primarily carried by the deer mouse (Peromyscus maniculatus) and was identified following an outbreak in the southwestern United States in 1993. In South America, the Andes virus is the dominant strain; it is notable for its high virulence and is the only hantavirus known to be transmitted between humans[8].

Members of the genus Orthohantavirus are enveloped viruses with a negative-sense, single-stranded RNA genome (Table 2). Their genome consists of three segments that encode the RNA-dependent RNA polymerase (RdRp), glycoproteins, and nucleocapsid (N) protein. The viral particles measure approximately 70-160 nm in diameter. Hantaviruses primarily infect endothelial and epithelial cells, as well as dendritic cells and lymphocytes, through interactions between viral glycoproteins and specific host cell surface receptors[9].

Table 2 Classification and geographic distribution of major hantaviruses.

Virus name (orthohantavirus)	Primary reservoir host	Geographic distribution	Associated disease	Approximate case fatality rate	Human-to-human transmission
HTNV	Apodemus agrarius (Striped field mouse)	China, Korea, Russia	HFRS	5%-12%	No
PUUV	Myodes glareolus (Bank vole)	Northern and Central Europe	HFRS/nephropathia epidemica	< 1%	No
SEOV	Rattus norvegicus, Rattus rattus	Worldwide (Urban areas)	HFRS	~ 1%	No
DOBV	Apodemus flavicollis	Balkans, Eastern Europe	Severe HFRS	Up to 10%	No
SNV	Peromyscus maniculatus (Deer mouse)	North America (United States, Canada)	HPS	30%-40%	No
ANDV	Oligoryzomys longicaudatus	Argentina, Chile	HPS	35%-50%	Yes (documented)
BCCV	Sigmodon hispidus (Cotton rat)	Southeastern United States	HPS	~ 30%	No
BAYV	Oryzomys palustris (Marsh rice rat)	Southern United States	HPS	Variable	No
LANV	Calomys laucha	Paraguay, Bolivia	HPS	~ 20%-30%	No
PHV	Microtus pennsylvanicus (Vole)	North America	Non-pathogenic	Not applicable	No

HTNV: Hantaan virus; PUUV: Puumala virus; SEOV: Seoul virus; DOBV: Dobrava-Belgrade virus; SNV: Sin Nombre virus; ANDV: Andes virus; BCCV: Black Creek Canal virus; BAYV: Bayou virus; LANV: Laguna Negra virus; PHV: Prospect Hill virus; HFRS: Hemorrhagic fever with renal syndrome; HPS: Hantavirus pulmonary syndrome.

Immature dendritic cells are thought to facilitate viral dissemination through lymphatic tissues, enabling replication within regional lymph nodes. Infection of endothelial cells triggers a strong immune response, particularly involving CD8⁺ T lymphocytes and macrophages. Unlike several other hemorrhagic fever viruses that suppress dendritic cell maturation, hantaviruses promote the maturation of infected dendritic cells and induce a robust T-cell-mediated immune reaction during the acute phase of disease[10].

Cellular entry of the virus is mediated by β3 integrins, which also play a role in platelet activation and regulation of vascular permeability. Endothelial infection stimulates the production of interferon-alpha, contributing to the early prodromal symptoms. As the disease progresses, circulating immunoblasts and hantavirus-specific T-cell clones can be detected in peripheral blood. Activated macrophages and lymphocytes migrate to the pulmonary interstitium, where the release of pro-inflammatory mediators such as tumor necrosis factor-alpha, interferon-gamma, and nitric oxide leads to marked capillary leakage and pulmonary edema. These soluble factors are also implicated in myocardial depression, which may culminate in cardiogenic shock in severe cases[11].

Hantaviruses infect endothelial, epithelial, dendritic, and lymphoid cells through interactions between viral glycoproteins and host-cell receptors. Pathogenic hantaviruses are mainly associated with β3-integrin usage, whereas non-pathogenic hantaviruses may preferentially interact with β1-integrins. After receptor binding, viral entry occurs mainly through endocytosis. Acidification of the endosome induces conformational changes in the Gn/Gc glycoproteins, resulting in membrane fusion and release of viral ribonucleoprotein (RNP) complexes into the cytoplasm.

VIROLOGY

According to the current International Committee on Taxonomy of Viruses classification, hantaviruses are assigned to the family Hantaviridae within the order Bunyavirales. The earlier classification of hantaviruses under the family Bunyaviridae is now considered historical. Therefore, in this article, the term Hantaviridae is used consistently for current taxonomy, while Bunyaviridae is mentioned only where older literature or historical classification is being discussed. The virions are enveloped, roughly spherical, and measure about 95-120 nm in diameter. Under electron microscopy, they display a characteristic surface pattern produced by the helical arrangement of the N protein. Their genome is composed of three segments of negative-sense, single-stranded RNA, designated as L, M, and S. The L segment encodes the viral RdRp, the M segment codes for the two envelope glycoproteins (G1/Gn and G2/Gc), and the S segment encodes the N protein responsible for forming the filamentous RNP complex[12].

Phylogenetic analyses based mainly on the S and M genome segments have identified multiple hantavirus clades, each usually associated with a specific small-mammal reservoir and geographic range. New world hantaviruses are generally associated with HPS, whereas old world hantaviruses are more commonly linked to HFRS; however, overlapping clinical manifestations can occur. Genetic reassortment between distant hantavirus lineages appears uncommon, although limited reassortment has been observed among closely related Sin Nombre virus variants. Sequence variation, especially in the S segment and in glycoprotein regions containing neutralizing epitopes, may influence host adaptation, immune recognition, and viral evolution[13].

In contrast to other segmented RNA viruses such as influenza and rotavirus, genetic reassortment between distant hantavirus lineages appears to be uncommon. Limited reassortment has been observed among closely related Sin Nombre virus variants in cell culture, occasionally producing transient diploid particles containing duplicated genome segments; however, these forms are unstable and not maintained. Generally, hantaviruses in the Americas are associated with HPS, whereas those with a broader Eurasian distribution are linked to HFRS, although overlapping clinical manifestations can occur.

For laboratory propagation, hantaviruses grow more efficiently in vero cell lines than in primary human cells. Unlike many negative-strand RNA viruses, they lack a matrix protein typically involved in viral assembly. During replication, granular or filamentous inclusions can be seen within the cytoplasm. Most old world hantaviruses assemble and bud into smooth intracellular vesicles, whereas certain new world species, including Sin Nombre and Black Creek Canal viruses, bud directly from the plasma membrane. Studies using polarized epithelial cells have shown that Black Creek Canal virus preferentially infects the apical surface and releases substantially higher amounts of virus from this domain[14].

Phylogenetic classification based mainly on the S and M genome segments has identified numerous hantavirus clades, each usually associated with a specific rodent reservoir that is geographically restricted. New world hantaviruses form a separate evolutionary group from old world strains. Since the identification of Sin Nombre virus in 1993, many additional hantaviruses have been discovered. Sequence variation is often silent or well tolerated, but single amino acid substitutions in the glycoproteins can alter key neutralizing epitopes and enable escape from antibody recognition. In Puumala virus, the major immunodominant region is located within the N-terminal portion of the N protein. The S segment tends to exhibit greater sequence variability than the M segment. Adaptation of Puumala virus to high-titer growth in vero E6 cells has been shown to reduce its ability to infect its natural rodent host, a change linked to mutations in noncoding regions of the S segment rather than in protein-coding sequences.

Hantaviruses are spherical to pleomorphic, enveloped viruses that belong to the family Hantaviridae. Their virion typically measures 80-120 nm in diameter and possesses a lipid envelope derived from the host cell membrane[15].

Viral envelope

The outer layer is a host-derived lipid bilayer embedded with two viral glycoproteins, glycoprotein precursor (Gn and Gc). These glycoproteins are arranged as spike-like projections on the surface and play a key role in attachment to host cell receptors, membrane fusion, and viral entry. The glycoproteins are produced as a single precursor that is later cleaved into Gn and Gc within the Golgi apparatus.

Genome organization

Hantaviruses contain a tripartite, single-stranded, negative-sense RNA genome consisting of three segments (Figure 2).

Figure 2 Structural organization of hantavirus virion. AI tools were used only to generate this figure using OpenAI’s ChatGPT image generation system (DALL·E) based on author-prepared scientific prompts. The schematic shows the enveloped hantavirus virion with Gn/Gc glycoproteins, three ribonucleoprotein complexes, and the S, M, and L genome segments encoding N protein, Gn/Gc, and RNA-dependent RNA polymerase, respectively. RdRp: RNA-dependent RNA polymerase; RNP: Ribonucleoprotein.

S segment: Encodes the N protein.

M segment: Encodes the Gn and Gc.

L segment: Encodes the RdRp.

Each RNA segment is coated with multiple copies of the N protein, forming RNP complexes.

N protein

The N protein binds tightly to the viral RNA, protecting it from degradation and maintaining the genome in a stable conformation. It also plays regulatory roles in transcription, replication, and assembly of new virions.

Viral polymerase

Associated with each RNP is the L protein, which functions as the viral RdRp. This enzyme is responsible for both mRNA synthesis and genome replication within the cytoplasm of infected cells.

Internal organization

Unlike some enveloped viruses, hantaviruses lack a classical matrix protein. Instead, interactions between the cytoplasmic tails of Gn/Gc and the RNP complexes help coordinate virion assembly within the Golgi compartment.

Life cycle of hantavirus

Hantaviruses are enveloped, negative-sense, single-stranded RNA viruses belonging to the family Hantaviridae. Their replication cycle occurs entirely in the cytoplasm of host cells, primarily targeting endothelial cells[16].

Viral attachment and entry: The infection begins when the viral surface glycoproteins (Gn and Gc) bind to specific host cell receptors, mainly β-integrins and other attachment factors present on endothelial and immune cells. Following receptor engagement, the virus enters the cell through clathrin-mediated endocytosis, forming an endocytic vesicle.

Membrane fusion and uncoating: Acidification of the endosome triggers conformational changes in the viral glycoproteins, allowing fusion of the viral envelope with the endosomal membrane. This process releases the viral RNP complexes into the cytoplasm.

Transcription of viral RNA: Hantaviruses carry a tripartite genome consisting of the S, M, and L segments. The viral RdRp, encoded by the L segment, initiates transcription by a cap-snatching mechanism, stealing capped primers from host mRNAs to synthesize viral messenger RNAs.

Translation of viral proteins: The S segment produces the N protein, which encapsidates viral RNA and regulates replication. The M segment encodes a glycoprotein precursor that is processed in the endoplasmic reticulum and Golgi apparatus into the Gn and Gc envelope glycoproteins. The L segment is translated into the viral polymerase.

Genome replication: Once sufficient N protein is available, the virus switches from transcription to replication, generating full-length positive-sense antigenomes, which then serve as templates for the production of new negative-sense genomic RNA segments.

Assembly of viral particles: Newly synthesized genomic RNA segments associate with N protein and RdRp to form RNP complexes. These complexes are transported to the Golgi complex, where they interact with Gn and Gc embedded in Golgi membranes.

Budding and release: Unlike many enveloped viruses that bud at the plasma membrane, hantaviruses assemble and bud into the Golgi cisternae. The mature virions are then transported in secretory vesicles to the cell surface and released by exocytosis (Figure 3).

Figure 3 Hantavirus infection and life cycle. AI tools were used only to generate this figure using OpenAI’s ChatGPT image generation system (DALL·E) based on author-prepared scientific prompts. RdRp: RNA-dependent RNA polymerase; RNP: Ribonucleoprotein; ssRNA: Single-stranded ribonucleic acid; vRNA: Viral ribonucleic acid; ER: Endoplasmic reticulum.

Epidemiology

Hantavirus infection in humans is regarded as a zoonotic spillover event that can lead to two major clinical syndromes: HFRS and HPS. Transmission typically occurs through inhalation of aerosolized viral particles originating from the urine, feces, or saliva of infected rodents. Direct contact with contaminated materials or rodent hosts also contributes to infection. Human-to-human transmission is rare but has been documented for Andes virus[17]. HFRS is associated with old world hantaviruses and is predominantly reported in East Asia and Europe, particularly in China, Korea, and parts of Russia. China alone accounts for more than 100000 cases annually, while several hundred cases are reported each year in Korea and eastern Russia. In Europe, most cases occur in Russia, Finland, and Sweden. The disease is more common among males between 20 years and 50 years of age and is largely observed in rural settings where rodent reservoirs are abundant. The case fatality rate varies according to the viral strain but generally ranges from approximately 0.1% to 10%. Unlike other hantaviruses, Seoul virus can cause infections in urban environments because its reservoir hosts are commensal rats (Rattus norvegicus and Rattus rattus)[18]. HPS, which has a significantly higher mortality rate of about 40%-50%, is caused by new world hantaviruses such as Sin Nombre virus, Andes virus, Monongahela virus, New York virus, Black Creek Canal virus, Bayou virus, and several recently identified strains. In the United States, most HPS cases occur in the western regions and are primarily linked to Sin Nombre virus infection. Outbreaks are often associated with increases in the population of the deer mouse (Peromyscus maniculatus), the principal reservoir host. Beyond North America, HPS has also been reported in multiple countries across Central and South America, including Argentina, Brazil, Chile, Bolivia, Paraguay, Uruguay, and Panama.

General properties of hantaviruses

Hantaviruses are enveloped, spherical to pleomorphic RNA viruses classified within the family Hantaviridae, order Bunyavirales. Members associated with human disease are mainly placed in the genus Orthohantavirus. Their genome consists of three segments of negative-sense, single-stranded RNA that share conserved terminal sequences. These segments are designated as S, M, and L, encoding the N protein, the envelope glycoproteins (Gn and Gc), and the viral RdRp, respectively. Similar to other enveloped viruses, hantaviruses are sensitive to heat, detergents, ultraviolet radiation, organic solvents, and disinfectants such as hypochlorite, which can effectively inactivate the virus. Cellular infection occurs when viral glycoproteins bind to specific host surface receptors on endothelial, epithelial, dendritic, and lymphoid cells. Evidence suggests that nonpathogenic hantaviruses preferentially utilize β1-integrins for cell entry, whereas pathogenic strains interact mainly with β3-integrins. Viral replication takes place in the cytoplasm, and the glycoproteins are transported to the Golgi apparatus, where viral assembly and budding occur for most hantaviruses[14]. In contrast, Sin Nombre virus has been shown to bud from the plasma membrane. Although hantaviruses from Eurasia and the Americas share similar replication strategies, recent studies indicate that they may have undergone distinct evolutionary adaptations in their interactions with host cellular machinery.

Symptoms

The incubation period for hantavirus infection is typically about two to three weeks before symptoms begin. HPS generally progresses through two clinical phases. The initial phase lasts several days and is characterized by nonspecific symptoms such as fever, chills, myalgia, and headache. Gastrointestinal complaints, including nausea, abdominal discomfort, vomiting, and diarrhea, may also be present in some patients[19]. As the illness advances, the cardiopulmonary phase develops, marked by injury to the pulmonary endothelium and accumulation of fluid within the lungs. This leads to rapidly worsening respiratory distress along with cardiovascular involvement. Patients may present with cough, shortness of breath, hypotension, and cardiac rhythm abnormalities, reflecting impaired lung and heart function.

Transmission

Hantaviruses are shed in the urine, feces, and saliva of infected rodents, and humans become infected through several exposure routes. The most common mode of transmission is inhalation of aerosolized viral particles released when rodent excreta or nesting materials are disturbed. Infection can also occur through ingestion of food contaminated with rodent secretions, or by touching contaminated surfaces and subsequently contacting the mouth, nose, or eyes. Less frequently, transmission may result from rodent bites or scratches.

Person-to-person spread of hantaviruses is considered very rare. So far, this type of transmission has only been confirmed with the Andes virus, which is found in parts of South America. In most cases, people become infected through exposure to infected rodents or their waste products, not through contact with other individuals.

Diagnosis

Initial suspicion of hantavirus infection is based on clinical presentation consistent with HFRS, HCPS, or nephropathia epidemica, along with epidemiological risk factors. A detailed patient history is essential, particularly regarding recent travel to rodent-infested areas or exposure to rodents and their excreta. Basic laboratory investigations such as a complete blood count and peripheral smear may provide supportive findings, including thrombocytopenia and leukocytosis.

Definitive diagnosis is primarily achieved through serological testing. Detection of anti-hantavirus antibodies in patient serum is the most widely used approach. IgM antibodies typically appear early in the course of infection, whereas IgG antibodies develop later and indicate either current or past exposure. Enzyme-linked immunosorbent assay and strip immunoblot assays are commonly employed for antibody detection; although cross-reactivity with other viral antigens may occur, they remain valuable diagnostic tools. Indirect immunofluorescence assays offer higher specificity but are more time-consuming. Virus neutralization tests provide the greatest specificity; however, they are technically demanding, costly, and require biosafety level-3 laboratory facilities. Rapid immunochromatographic assays are simple and inexpensive but may have reduced accuracy due to cross-reactivity[20].

Molecular diagnostic methods include real-time reverse transcription polymerase chain reaction, which is a rapid and sensitive technique for detecting viral RNA in blood, clots, or tissue samples. Its utility is limited to the viremic phase of infection. Advanced methods such as microarray analysis allow simultaneous detection of multiple viral pathogens, while next-generation sequencing enables complete genomic characterization; both techniques are expensive and require specialized data analysis[21].

Virological confirmation can be achieved through virus isolation in cell culture, which facilitates detailed functional studies but is labor-intensive and requires specialized personnel and high-containment laboratories. Immunohistochemical and immunofluorescence techniques can also detect viral antigens in tissue specimens, although these methods involve complex preparation procedures (Table 3).

Table 3 Diagnostic methods for hantavirus infection.

Diagnostic method	Target detected	Diagnostic accuracy	Field/clinical utility	Limitations	Optimal timing of use
ELISA (IgM/IgG detection)	Anti-hantavirus antibodies	High sensitivity	Widely available, cost-effective, suitable for screening large populations	Possible cross-reactivity with other viral antigens	Acute and convalescent phases
IFA	Viral antibodies	High specificity	Reliable confirmation method; useful for sero-epidemiological studies	Labor-intensive, requires fluorescence microscopy	Acute phase confirmation
NeutralizationTest (PRNT/FRNT)	Neutralizing antibodies	Very high specificity (gold standard)	Confirms protective immunity and virus strain identification	Requires BSL-3 Laboratory, expensive, technically demanding	Research and confirmatory diagnosis
Immunochromatographic rapid tests	IgM/IgG antibodies	Moderate sensitivity	Rapid, easy to perform, suitable for field settings	Reduced accuracy and cross-reactivity issues	Early screening in endemic regions
RT-PCR	Viral RNA (S, M, L segments)	Very high sensitivity during viremia	Rapid and highly specific detection; useful for early diagnosis	Limited detection window; requires molecular laboratory	Early acute phase (viremic stage)
NGS	Whole viral genome	Very high accuracy	Enables strain identification, mutation analysis, and outbreak tracking	High cost, complex bioinformatics analysis	Research and surveillance
Microarray analysis	Multiple viral sequences	High sensitivity	Simultaneous detection of diverse pathogens	Expensive and technically complex	Advanced research settings
Virus isolation in cell culture	Live virus	Highly specific	Enables functional studies and antiviral testing	Time-consuming; requires BSL-3 containment	Research applications
IHC	Viral antigens in tissues	High specificity	Useful in post-mortem or biopsy samples	Requires skilled personnel and tissue preparation	Severe or fatal cases

ELISA: ; IFA: Indirect immunofluorescence assay; PRNT: Plaque reduction neutralization test; FRNT: Focus reduction neutralization test; RT-PCR: Reverse transcription-polymerase chain reaction; NGS: Next-generation sequencing; BSL: Biosafety level; IHC: Immunohistochemistry.

TREATMENT AND PREVENTION

At present, there are no antiviral drugs, vaccines, or immunotherapeutic agents that have received United States Food and Drug Administrations approval for the treatment of hantavirus-associated diseases, including HFRS and nephropathia epidemica. Ribavirin has demonstrated antiviral activity against several members of the order Bunyavirales, including hantaviruses, in experimental and limited clinical settings. Experimental models, such as HTNV-infected suckling mice, have shown improved survival following ribavirin administration. Clinical studies conducted in China indicate that early initiation of ribavirin therapy in HFRS patients is associated with better outcomes, including a substantial reduction in mortality when given within the first week of illness. Intravenous ribavirin has also been reported to decrease the incidence of oliguria and lessen the severity of renal impairment in HFRS. The different clinical response to ribavirin in HFRS and HPS may be related to differences in disease kinetics and dominant pathology. In HFRS, the clinical course is comparatively slower and renal involvement develops over several phases, allowing a wider window for early antiviral intervention before severe organ injury occurs. In contrast, HPS often progresses abruptly from nonspecific prodromal symptoms to pulmonary edema and cardiovascular shock. By the time HPS is clinically recognized, immune-mediated endothelial dysfunction and capillary leakage may already dominate over active viral replication, reducing the benefit of direct antiviral therapy such as ribavirin. Therefore, ribavirin appears more useful when given very early in HFRS, whereas its role in established HPS remains limited and uncertain. Clinical trials in HPS patients have not demonstrated clear therapeutic benefit, although the drug was generally well tolerated; anemia was a common adverse effect, and some patients required blood transfusion. These findings suggest that the effectiveness of ribavirin may depend on the timing of administration and the stage of disease[22].

Because HPS often progresses rapidly to respiratory failure and circulatory shock, management is primarily supportive and requires prompt intensive care. Early transfer to a facility capable of advanced cardiopulmonary monitoring is essential. Treatment focuses on maintaining adequate oxygenation and hemodynamic stability, often necessitating mechanical ventilation for several days. In severe cases, invasive monitoring with a pulmonary artery catheter may be required to guide fluid and cardiovascular management. Pulmonary edema, hypotension, and cardiac arrhythmias are important indicators of poor prognosis and require aggressive treatment[23].

Prevention of hantavirus infection relies mainly on minimizing exposure to rodent reservoirs. Key measures include reducing rodent access to food and shelter in and around dwellings, eliminating infestations, and using appropriate protective precautions when cleaning areas contaminated with rodent excreta. Additional preventive strategies are recommended for individuals with occupational or recreational exposure to rodents, such as agricultural workers, military personnel, and campers. The development of effective vaccines remains a priority, particularly for populations in endemic regions and for high-risk professional groups. Current vaccine research has largely focused on viral glycoproteins that induce neutralizing antibody responses, and DNA-based vaccine candidates for HTNV are undergoing early clinical evaluation. Such approaches may play an important role in reducing the future burden of hantavirus disease[24].

Future perspective and policy recommendation

Current knowledge regarding the pandemic potential and pathogenesis of hantavirus infections remains incomplete. Important gaps persist in understanding the environmental drivers of outbreaks, the mechanisms of viral maintenance in natural reservoirs, and the processes that facilitate transmission to humans. With more than 35 recognized hantavirus species and the likelihood of additional variants being identified, the genetic and evolutionary diversity of these viruses is greater than previously appreciated.

Given these uncertainties, proactive measures are essential. Strengthening international scientific collaboration, increasing funding support, and promoting coordinated efforts by public health authorities and research institutions are critical for advancing knowledge of hantavirus ecology, transmission dynamics, and human disease. Detailed investigation of zoonotic spillover pathways and the rare instances of person-to-person transmission will be vital for designing effective prevention and control strategies. Identification of ecological and environmental factors that promote rodent population growth and human exposure should also be prioritized[25].

From a therapeutic perspective, rapid evaluation of repurposed drugs offers a practical short-term approach, as the development of novel antivirals and vaccines is time-consuming. Integration of artificial intelligence-based platforms may accelerate the discovery of candidate therapeutics and improve predictive modeling of outbreaks. In parallel, establishing open data-sharing networks that include genomic, proteomic, immunological, and host-response information will enhance global research capacity and preparedness[26].

Overall, a multidisciplinary and coordinated strategy is required to mitigate the risk of future hantavirus outbreaks. Continued surveillance, improved diagnostics, targeted prevention measures, and accelerated therapeutic research are essential to protect public health and reduce the impact of these emerging zoonotic infections[27].

Surveillance of hantavirus infections remains weak in many low-resource countries due to limited laboratory facilities, poor access to molecular diagnostics, and low clinical awareness. Mild or atypical cases are often misdiagnosed as other febrile illnesses, leading to underreporting. Rodent reservoir monitoring is also inadequate, and environmental risk data are rarely integrated with human case reporting. Strengthening affordable diagnostics, clinician training, rodent surveillance, and One Health-based reporting systems is essential for early detection and outbreak preparedness.

CURRENT CHALLENGES AND KNOWLEDGE GAPS

Despite improved understanding of hantavirus infections, several gaps remain. The mechanisms that determine renal involvement in HFRS and severe cardiopulmonary injury in HPS are not fully defined. Differences in disease progression may also explain why ribavirin appears more useful in early HFRS but has limited benefit in HPS, where rapid immune-mediated vascular leakage often dominates.

Diagnosis is another major challenge

Serological tests are useful but may miss very early infections, while real-time reverse transcription polymerase chain reaction is limited by the short viremic window and need for molecular facilities. Field-friendly, rapid, affordable, and strain-inclusive diagnostic tools are still lacking.

Vaccine development also remains difficult because of viral diversity, limited cross-protection, unclear immune correlates, and the need for large clinical trials. In low-resource settings, underreporting is common due to weak surveillance, poor laboratory access, and limited rodent monitoring. Strengthening One Health-based surveillance, diagnostics, and translational research is essential for better preparedness.

Future treatment strategies for hantavirus infection

Hantavirus infections continue to pose a serious public health challenge due to their high mortality rates and the absence of specific, universally effective antiviral therapies[28,29]. Current management is largely supportive, highlighting the urgent need for improved treatment approaches. Future therapeutic strategies are therefore focused on antiviral development, immune modulation, and preventive interventions.

One promising area of research involves the development of targeted antiviral drugs that can inhibit viral replication at an early stage of infection. Novel small-molecule inhibitors aimed at blocking viral RNA synthesis and entry into host cells are under investigation. Advances in molecular virology may enable the identification of viral proteins that serve as ideal drug targets, potentially reducing disease severity when administered promptly.

Monoclonal antibody therapy represents another emerging strategy. Neutralizing antibodies designed to bind specific hantavirus surface glycoproteins could prevent viral entry into host cells. Passive immunotherapy using human or humanized antibodies may be especially beneficial for high-risk individuals or during outbreak situations, offering immediate but temporary protection.

Research is also expanding into host-directed therapies that modulate the immune response. Since severe hantavirus disease is often associated with an exaggerated inflammatory reaction, drugs that regulate cytokine release and endothelial dysfunction may reduce complications such as pulmonary edema and vascular leakage. Immunomodulatory agents could help balance antiviral immunity while limiting tissue damage.

The use of RNA-based therapies, including siRNA, is an innovative approach being explored. These therapies aim to silence viral genes essential for replication, thereby limiting viral spread within the host. Although still in experimental stages, such technologies offer high specificity and reduced off-target effects.

In addition to treatment, vaccine development remains a critical long-term goal. Future vaccines may utilize recombinant proteins, viral rodent reservoirs, or mRNA platforms to induce durable immunity against multiple hantavirus strains. Successful vaccination would significantly reduce the global burden of hantavirus disease and minimize reliance on therapeutic interventions.

hantavirus vaccine approval remains difficult due to wide viral diversity, limited cross-protection, sporadic outbreaks, and challenges in conducting large clinical trials. Unclear correlates of protective immunity, limited long-term safety data, regulatory requirements, and low commercial investment further delay vaccine development. Multicenter studies, standardized endpoints, and stronger global funding are needed to advance vaccine approval.

In conclusion, future treatment of hantavirus infection is likely to involve a combination of antiviral agents, immune-based therapies, and preventive vaccines. Continued research and clinical trials are essential to translate these promising strategies into effective and accessible treatments.

RECENT ADVANCEMENTS IN HANTAVIRUS TREATMENT AND PREVENTION

Neutralizing antibodies and immunotherapy

One of the most promising areas of research is the development of neutralizing antibodies that can block the virus from infecting cells. Scientists have identified broadly neutralizing antibodies that target key surface proteins of hantaviruses and can protect against different strains when given before or even after exposure. These advances improve our understanding of how the human immune system can neutralize hantaviruses and support the design of antibody-based therapies[30].

Additionally, a major research initiative funded through an small business innovation research award aims to develop human neutralizing antibody therapies specifically against Andes virus, which causes severe HCPS. These antibodies could serve as both treatment and prophylaxis (pre-exposure protection) for high-risk populations.

Vaccine development - including mRNA platforms

A major recent development is the collaboration between Korea University’s Vaccine Innovation Center and Moderna to create an mRNA-based hantavirus vaccine. This partnership leverages mRNA vaccine technology (similar to that used for coronavirus disease 2019) to develop vaccines that can induce strong immune responses and potentially protect against a broader range of hantavirus strains. Preclinical studies in mice have shown effective protection against infection when vaccinated with experimental mRNA candidates.

In addition, experimental hantavirus vaccines using DNA-based platforms have shown the ability to elicit strong neutralizing antibody responses in animal models, suggesting protection both as preventive vaccines and for post-exposure therapy.

Antiviral drug candidates

Although specific antiviral drugs for hantavirus are not yet approved, novel antiviral compounds are being explored: (1) Favipiravir, an antiviral originally developed for influenza, has shown activity against Andes virus in cell models, indicating it might help limit viral replication; (2) Natural compounds like urolithin B, found in some foods, also demonstrated the ability to inhibit hantavirus infection in lab models and may have protective effects on infected cells; and (3) These findings provide early leads for drug development that could reduce disease severity even if they cannot eliminate the virus completely.

RNA-based approaches and gene silencing

Research into RNAi - which uses short RNA molecules like siRNAs to target and degrade viral genetic material - has shown effectiveness against hantavirus in cell cultures, suggesting a potential antiviral strategy that directly disrupts viral replication.

CONCLUSION

Hantavirus infections remain important emerging zoonotic diseases with significant clinical and public health consequences. Although supportive care is currently the mainstay of management, the absence of widely approved specific antivirals and globally accepted vaccines continues to limit disease control. Ribavirin and other antiviral candidates have shown encouraging results in experimental studies and selected clinical settings, but stronger evidence from well-designed human trials is still required.

Recent progress in neutralizing antibodies, RNA-based approaches, and DNA or mRNA vaccine platforms provides promising directions for future prevention and treatment. However, these strategies must be further evaluated for safety, efficacy, durability, affordability, and field applicability. To enable widespread deployment, larger phase clinical studies are required to confirm efficacy, durability of protection, and safety across diverse populations.

Overall, effective control of hantavirus disease requires integrated surveillance, early diagnosis, rodent exposure reduction, ecological monitoring, and international research collaboration. Strengthening these areas will be essential to reduce morbidity and mortality and improve preparedness for future outbreaks.

At present, there are no regulatory-approved specific treatments for hantavirus infections. Nevertheless, several antiviral agents have demonstrated potential activity against hantaviruses, primarily in cell culture systems and experimental animal models. Because clinical evidence in humans remains limited, well-designed controlled trials are essential to determine their true therapeutic value and safety profile. Although supportive care remains the cornerstone of current management, these emerging approaches highlight a shift toward targeted and mechanism-based interventions. Continued research, clinical trials, and global collaboration are essential to translate these scientific advances into effective, safe, and accessible treatments for hantavirus infection in the future.

ACKNOWLEDGEMENTS

I acknowledge my Sincere thanks to Maharajah’s College of Pharmacy, Vizianagaram for its continuous support and cooperation.