Hantavirus: Complete Microbiology Guide on Structure, Transmission, Pathogenesis, Diagnosis, Treatment, and Vaccine Development

 

• Introduction to Hantavirus 
• History and Discovery of Hantavirus 
• Classification and Taxonomy of Hantavirus 
• Types of Hantaviruses 
• Structure of Hantavirus 
• Genome Organization of Hantavirus 
• Transmission of Hantavirus 
• Life Cycle and Replication Mechanism of Hantavirus 
• Pathogenesis of Hantavirus 
• Geographical Distribution of Hantavirus
• Diseases Caused by Hantavirus 
• Signs and Symptoms of Hantavirus
• Diagnosis of Hantavirus Infection 
• Treatment and Clinical Management of Hantavirus
• Prevention and Control Measures of Hantavirus
• Recent Global Outbreaks and Epidemiology 
• Public Health Importance of Hantavirus
• Challenges in Hantavirus Research of Hantavirus
• Current Advances in Vaccine Development of Hantavirus
• Conclusion 
• References

Introduction to Hantavirus 

• Hantaviruses are enveloped, negative-sense, single-stranded RNA viruses with a tri-segmented genome (S, M, L segments) encoding nucleoprotein (N), glycoproteins (Gn and Gc), and RNA-dependent RNA polymerase (RdRp).
• They belong to the family Hantaviridae (order Bunyavirales) and are primarily maintained in populations of rodents, shrews, moles, bats, and occasionally other animals; each virus is typically associated with a specific host species.
• Transmission to humans occurs mainly through inhalation of aerosolized excreta (urine, feces, saliva) from infected reservoir hosts; human-to-human transmission is rare but has been documented for Andes virus.
• Hantavirus infection in humans can cause two main clinical syndromes: hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS/HPS) in the Americas; both syndromes involve increased vascular permeability and can be severe or fatal.
• The morphology of hantaviruses is generally spherical or pleomorphic with a diameter of 80–160 nm; the viral envelope contains tetrameric spikes formed by Gn and Gc glycoproteins.
• The genome organization is highly conserved: S segment encodes nucleocapsid protein, M segment encodes glycoprotein precursor (cleaved into Gn and Gc), L segment encodes RdRp; some S segments also encode a nonstructural protein involved in immune evasion.
• In their natural hosts, hantaviruses establish persistent infections without causing disease; in humans, infection leads to acute febrile illness with potential for severe complications such as renal failure (HFRS) or respiratory failure (HCPS).
• The pathogenesis involves immune-mediated mechanisms leading to increased capillary permeability, thrombocytopenia, and organ dysfunction; genetic predisposition may influence disease severity.
• There are currently no FDA/EMA-approved vaccines or specific antiviral treatments for hantavirus infections outside of China and Korea; management is primarily supportive care. Prevention relies on rodent control and minimizing exposure to contaminated environments.
• Hantaviruses are considered an emerging global public health threat, with outbreaks linked to ecological changes affecting reservoir populations. Surveillance and public awareness are critical for risk reduction.

History and Discovery of Hantavirus

Early clinical descriptions (pre-20th century–1940s)

• Illnesses resembling hantavirus disease were described in Chinese writings ~900 years ago and in Russian records from Siberia by 1913, often with kidney complications later recognized as hemorrhagic fever with renal syndrome (HFRS).
• Similar “field nephritis” affected troops in World Wars I and II in Europe and Asia, likely hantavirus disease before the virus was known.

Korean War and search for the agent (1950s–1970s)

• During the Korean conflict (1950–53), >3,000 UN troops developed “Korean hemorrhagic fever,” bringing global attention but the cause remained unknown.
• In 1964, Thottapalayam virus was isolated from an Asian house shrew in India, later recognized as a hantavirus but initially seen as an anomaly.

Discovery of Hantaan virus and classic HFRS agents (1970s–1980s)

• In 1976–78, Hantaan virus was isolated from striped field mice, definitively linking a rodent-borne virus to Korean hemorrhagic fever and launching modern hantavirus research.
• Soon after, Puumala virus (mild nephropathia epidemica) and Seoul virus (urban rat–associated) were identified, followed by other rodent-borne hantaviruses across Eurasia.
• The genus Hantavirus was formally created in 1987, with Hantaan virus as the prototype, within family Bunyaviridae.

Emergence in the Americas and global recognition (1990s)

• In 1993, a lethal respiratory disease in the U.S. Four Corners region was traced within weeks to a new hantavirus, Sin Nombre virus, causing hantavirus pulmonary/cardiopulmonary syndrome (HPS/HCPS) and carried by deer mice.
• This discovery revealed hantaviruses as global zoonotic pathogens, with many novel New World hantaviruses soon described.

Expansion beyond rodents and taxonomic changes (2000s–present)

• Since the 2000s, many divergent hantaviruses have been found in shrews, moles, and bats, including Nova virus in European moles and multiple new African, Asian, and American soricomorph and bat viruses, challenging the rodent-only paradigm and suggesting deeper evolutionary origins in nonrodent hosts.
• The family has expanded to numerous genera and >50 species; the former genus Hantavirus was elevated to family Hantaviridae in the order Bunyavirales, reflecting this diversity and complex host range.

Classification and Taxonomy of Hantavirus 

• Hantaviruses are classified in the order Bunyavirales as the family Hantaviridae; they are most closely related to other bunyaviral families like Peribunyaviridae and Phasmaviridae.
• Hantaviridae viruses share a tri-segmented, negative-sense RNA genome (S, M, L) encoding nucleoprotein (N), glycoprotein precursor (GPC), and L protein (RdRP) and thus form a well-defined taxonomic group.
• Modern taxonomy divides Hantaviridae into 4 subfamilies: Actantavirinae, Agantavirinae, Mammantavirinae, and Repantavirinae.
• Across these subfamilies there are 7 recognized genera: Actinovirus, Agnathovirus, Loanvirus, Mobatvirus, Orthohantavirus, Thottimvirus, and Reptillovirus (earlier work listed 4 genera; taxonomy expanded with new data).
• As of 2023–2024, the family contains ~47–53 accepted species, with numbers increasing as more complete genomes are classified by ICTV.
• The subfamily Mammantavirinae includes the classic mammalian hantaviruses in four genera: Orthohantavirus, Loanvirus, Mobatvirus, Thottimvirus, each largely associated with particular host categories (rodents, shrews, moles, and bats).
• Non-mammalian hantavirids (from fish and reptiles) are placed in separate subfamilies, Actantavirinae, Agantavirinae, and Repantavirinae, reflecting deep evolutionary divergence from mammalian lineages.
• Within species, additional taxonomic levels such as lineages and genotypes are used (e.g., multiple lineages of Hantaan and Seoul viruses defined by S or M segment sequences) to capture finer genetic structure.
• ICTV species demarcation uses genetic distance (e.g., >7% aa difference in glycoproteins), distinct reservoir host/ecological niche, serology (neutralization ≥4 fold differences), and lack of natural reassortment.
• Ongoing revisions by the ICTV Hantaviridae Study Group rely heavily on full-genome phylogenetics (DEmARC analysis) to refine genera, subfamilies, and to reassign misplaced species.

Table 1: Core Taxonomic Hierarchy of the Family Hantaviridae

Taxonomic Level	Classification / Examples
Order	Bunyavirales
Family	Hantaviridae
Subfamilies (4)	Actantavirinae, Agantavirinae, Mammantavirinae, Repantavirinae
Genera (7)	Actinovirus, Agnathovirus, Loanvirus, Mobatvirus, Orthohantavirus, Thottimvirus, Reptillovirus

Types of Hantavirus 

• Hantaviruses are often grouped by geographic distribution and disease type into Old World and New World viruses.
• Old World hantaviruses are mainly found in Europe and Asia and usually cause haemorrhagic fever with renal syndrome (HFRS).
• New World hantaviruses circulate in North, Central and South America and typically cause hantavirus cardiopulmonary/pulmonary syndrome (HCPS/HPS).

Old World Hantaviruses (Asia, Europe, Africa)

• Principal human‑pathogenic Old World viruses include Hantaan (HTNV), Dobrava(-Belgrade) (DOBV), Amur (AMV), Seoul (SEOV), Puumala (PUUV), Saaremaa (SAAV), Tula (TULV).
• Disease: Mainly HFRS; HTNV, AMV, DOBV tend to cause severe HFRS (mortality ~5–15%), SEOV causes moderate, and PUUV/SAAV usually mild disease with mortality <1%.
• Geography & reservoirs:
• HTNV/AMV/DOBV: Asia/Eastern Europe, mainly Apodemus mice.
• PUUV: Northern and central Europe, bank vole (Myodes glareolus).
• SEOV: Worldwide in urban Rattus rats (including U.S. cities).
• Old World–related viruses also identified in Africa (e.g., Sangassou virus) in rodents and shrews.

New World Hantaviruses (Americas)

• Key human‑pathogenic New World viruses: Sin Nombre virus (SNV) in North America and Andes virus (ANDV) in South America; many additional lineages (e.g., Lechiguanas, Andes Central Plata) associated with Sigmodontinae rodents.
• Disease: Primarily HCPS/HPS, a severe cardiopulmonary syndrome with high mortality (~30–50%).
• Reservoirs & features:
• SNV: Deer mice (Peromyscus) in North America.
• ANDV: Main HCPS agent in much of Latin America and only hantavirus with confirmed human‑to‑human transmission.
• Numerous additional New World lineages linked to different sigmodontine rodents in Central/South America.

Overlap and Evolving View

• Old vs New World is mainly geographic and clinical shorthand; phylogenetically, rodent-borne viruses cluster with host subfamilies (Arvicolinae, Murinae, Sigmodontinae) rather than strict “Old/New” labels.
• Clinical overlap exists: Old World PUUV and others can show lung involvement, while New World viruses can involve kidneys, supporting a continuum of “hantavirus disease” rather than two completely separate syndromes.

Table 2: Contrasts Between Old World and New World Hantavirus Groups

Group	Representative Viruses	Main Disease	Typical Regions
Old World	HTNV, DOBV, AMV, SEOV, PUUV, SAAV, TULV	HFRS (mild–severe)	Europe, Asia, parts of Africa, global cities (SEOV)
New World	SNV, ANDV, Lechiguanas / Andes lineages	HCPS / HPS	North, Central, and South America

Structure of Hantavirus 

Enveloped, pleomorphic particles (mostly round, sometimes elongated or tubular) about 80–160 nm in diameter; many studies report averages ~120–150 nm.

Envelope and surface spikes

• Lipid bilayer envelope derived from intracellular membranes, mainly Golgi.
• Envelope is covered by a square, grid‑like lattice of spikes formed by Gn/Gc heterodimers; spikes are tetrameric and extend ~10 nm from the membrane.
• Spikes form ordered patches/lattices on the surface but overall particles lack strict icosahedral symmetry.

Glycoprotein architecture (Gn and Gc)

• Encoded as a single glycoprotein precursor (GPC) from the M segment, cleaved into Gn and Gc.
• Gn: modular protein with head and base ectodomains, transmembrane region and cytoplasmic tail; can form pH‑dependent oligomers and tetramers and helps organize the lattice.
• Gc: class II fusion protein, ectodomain (~450 aa), single transmembrane helix and short tail; trimerizes in post‑fusion state and drives membrane fusion.

Internal ribonucleoproteins (RNPs)

• Genome: three negative‑sense RNA segments (S, M, L) encoding N, GPC (→ Gn/Gc), and L (polymerase).
• Each RNA segment is coated by nucleocapsid protein (N/NP) plus L polymerase, forming rod‑like helical RNPs.
• RNPs appear as 10‑nm rods arranged in parallel pairs/triplets; bends often approach the inner membrane, suggesting contact with glycoprotein cytoplasmic tails.

Nucleocapsid protein structure

• N/NP (~50 kDa) has N‑ and C‑lobes forming an RNA‑binding groove; assembles into helices via domain exchanges between protomers.
• Forms dimers/trimers and higher oligomers; coiled‑coil N‑terminus promotes trimerization, likely an assembly intermediate in RNP and virion formation.

Genome Organization of Hantavirus

Hantaviruses have a tri-segmented, negative-sense RNA genome of about 10.5–14.6 kb divided into small (S), medium (M), and large (L) segments.

Genes encoded by each segment

• S segment: encodes the nucleoprotein (N); in several hantaviruses it also encodes a small nonstructural NSs protein in an overlapping reading frame.
• M segment: encodes a glycoprotein precursor (GPC) that is cleaved into the two envelope glycoproteins Gn and Gc.
• L segment: encodes the L protein, a ~250 kDa RNA‑dependent RNA polymerase (RdRp) that also contains endonuclease, helicase, and cap‑binding regions.

Segment sizes and structure

• Typical size ranges: S ~1.0–3.0 kb, M ~3.4–4.8 kb, L ~5.3–6.8 kb.
• Individual S, M, and L RNAs are single-stranded, negative sense, each with one main open reading frame flanked by untranslated regions (UTRs) at both ends.

Termini and “panhandle” promoter

• The 3′ and 5′ ends of each segment have conserved, complementary sequences, allowing them to base‑pair and form a panhandle structure that acts as the promoter for replication and transcription.
• Terminal complementarity and panhandle integrity are important; deletions at the ends reduce replication efficiency.

Ribonucleoprotein (RNP) organization

• In virions and infected cells, each RNA segment is encapsidated by many N proteins and associated with one L protein, forming three separate RNP complexes.
• These RNPs are helical/rod‑shaped and are the functional templates for mRNA synthesis and genome replication.

Noncoding regions and variability

• Some hantaviruses (e.g., Sin Nombre and related HPS viruses) have unusually long 3′ noncoding regions in the S segment with repetitive elements.
• Genome‑wide analyses show highest sequence divergence in the M segment, followed by S and L, with notable diversity in S‑segment noncoding regions in some species.

Table 3: Hantavirus Genome Segments and Their Functional Roles

Segment	Main Products	Key Roles
S	N (± NSs)	Genome encapsidation, ribonucleoprotein (RNP) formation, immune modulation
M	GPC → Gn, Gc	Envelope spike formation, receptor binding, host cell entry, viral budding
L	L (RdRp)	Replication, transcription, cap snatching

Transmission of Hantavirus

Primary source and reservoir hosts

Hantaviruses are maintained in chronically infected small mammals (mainly rodents; also shrews, moles, bats) that shed virus in urine, feces, and saliva without obvious disease.

Main route to humans: inhalation of contaminated aerosols

• Humans are spillover hosts, usually infected by inhaling aerosolized particles from dried rodent excreta or secretions in homes, barns, fields, or workplaces.
• High risk situations include cleaning rodent infested spaces, agricultural and forestry work, military training, and recreation in endemic rural areas.

Other environmental/indirect exposure routes

• Infection can occur via infectious droplets in dusty, rodent infested areas, and through contaminated food or drinking water.
• Experimental and animal data show the gastrointestinal tract can serve as an entry route; virus can survive gastric conditions (pH > 3), infect intestinal epithelium, and cross into the body.

Direct contact and bites

• Rodent to rodent transmission is largely horizontal, via aggressive interactions (biting) and exposure to fresh excreta; higher host density increases transmission.
• Humans can rarely be infected by rodent bites or direct contact with fresh excreta or carcasses.

Human-to-human transmission

• For almost all hantaviruses, person to person transmission is not supported by comparative epidemiologic studies.
• Andes virus (ANDV) is an exception: clustered cases and observational data indicate limited person to person spread, especially among sex partners, close household contacts, or those exposed to patient body fluids.
• A systematic review concludes that evidence for ANDV human to human transmission exists but is weak and confounded; most contacts do not get infected, and rodent exposure remains the dominant explanation.

Ecological and environmental drivers of transmission

• Rodent population density and community composition strongly shape virus maintenance and spillover risk; transmission can fade out below a critical host density.
• Climate change, rainfall, food supply, landscape alteration, and disturbed habitats (agricultural land, plantations, peridomestic areas) can increase rodent abundance, infection prevalence, and thus human exposure.
• Human mobility between urban and rural/forested zones can amplify the number of exposure events and infections.

Cross-species and spillover transmission

• Hantaviruses are horizontally transmitted within and between rodent species, sometimes infecting multiple sympatric species in a region.
• Spillover to novel rodent hosts and domestic animals occurs and may create additional reservoirs or “bridge hosts” important for local transmission cycles.
• Network studies using rodent–ectoparasite sharing suggest that highly connected rodent species and hotspots of host diversity correspond to higher spillover risk to humans.

Life Cycle and Replication Mechanism of Hantavirus 

Attachment and entry into host cells

• Infection starts when viral Gn/Gc glycoproteins bind cellular receptors (e.g., integrins, PCDH1 for some New World viruses), then virions are internalized by clathrin-mediated or macropinocytosis-like endocytosis and trafficked to endosomes.
• In acidic, cholesterol-rich endosomes, Gc drives membrane fusion, releasing ribonucleoproteins (RNPs) into the cytoplasm to start replication.

Uncoating, transcription, and translation

• After fusion, the three genomic RNPs (S, M, L RNAs coated with N and bound by L polymerase) are released into the cytoplasm, where all further steps occur.
• L polymerase performs cap‑snatching: host mRNA caps are bound and protected by N, then cleaved by the L endonuclease (with a required host factor) to make 10–14 nt capped primers used to start viral mRNA synthesis.
• Polymerase synthesizes one capped mRNA from each segment; S and L mRNAs are translated on free ribosomes, M mRNA on membrane‑bound ribosomes to make GPC → Gn/Gc.
• N also helps preferential translation of viral mRNAs over cellular ones.

Genome replication mechanism

• L polymerase replicates the genome de novo (no primer), using a prime‑and‑realign mechanism: initiation occurs internally (e.g., around nt 3–4) to form a short primer that is then realigned to the 3′ end of the RNA.
• Replication is two‑step: negative‑sense vRNA → positive‑sense cRNA intermediate → new vRNA copies, all packaged as RNPs with N and L.
• Structures of HTNV L show conformational switches between inactive, promoter‑bound, pre‑initiation, and elongation states, coordinating RNA recognition, initiation, and elongation.

Assembly, budding, and release

• Gn/Gc are synthesized in ER, processed, and move to Golgi/ERGIC, where they form spikes; N and RNPs traffic along microtubules to perinuclear ERGIC/Golgi regions.
• Viral assembly likely occurs at internal membranes (Golgi/ERGIC) and/or 
• membrane; budding into these compartments generates enveloped virions that are transported and released, though exact sites remain debated.

Modulation of host pathways for efficient replication

• N protein modulates innate immunity and apoptosis, helps RNP transport, and uses host cytoskeleton and SUMOylation machinery to support replication.
• Some hantaviruses induce autophagy; controlled autophagic clearance of Gn is actually required for efficient replication, and accumulating N, Gc, and genomic RNA later stabilize Gn during assembly.
• HTNV enhances mitochondrial OXPHOS via AKT–PNPT signaling to boost energy supply for replication.

Pathogenesis of Hantavirus

• The primary pathological features of hantavirus infection are increased vascular permeability (capillary leak) and acute thrombocytopenia, which together contribute to fluid leakage into tissues, resulting in edema, hypotension, shock, and hemorrhagic manifestations characteristic of both Hemorrhagic Fever with Renal Syndrome (HFRS) and Hantavirus Cardiopulmonary Syndrome (HCPS).
• Hantaviruses primarily target and infect microvascular endothelial cells located in the lungs, kidneys, and other organs, but notably produce little to no direct cytopathic effect, meaning the infected endothelial cells are generally not destroyed by viral replication itself.
• Despite limited direct cell damage, hantavirus infection causes significant endothelial dysfunction by disrupting normal endothelial barrier integrity, including disturbances in cell-to-cell junctions, downregulation of vascular endothelial cadherin (VE-cadherin), and increased endothelial permeability.
• This enhanced vascular leakage is partly mediated through activation of several molecular pathways, including vascular endothelial growth factor (VEGF) signaling, bradykinin release, and activation of the kallikrein–kinin system, all of which contribute to weakening of the vascular barrier.
• The disease process is considered largely immunopathological, meaning much of the tissue damage and clinical severity results from the host’s exaggerated immune response rather than direct viral destruction of infected cells.
• Hantavirus infection triggers strong innate and adaptive immune responses, often accompanied by hypercytokinemia (cytokine storm-like responses) and excessive activation of natural killer (NK) cells and CD8⁺ cytotoxic T lymphocytes, both of which strongly correlate with the degree of vascular leakage and disease severity.
• Elevated levels of pro-inflammatory mediators, including tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), interleukin-6 (IL-6), chemokines, complement factors, and endothelial adhesion molecules, are commonly observed during infection.
• These inflammatory mediators promote leukocyte recruitment and adhesion to endothelial surfaces, which further amplifies endothelial injury and contributes to progressive barrier dysfunction.
• IL-6 trans-signaling plays a particularly important role in pathogenesis by enhancing cytokine secretion in infected endothelial cells, increasing intercellular adhesion molecule-1 (ICAM-1) expression, and directly promoting endothelial barrier disruption; increased IL-6 trans-signaling has also been closely linked to greater clinical severity in HFRS.
• Platelets interact directly with infected endothelial cells and viral glycoproteins, leading to platelet activation, adhesion, and subsequent depletion from circulation, which contributes to the development of acute thrombocytopenia.
• This platelet consumption not only increases the risk of bleeding complications but may also contribute to intravascular coagulation abnormalities in severe cases.
• Host genetic factors influence disease severity, with certain human leukocyte antigen (HLA) haplotypes, such as HLA-B8, DRB103:02, and HLA-B35, being associated with an increased risk of developing more severe forms of HFRS and HCPS, suggesting an important role for genetic susceptibility in disease outcome.
• A striking contrast exists between humans and natural rodent reservoirs: in reservoir rodents, hantavirus infection is typically persistent but asymptomatic, largely due to locally suppressed pro-inflammatory responses that limit immunopathology.
• In humans, the absence of this immune regulatory balance is thought to permit excessive inflammatory responses, thereby favoring disease development and severe vascular pathology.
• The clinical manifestations depend on the primary site of vascular leakage: predominant leakage in the renal medullary capillaries results in acute kidney injury, the hallmark of HFRS, whereas leakage in pulmonary capillaries causes pulmonary edema and cardiopulmonary failure, which define HCPS.
• Although classically described as separate syndromes, HFRS and HCPS represent overlapping clinical entities that exist along a continuum of hantavirus disease, with shared pathogenic mechanisms centered on endothelial dysfunction, immune dysregulation, and vascular leakage.

Geographical Distribution of Hantavirus

• Hantavirus infections in humans occur worldwide, with major disease forms: hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia and hantavirus pulmonary/cardiopulmonary syndrome (HPS/HCPS) in the Americas (Tian & Stenseth, 2019; Watson et al., 2014; Jiang et al., 2017; Milholland et al., 2019).
• Asia (especially China and Korea) has historically carried a large HFRS burden, mainly linked to Hantaan virus (HTNV) and other rodent‑borne viruses (Tian & Stenseth, 2019; Jiang et al., 2017). Incidence has declined in some Asian countries due to control measures, but suitable environments remain in places like Mongolia and North Korea (Jiang et al., 2017).
• In Europe, Puumala virus (PUUV) and Dobrava virus cause HFRS/nephropathia epidemica in endemic areas including the Balkans, Fennoscandia, Germany, Belgium, the Netherlands, France, and the UK (Tian & Stenseth, 2019; Ulrich et al., 2008; Filippone et al., 2019; Jiang et al., 2017). Bank voles in Germany show persistent PUUV circulation in outbreak regions such as Baden‑Württemberg and Bavaria (Astorga et al., 2018; Filippone et al., 2019).
• Americas (New World hantaviruses): HPS/HCPS occurs from Canada and the USA through Mexico, Central and South America (Tian & Stenseth, 2019; Milholland et al., 2018; García‐Peña & Rubio, 2024; Lopez et al., 2023; De Oliveira et al., 2013; De Oliveira et al., 2014). Sin Nombre virus dominates in North America; multiple lineages (e.g., Andes, Lechiguanas, Central Plata) circulate in Argentina, Chile, Uruguay, Brazil, and other countries (Tian & Stenseth, 2019; Cabrera et al., 2023; Astorga et al., 2018; García‐Peña & Rubio, 2024; Lopez et al., 2023; De Oliveira et al., 2013; De Oliveira et al., 2014).
• Within the USA, seropositive rodents and hantavirus are widely but unevenly distributed, with higher rodent seroprevalence in states like Virginia, Colorado, and Texas (Astorga et al., 2025; Goodfellow et al., 2025).
• In Brazil, rodent reservoirs are broadly distributed across Cerrado, Caatinga, and Atlantic Forest, giving potential transmission risk across most of the country outside the Amazon Basin (De Oliveira et al., 2013; Júnior et al., 2024; De Oliveira et al., 2014).
• Africa shows documented hantavirus circulation in rodents and some human seroprevalence, but disease burden is likely underestimated (Tian & Stenseth, 2019; Tortosa et al., 2024; Jiang et al., 2017).
• Globally, Asia currently shows the highest human seroprevalence (~6.8%), followed by Europe (~3%), the Americas (~2.4%), and Africa (~2.2%) in non‑epidemic settings (Tortosa et al., 2024).

Table 4: Geographic Patterns of Hantavirus Disease and Reservoirs

Region	Main Clinical Syndrome	Example Viruses / Notes	Citations
Europe & Asia	HFRS / NE	HTNV, PUUV, DOBV, SEOV	Tian & Stenseth (2019); Watson et al. (2014); Astorga et al. (2018); Ulrich et al. (2008); Filippone et al. (2019); Jiang et al. (2017)
Americas	HPS / HCPS	SNV, ANDV, multiple New World lineages	Tian & Stenseth (2019); Milholland et al. (2018); Cabrera et al. (2023); García-Peña & Rubio (2024); Lopez et al. (2023); De Oliveira et al. (2013, 2014); Goodfellow et al. (2025)
Africa	Underrecognized HFRS-like disease	Underdiagnosed; rodent evidence present	Tian & Stenseth (2019); Tortosa et al. (2024); Jiang et al. (2017)

Diseases Caused by Hantavirus 

• Hantaviruses cause two main acute zoonotic diseases in humans: Hemorrhagic Fever with Renal Syndrome (HFRS) and Hantavirus Pulmonary Syndrome (HPS) / Hantavirus Cardiopulmonary Syndrome (HCPS) (Brocato & Hooper, 2019; Sehgal et al., 2023; Bi et al., 2008; Peters et al., 1999; , 2022; Taylor et al., 2025; De Lacerda Barbosa et al., 2016).
• At least 24–38 orthohantavirus species are known, with ≥22–24 pathogenic for humans; different species are associated with different clinical severities and geographic regions (Sehgal et al., 2023; Bi et al., 2008; Tariq & Kim, 2022; Jiang et al., 2016).
• Old World hantaviruses (e.g., Hantaan, Dobrava, Seoul, Puumala, Amur) mainly cause HFRS in Europe and Asia, ranging from mild nephropathia epidemica to severe, sometimes fatal disease (Tariq & Kim, 2022; Jiang et al., 2016; Sehgal et al., 2023; Muthugala et al., 2022; , 2022; Tkachenko et al., 2023).
• New World hantaviruses (e.g., Sin Nombre, Andes, Araraquara, Juquitiba) mainly cause HPS/HCPS in the Americas, a severe cardiopulmonary form of hantavirus disease (Tariq & Kim, 2022; Jiang et al., 2016; Sehgal et al., 2023; Khaiboullina et al., 2017; Alonso et al., 2019; MacNeil et al., 2011; De Lacerda Barbosa et al., 2016; Peters & Khan, 2002).
• Clinical and pathogenetic overlap between HFRS and HPS/HCPS has led some authors to group them under the broader term “hantavirus fever” or “hantavirus disease” (Tkachenko et al., 2025; Sehgal et al., 2023; , 2022).

Hantavirus Pulmonary Syndrome (HPS / HCPS)

• Acute, often severe disease with pneumonia, non‑cardiogenic pulmonary edema, respiratory failure, cardiovascular failure, shock, and high fatality (~21–40% overall; up to ~35–40% in many series) (Bi et al., 2008; Khaiboullina et al., 2017; Peters et al., 1999; MacNeil et al., 2011; Taylor et al., 2025; De Lacerda Barbosa et al., 2016).
• Typical course: prodromal febrile flu‑like phase (2–5 days) → rapid cardiopulmonary phase with dyspnea, cough progressing to respiratory distress, hypotension, tachycardia, and sometimes hemorrhagic manifestations (Khaiboullina et al., 2017; Peters et al., 1999; De Lacerda Barbosa et al., 2016).
• Imaging (HRCT): bilateral ground‑glass opacities, smooth septal thickening, pleural effusion; reflects diffuse pulmonary capillary leak (De Lacerda Barbosa et al., 2016).
•  Caused mainly by New World hantaviruses such as Sin Nombre and Andes viruses; Andes virus also linked to occasional person‑to‑person transmission (Khaiboullina et al., 2017; Peters et al., 1999; De Lacerda Barbosa et al., 2016).
• Severe immune activation and cytokine storm; mortality in some national series ~21–39% but shows declining trend over time with better recognition and care (Khaiboullina et al., 2017; Alonso et al., 2019; Thorp et al., 2023).

Hemorrhagic Fever with Renal Syndrome (HFRS)

• Zoonotic disease marked by fever, thrombocytopenia, hemorrhagic manifestations, and acute kidney injury due to vascular leakage, especially in renal medullary capillaries (Tariq & Kim, 2022; Hennig et al., 2023; Jiang et al., 2016; Sehgal et al., 2023; Sargianou et al., 2012; Muthugala et al., 2022; Kalinina et al., 2022; , 2022; Tkachenko et al., 2023).
• Clinical spectrum from mild nephropathia epidemica (Puumala virus; mortality ~0.1–0.4%) to moderate/severe forms caused by Hantaan, Dobrava, Seoul, Amur, with case‑fatality typically <1–12%, often 5–10% depending on virus and host factors (Tariq & Kim, 2022; Jiang et al., 2016; Sehgal et al., 2023; Sargianou et al., 2012; Muthugala et al., 2022; Taylor et al., 2025; Tkachenko et al., 2023; Peters & Khan, 2002).
• Key features: bleeding (petechiae to severe internal hemorrhage), oliguria → polyuria phases of renal dysfunction, coagulation abnormalities; some cases complicated by DIC and shock (Tariq & Kim, 2022; Hennig et al., 2023; Sehgal et al., 2023; Khaiboullina et al., 2017; Sargianou et al., 2012; Muthugala et al., 2022; Kalinina et al., 2022).
• Highly endemic in parts of Asia and Europe, with large national burdens (e.g., 150,000–200,000 HFRS hospitalizations/year globally; >160,000 cases in Russia 2000–2022) (Sehgal et al., 2023; Bi et al., 2008; Muthugala et al., 2022; Tkachenko et al., 2023).
• While classically “renal,” lung involvement and even HPS‑like presentations can occur, reinforcing that HFRS and HPS form a clinical continuum of hantavirus disease (Tkachenko et al., 2025; Hennig et al., 2023; Sehgal et al., 2023; Khaiboullina et al., 2017; Peters et al., 1999; , 2022).

Signs and Symptoms of Hantavirus

• The incubation period of hantavirus infection is typically 2–6 weeks following exposure before the onset of clinical symptoms.
• The illness usually begins abruptly with high fever, chills, generalized malaise, marked fatigue, myalgia (muscle pain), backache, headache, and flu-like symptoms, which are common early manifestations in both Hemorrhagic Fever with Renal Syndrome (HFRS) and Hantavirus Cardiopulmonary Syndrome (HCPS/HPS).
• Early gastrointestinal symptoms are also frequently reported and include abdominal pain, nausea, vomiting, loss of appetite (anorexia), and diarrhea.
• Some patients additionally experience blurred vision or transient myopia (temporary nearsightedness) during the early phase of infection, which is considered a notable clinical feature in certain cases.
• In HFRS (the renal form of hantavirus disease), the illness classically progresses through five distinct clinical phases: febrile phase, hypotensive phase, oliguria phase, polyuria phase, and convalescent phase.
• The febrile phase is characterized by a sudden onset of high fever, severe myalgia, profound fatigue, abdominal pain, lower back pain, headache, blurred vision, and occasionally somnolence (excessive drowsiness).
• As the disease progresses into the hypotensive phase, patients may develop vascular leakage leading to hypotension and, in severe cases, circulatory shock.
• Hemorrhagic manifestations may occur during this stage and can include conjunctival suffusion, petechiae, epistaxis (nosebleeds), hematemesis (vomiting blood), melaena (black tarry stools), hematuria (blood in urine), and in rare severe cases, intracranial hemorrhage.
• This phase is often accompanied by acute thrombocytopenia, which increases bleeding tendency and reflects platelet consumption.
• During the oliguric phase, patients develop acute kidney injury (AKI) characterized by markedly reduced urine output (oliguria) due to renal capillary leakage and impaired kidney function.
• This is followed by the polyuric phase, during which urine output significantly increases as renal function begins to recover.
• Recovery then progresses into the convalescent phase, which may last for weeks to months.
• Even after apparent clinical improvement, many HFRS patients continue to report prolonged malaise, persistent fatigue, arthralgia (joint pain), swelling of the face, neck, or extremities, skin rash, and hepatomegaly (enlarged liver) accompanied by abnormal liver function test results.
• In HCPS/HPS (the cardiopulmonary form of hantavirus disease), the initial prodromal phase presents with fever, chills, myalgia, headache, dizziness, nausea, abdominal pain, vomiting, anorexia, and diarrhea.
• Unlike many other respiratory viral illnesses, this early phase often occurs without prominent cough or coryza (nasal congestion/runny nose), which can delay recognition of the disease.
• The illness then rapidly progresses to the cardiopulmonary phase, marked by rapidly worsening dyspnea (shortness of breath), dry cough, bilateral interstitial pulmonary infiltrates visible on chest imaging, non-cardiogenic pulmonary edema, acute respiratory failure, and severe hypotension or shock.
• This progression is often sudden and may become life-threatening within a short period due to massive pulmonary capillary leakage.
• Several laboratory and clinical findings are considered important diagnostic clues for hantavirus infection.
• Common hematological abnormalities include thrombocytopenia, leukocytosis or neutrophilic leukocytosis with a left shift, indicating an intense inflammatory response.
• Hemoconcentration is frequently observed as a result of plasma leakage into tissues.
• In HFRS, renal involvement is reflected by elevated serum creatinine and blood urea levels, proteinuria, and hematuria.
• Many patients also demonstrate elevated liver enzymes, suggesting hepatic involvement or systemic inflammation.
• In severe cases, disseminated intravascular coagulation (DIC) and other coagulopathies may develop, further increasing the risk of hemorrhagic complications.
• Some patients may exhibit neurological manifestations, including altered mental status, encephalopathy, and transient visual disturbances, reflecting systemic vascular dysfunction and possible central nervous system involvement.

Diagnosis of Hantavirus Infection 

• Clinical suspicion is based on acute febrile illness with thrombocytopenia, renal impairment and/or respiratory distress in a person from an endemic area or with rodent exposure; early symptoms are non specific, so lab tests are essential.
• Serology is the mainstay: almost all acute patients have IgM (and usually IgG) antibodies at symptom onset; diagnosis commonly uses IgM-/IgG-ELISA, IgM capture ELISA, IFA, immunoblot, and sometimes FRNT for confirmation or genotyping.
• Rapid tests: immunochromatographic IgM “rapid tests” can provide user friendly, near patient diagnosis in minutes, but require quality control and may differ from reference assays.
• Molecular detection (RT-PCR/RT qPCR/RT nPCR): detects viral RNA in blood, serum, or tissues during early viremic phase and can confirm infection even before antibodies appear. Real time RT PCR assays for PUUV and South American hantaviruses show high sensitivity and allow virus typing and quantification.
• RT nPCR targeting the L segment improves early HFRS diagnosis; virus can be detected in urine when serum is negative, and may remain detectable for up to a month after onset.
• Antigen and tissue-based methods: hantavirus N antigen can be identified by immunohistochemistry in autopsy or biopsy tissues; viral RNA also from paraffin blocks by RT PCR or in situ hybridization, aiding diagnosis in fatal or unclear cases.
• Routine lab abnormalities that support suspicion include thrombocytopenia, leukocytosis, elevated hematocrit, proteinuria, hematuria, and raised creatinine and liver enzymes, but these are not specific and require virological confirmation.

Treatment and Clinical Management of Hantavirus

General principles of treatment and clinical management

• No widely licensed specific antivirals or vaccines; management is mainly supportive, often in ICU for severe HFRS or HPS/HCPS.
• Early clinical suspicion, rapid diagnosis, and early transfer to critical care strongly influence outcomes, especially in HCPS.

Supportive care: fluids, hemodynamics, and respiratory support

• Core goals: maintain euvolemia and electrolyte balance, avoid fluid overload in leaky capillary states, and support blood pressure and organ perfusion.
• Severe HCPS often needs oxygen, mechanical ventilation, inotropes/vasopressors, and in selected refractory shock/ARDS cases veno arterial ECMO.
• In HFRS, careful fluid management plus renal replacement therapy (intermittent hemodialysis or continuous RRT) for acute kidney injury; RRT rates range from <5% in mild Puumala to up to 40–50% in severe HTNV infection.

Adjunctive and disease specific interventions

• Platelet and plasma transfusions may be used for severe thrombocytopenia, major bleeding, or DIC.
• Ribavirin has shown mortality reduction when given very early in HTNV HFRS but was ineffective/unsafe in PUUV and ANDV; benefit depends on virus and timing.
• Case reports/early data suggest possible benefit of icatibant (bradykinin B2 blocker) in severe capillary leak HFRS and human immune plasma for Andes virus HCPS, while high dose steroids showed no clear benefit.

Emerging/experimental therapies and prevention

• Multiple antiviral candidates (favipiravir, ETAR, lactoferrin, vandetanib, siRNA approaches) and neutralizing monoclonal antibodies show promise mainly in vitro/animal models; human efficacy data are limited.
• Several vaccine candidates (including inactivated and newer platforms) induce protective immunity in animals and some human trials, but no WHO/FDA approved vaccine yet; rodent control and public education remain key preventive tools.

Prevention and Control Measures of Hantavirus

Environmental and Rodent Control Measures

• Core strategy is keeping rodents away from homes and workplaces: remove food sources, nesting materials, and clutter; store grain and trash in rodent proof, closed containers; move wood/forage piles away from houses; cut grass and weeds around homes; seal holes and cracks to block entry; use traps and, where appropriate, rodenticides.
• Large scale control includes identifying high risk areas with surveillance and GIS tools, then targeting pest control treatments (rodent population reduction in defined hectares).
• In urban settings, measures focus on eliminating or reducing rat and mouse populations, reducing shelters, and restricting rodent access to residences, water, and food supplies.

Safe Cleaning and Personal Protection

• When cleaning rodent contaminated areas, recommended practices include ventilating rooms, wetting surfaces with water or disinfectant to avoid dust, using disinfectants that inactivate hantaviruses, and wearing rubber gloves, masks/respirators to avoid inhaling aerosols.
• Community surveys show household hygiene (clean patios, mopping, keeping trash and food covered) is common, but use of masks and gloves is much less frequent, highlighting a gap in practice.

Public Education, Community Based Interventions, and Surveillance

• Prevention relies heavily on public health education about rodent borne transmission, safe cleaning, and environmental hygiene; culturally tailored, community based programs and involvement of people who experienced disease improve uptake.
• Active rodent and human case surveillance, including climate and rodent abundance monitoring, helps forecast outbreaks and guide early warning systems and targeted campaigns.

Vaccines and Medical Countermeasures

• There is no widely approved human vaccine or specific antiviral yet; prevention is therefore dominated by exposure reduction.
• Experimental and regional vaccines (including inactivated and DNA based) and topical microbicides like griffithsin (GRFT/3mGRFT) show promise, and vaccination of high risk groups in some countries (e.g., for HFRS) can reduce disease severity.

Recent Global Outbreaks and Epidemiology 

Hantavirus infections remain an important but unevenly recognized global zoonosis. Recent work highlights substantial endemic burdens in Eurasia and the Americas, frequent localized outbreaks, and a much larger pool of silent or under‑diagnosed infections than official case counts suggest.

Global Burden and Seroprevalence

• Recent reviews estimate ~150,000–200,000 hantavirus cases per year worldwide, mainly HFRS in Eurasia and HCPS/HPS in the Americas (Douglas et al., 2021; Kim et al., 2021; Liu et al., 2020).
• A 2024 meta‑analysis found global seroprevalence ~2.9%, with higher exposure in Asia (6.8%), then Europe (~3.0%), Americas (~2.4%), and Africa (~2.2%) (Tortosa et al., 2024).
• Seroprevalence studies in specific countries show ongoing transmission even where few cases are reported, e.g. Italy 1.7%, West Kazakhstan 3.1%, Senegal 2.2% for Hantaan virus, and French Guiana 5.1% IgG positivity in informal settlements (Riccò et al., 2021; Gubareva et al., 2025; Diarra et al., 2026; Oberlis et al., 2024).

Table 5: Recent Regional Hantavirus Patterns and Outbreak Trends

Region / Country	Recent Patterns / Outbreaks	Citations
China	2004–2016: 166,975 HFRS cases, CFR ~0.99%; decline until 2009 followed by resurgence. China accounts for approximately 90% of global HFRS burden, with endemicity across 28 of 31 provinces. 2004–2023: 204,039 cases, CFR 0.88%, showing an aging patient population and geographic shift from Heilongjiang toward the Guanzhong Plain.	(Wang et al., 2021; Zhai et al., 2025)
Europe	Increasing incidence and more frequent severe outbreaks associated with climate variability and rodent food availability. Notable peaks occurred in Germany (2012), with consistently high incidence reported in Finland.	(Liu et al., 2020; Koehler et al., 2021; Vaheri et al., 2021)
Americas	Recurrent HCPS/HPS outbreaks in Argentina, Chile, and Brazil. Major examples include climate-associated outbreaks in northwest Argentina (1997–2017) and the significant Andes virus person-to-person outbreak in Argentina (2018–2019), involving 34 cases and 11 deaths.	(Douglas et al., 2021; Martínez et al., 2020; Ferro et al., 2020)
Africa	Human exposure has been documented, particularly among high-risk populations in Senegal, but routine surveillance systems likely under-detect infections.	(Diarra et al., 2026)

Drivers and Risk Groups

• Climate variability (rainfall, temperature) strongly influences rodent populations and precedes outbreaks in Latin America and Argentina, with 2–6‑month lags (Douglas et al., 2021; Ferro et al., 2020).
• Global warming, intense rainfall, and flooding are highlighted as amplifiers of outbreak risk via rodent population dynamics (Riccò et al., 2021; Douglas et al., 2021).
• Rural residents, farmers, forestry workers, and indigenous groups have higher exposure; farmers and forestry workers show about 2–3‑fold higher odds of infection than general populations (Tortosa et al., 2024; Kim et al., 2021).
• Older age and male sex are consistently associated with higher seroprevalence in several settings (Tortosa et al., 2024; Diarra et al., 2026; Gubareva et al., 2025; Wang et al., 2021).

Surveillance and Emerging Tools

• Under‑detection is substantial: in Senegal and Kazakhstan, serological evidence far exceeds cases detected by national systems (Diarra et al., 2026; Gubareva et al., 2025).
• New platforms such as HantaReg and HantaNet aim to standardize multinational clinical data and genomic surveillance, enabling earlier outbreak detection and better mapping of viral spread (Koehler et al., 2021; Cintron et al., 2023; Romeo et al., 2025).

Figure 1: Chronology of Recent Hantavirus Epidemiology Studies

Publication Date	Study	Research Focus
Jan 2020	Liu et al., 2020	European hantavirus epidemiology
Nov 2020	Ferro et al., 2020	South American outbreak investigations
Dec 2020	Martínez et al., 2020	Andes virus transmission analysis
Jan 2021	Kim et al., 2021	Clinical surveillance updates
Feb 2021	Wang et al., 2021	China HFRS epidemiological trends
Mar 2021	Koehler et al., 2021	European outbreak forecasting
Apr 2021	Singh et al., 2021	Regional surveillance findings
Jul 2021	Vaheri et al., 2021	Nordic hantavirus incidence
Sep 2021	Riccò et al., 2021	Meta-analysis of hantavirus burden
Oct 2021	Riccò et al., 2021	Expanded epidemiological review
Dec 2021	Douglas et al., 2021	Climate-linked outbreak studies
Jan 2023	Author missing, 2023	Reference incomplete
Nov 2023	Cintron et al., 2023	Emerging surveillance data
Jun 2024	Oberlis et al., 2024	Reservoir host ecology
Sep 2024	Tortosa et al., 2024	African hantavirus evidence
Jan 2025	Gubareva et al., 2025	Virological evolution studies
Mar 2025	Astorga et al., 2025	Latin American outbreak patterns
Apr 2025	Romeo et al., 2025	Global comparative epidemiology
Nov 2025	Zhai et al., 2025	Long-term Chinese HFRS shifts
Jan 2026	Diarra et al., 2026	African exposure surveillance

Public Health Importance of Hantavirus

• Hantaviruses are emerging rodent-borne zoonotic RNA viruses that cause severe human diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary/pulmonary syndrome (HCPS/HPS) in the Americas (Kim et al., 2021; Tian & Stenseth, 2019; Zhai et al., 2025; Dheerasekara et al., 2020).
• Globally, hantaviruses cause an estimated ~200,000 human infections per year, with case-fatality around 5–15% for HFRS and up to 35–40% for HPS/HCPS, making them high‑impact but relatively rare infections (Tian & Stenseth, 2019; Zhai et al., 2025; Llah et al., 2018; Dheerasekara et al., 2020).
• Europe reports >10,000 HFRS cases annually with frequent complications and long‑term renal and cardiovascular effects; HFRS is the most common natural‑focal viral disease in Russia and remains a major problem in China, which accounts for ~90% of global HFRS cases (Vaheri et al., 2013; Zhai et al., 2025; Ivanova et al., 2021; Zhang et al., 2014; Prist et al., 2016).
• A 2024 meta‑analysis found global hantavirus seroprevalence ~2.9%, higher in Asia (~6.8%), indicating substantial silent or underdiagnosed infection burden and geographic variation in exposure (Tortosa et al., 2024).
• Hantavirus risk is strongly linked to occupational and environmental exposure to rodents; farmers and forestry workers have roughly 2–3‑fold higher odds of infection than general populations (Kim et al., 2021; Martínez et al., 2020; Prist et al., 2016).
• Climate, land use, and landscape change (e.g., rainfall, temperature shifts, sugarcane expansion, forest fragmentation) can increase rodent populations and human contact, driving outbreaks and defining regional risk hotspots (Tian & Stenseth, 2019; Ferro et al., 2020; Prist et al., 2016; Kim et al., 2020).
• Person‑to‑person transmission is generally unsupported for most hantaviruses; limited, high‑risk events have occurred with Andes virus, where “super‑spreaders” at social gatherings caused clusters, highlighting outbreak potential and need for rapid control measures (Martínez et al., 2020; Toledo et al., 2021).
• There is no widely available, highly effective vaccine or specific antiviral treatment; existing inactivated vaccines (China, Korea) have uncertain protection, and current management is mostly intensive supportive care, so prevention, surveillance, and rodent control are central public‑health tools (Kim et al., 2021; Zhai et al., 2025; Liu et al., 2020; Dheerasekara et al., 2020).

Challenges in Hantavirus Research of Hantavirus

Hantaviruses cause severe diseases worldwide, but many aspects of their ecology, transmission, and clinical management remain poorly understood. The papers highlight gaps across surveillance, diagnostics, reservoir studies, pathogenesis, and prevention that limit outbreak prediction and control.

Surveillance & Outbreak Detection

• True burden is unclear: Many infections are mild, underdiagnosed, or not reported; global seroprevalence outside known epidemic settings is low but heterogeneous, stressing the need for targeted surveillance (Watson et al., 2014; Tortosa et al., 2024).
• Timely outbreak detection is difficult: Delays in reporting and lack of integrated genomic/epidemiologic tools can miss linked transmission events (Kim et al., 2021; Cintron et al., 2023; Koehler et al., 2021).
• New platforms such as HantaNet and HantaReg aim to standardize data, enable genomic surveillance, and support multinational outbreak investigation, but are still being built out (Cintron et al., 2023; Koehler et al., 2021).

Reservoir Ecology & Experimental Models

• Reservoir–virus pair diversity is high, but experimental work on most pairs is “too scarce” relative to the number of known viruses and hosts (Madrières et al., 2019).
• In vitro models cannot reproduce systemic within-host interactions; reservoir experiments are logistically difficult but essential for understanding persistence, transmission, and evolution (Madrières et al., 2019; Mills et al., 1999).
• Long-term field studies are demanding yet crucial to link rodent population dynamics, environment, and human risk (Tian & Stenseth, 2019; Mills et al., 1999).

Pathogenesis, Diagnosis, and Clinical Management

• Central mechanisms (vascular leakage, thrombocytopenia) are known, but molecular details of endothelial damage remain poorly understood (Avšič-Županc et al., 2019; Mir, 2022).
• Many infections occur in non-endemic or occupationally exposed groups where awareness and testing are limited, so prevalence and risk factors are underestimated (Iheukwumere et al., 2023; Watson et al., 2014; Romeo et al., 2025).
• There is no approved specific treatment; supportive care is standard, and correlates of protection and optimal antiviral/host-targeted strategies remain unclear (Avšič-Županc et al., 2019; Singh et al., 2021; Liu et al., 2020; Mir, 2022).

Vaccines, Prevention, and Future Directions

• Only inactivated vaccines in China and Korea exist; they show suboptimal immunity and uncertain protection, and no globally accepted vaccine is available (Avšič-Županc et al., 2019; Liu et al., 2020; Mir, 2022).
• Reviews emphasize needs for:
  • Better integration of ecology, evolution, and modeling to predict emergence (Tian & Stenseth, 2019; Jonsson et al., 2010; Wei et al., 2022)- Climate and land-use–aware prevention strategies (Tian & Stenseth, 2019; Koehler et al., 2021; Wei et al., 2022)- Global collaboration, data-sharing, and use of tools like AI and drug repurposing to accelerate therapeutics and vaccines (Khan et al., 2021; Liu et al., 2020; Mir, 2022).

Current Advances in Vaccine Development of Hantavirus

Hantavirus vaccines are moving from traditional inactivated products used only in a few Asian countries toward modern platforms (DNA, mRNA, viral‑vector, and multi‑epitope designs) aimed at stronger, broader, and longer‑lasting protection. No WHO/FDA‑approved global vaccine exists yet, but several candidates are in late preclinical and early clinical stages.

Existing Licensed / Late-Use Vaccines

• Inactivated whole-virus vaccines (HTNV, SEOV) have been used for decades in China and South Korea and clearly reduced HFRS incidence, especially in high‑risk groups (Chai et al., 2025; Zhang et al., 2024; Liu et al., 2020; Afzal et al., 2023).
• Limitations: multiple doses, waning neutralizing antibodies, suboptimal or uncertain protection, and safety concerns in some data (Chai et al., 2025; Liu et al., 2020; Maes et al., 2009; Krüger et al., 2011; Ismail et al., 2022; Afzal et al., 2023).
• New inactivated formulations based on recent field strains (e.g., HV004) generate strong neutralizing antibodies, IFN‑γ–producing CD8 T cells, and full protection in mice, suggesting improved strain‑matched products (Liu et al., 2023).

Next-Generation Vaccine Platforms

• DNA vaccines (M segment, Gn/Gc):
  • Protect rodents and non‑human primates; several HTNV, PUUV, ANDV DNA vaccines now in human trials (Liu et al., 2020; Engdahl & Crowe, 2020; Saavedra et al., 2021).
  • Phase 1 trial with needle‑free delivery: 100% seroconversion for monovalent HTNV or PUUV DNA; 44% for the bivalent mix (Hooper et al., 2024).
• mRNA and DNA–LNP vaccines:
  • HTNV glycoprotein mRNA and DNA‑LNP induce rapid, durable responses in mice, with mRNA favoring Th1 and DNA‑LNP inducing high neutralizing titers, matching inactivated‑vaccine protection (Zhang et al., 2024).
• Viral‑vector vaccines:
  • rVSV expressing HTNV GP gives single‑dose, year‑long neutralizing antibodies, strong cross‑neutralization of SEOV, and marked reduction of viral load and pathology in mice (Zhang et al., 2024).
  • MVA‑vectored chimeric SEOV/HTNV nucleoprotein reduces viral RNA after SEOV challenge in mice (Aram et al., 2025).

Novel Antigen Designs and Computational Vaccines

• LAMP‑targeted DNA vaccines (Gn/Gc): enhance antigen presentation, induce strong, long‑term humoral and cellular immunity and protection in mice (Almanaa et al., 2023; Ismail et al., 2022).
• Multi‑epitope / in silico vaccines: several groups designed T‑ and B‑cell epitope–based constructs (often with TLR‑adjuvants); simulations predict strong IgG/IgM, CTL/Th responses and good TLR3/TLR4 binding, but all still need experimental validation (Krüger et al., 2011; Ali et al., 2024; Jiang et al., 2018; Abdulla et al., 2020).
• Nanoparticle Gn “head” immunogens can elicit cross‑neutralizing antibodies between New World hantaviruses in mice, suggesting routes to broad coverage (Ramos et al., 2025).

Immune Correlates & Remaining Challenges

• Protection depends mainly on neutralizing antibodies to Gn/Gc, with early and durable nAb responses strongly linked to survival (Engdahl & Crowe, 2020; Saavedra et al., 2021; Engdahl et al., 2022).
• Key challenges: lack of definitive correlates of protection, limited disease models, modest real‑world performance of current inactivated vaccines, and the need for broad, cross‑species protection and simplified dosing schedules (Chai et al., 2025; Liu et al., 2020; Maes et al., 2009; Saavedra et al., 2021).

Conclusion 

• Hantavirus is an emerging zoonotic virus that poses a significant global public health threat.
• It causes two major severe diseases:
• Hemorrhagic Fever with Renal Syndrome (HFRS)
• Hantavirus Cardiopulmonary Syndrome (HCPS/HPS)
• The virus is mainly transmitted through inhalation of aerosolized rodent urine, feces, or saliva, making rodent exposure the primary risk factor.
• Its global distribution and strong link with ecological and environmental changes increase the risk of outbreaks.
• Hantavirus pathogenesis is mainly driven by immune-mediated vascular leakage, thrombocytopenia, and organ dysfunction, which can lead to life-threatening complications.
• Although major progress has been made in understanding its structure, replication, classification, and epidemiology, many aspects of disease mechanisms remain under investigation.
• Early diagnosis remains challenging because initial symptoms are often non-specific and resemble other febrile illnesses.
• Currently, no universally approved specific antiviral treatment or globally licensed vaccine is available, so management mainly depends on supportive clinical care.
• Recent advances in molecular diagnostics, surveillance systems, and next-generation vaccine development offer promising future solutions.
• Effective prevention relies on:
• Rodent control
• Environmental hygiene
• Public awareness
• Reducing exposure to contaminated environments
• Strengthening global surveillance, research collaboration, and public health preparedness is essential for controlling hantavirus and reducing its worldwide disease burden.

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