Introduction of Vaccinomics to Develop Personalized Vaccines in Light of Changes in the Usage of Hantaan Virus Vaccine (Hantavax®) in Korea / 예방의학회지

The Ministry of Food and Drug Safety of Korea made an official announcement in March 2018 that the total number of inoculations of Hantaan virus vaccine (Hantavax®) would change from 3 to 4. Some aspects of this decision remain controversial. Based on the characteristics of Hantaan virus (HTNV) and its role in the pathogenesis of hemorrhagic fever with renal syndrome, it might be difficult to develop an effective and safe HTNV vaccine through the isolate-inactivate-inject paradigm. With the development of high-throughput ‘omics’ technologies in the 21st century, vaccinomics has been introduced. While the goal of vaccinomics is to develop equations to describe and predict the immune response, it could also serve as a tool for developing new vaccine candidates and individualized approaches to vaccinology. Thus, the possibility of applying the innovative field of vaccinomics to develop a more effective and safer HTNV vaccine should be considered.

Our Hantaan Virus Became a New Family, Hantaviridae in the Classification of Order Bunyavirales. It will Remain as a History of Virology

In February 2019, the order Bunyavirales, previously family Bunyaviridae, was amended by new order of 10 families including Hantaviridae family, and now accepted by the International Committee on Taxonomy of Viruses (ICTV). Hantaviridae is now a family of the order Bunyavirales, and the prototype virus species is Hantaan orthohantavirus. The family Hantaviridae is divided into four subfamilies including Mammantavirinae, Repantavirinae, Actantavirinae and Agantavirinae. The subfamily Mammantavirinae is divided into four genera including Orthohantavirus, Loanvirus, Mobatvirus and Thottimvirus. The four Hantavirus species have been found in Korea including three Orthohantaviruses (Hantaan orthohantavirus, Seoul orthohantavirus and Jeju orthohantavirus) and one Thottimvirus (Imjin thottimvirus).

Effectiveness of inactivated hantavirus vaccine on the disease severity of hemorrhagic fever with renal syndrome

BACKGROUND: An inactivated Hantaan virus vaccine (iHV) has been broadly used as a preventive strategy for hemorrhagic fever with renal syndrome (HFRS) by the South Korean Army. After the vaccination program was initiated, the overall incidence of HFRS cases was reduced in the military population. While there are about 400 HFRS cases annually, few studies have demonstrated the efficacy of the iHV in field settings. Therefore, this study aimed to evaluate the iHV efficacy on HFRS severity. METHODS: From 2009 to 2017, HFRS cases were collected in South Korean Army hospitals along with patients’ vaccination history. HFRS patients were classified retrospectively into two groups according to vaccination records: no history of iHV vaccination and valid vaccination. Vaccine efficacy on the severity of acute kidney injury (AKI) stage and dialysis events were investigated. RESULTS: The effects of the iHV on renal injury severity in between 18 valid vaccinated and 110 non-vaccinated patients were respectively evaluated. In the valid vaccination group, six of the 18 HFRS patients (33.3%) had stage 3 AKI, compared to 60 of the 110 (54.5%) patients in the non-vaccination group. The iHV efficacy against disease progression (VEp) was 58.1% (95% confidence interval, 31.3% to 88.0%). CONCLUSION: The iHV efficacy against the progression of HFRS failed to demonstrate statistically significant protection. However, different severity profiles were observed between the iHV and non-vaccination groups. Additional studies with larger populations are needed to demonstrate the effectiveness of the iHV in patients with HFRS.

Production and Storage of Virus Simulants

We have examined isolation and identification protocols for three virus simulant candidates to biological warfare agents. MS2 phage, a simulant for yellow fever virus and Hantaan virus, was propagated using as a host an E. coli strain with F pilus. MS2 phage genome was examined by reverse transcription and polymerase chain reaction (RT-PCR). Coat protein of the phage preparation was examined by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometric analysis. Cydia pomonella granulosis virus (CpGV) is a virus simulant candidate to smallpox virus. CpGV was isolated from a commercialized CpGV pellet. In this study, we developed new isolation and identification protocols for CpGV. One disadvantage of using CpGV is that it is not easy to determine viability of the virus. Here, we have included T4 phage as an alternative. We established a high titer production protocol and developed an easy genome identification protocol that does not require purified phage DNA. Stability of these virus preparations was also examined under various storage conditions. When the virus preparations were not subjected to freeze drying, MS2 phage was most stable when it was stored in liquid nitrogen but unstable at 4℃. In contrast, T4 phage was most stable when it was stored at 4℃. CpGV was stable at −20℃ but not at 4℃. Stability during or after freeze drying was also investigated. The result showed that 70~80% MS2 survived the freeze drying process. In contrast, only about 15% of T4 phage survived during the freeze drying. CpGV was found to be degraded during freeze drying.

Becoming an International Scientist in South Korea: Ho Wang Lee's Research Activity about Epidemic Hemorrhagic Fever / 의사학

In the 1960-70s, South Korea was still in the position of a science latecomer. Although the scientific research environment in South Korea at that time was insufficient, there was a scientist who achieved outcomes that could be recognized internationally while acting in South Korea. He was Ho Wang Lee(1928~ ) who found Hantann Virus that causes epidemic hemorrhagic fever for the first time in the world. It became a clue to identify causative viruses of hemorrhagic diseases that were scattered here and there throughout the world. In addition, these outcomes put Ho Wang Lee on the global center of research into epidemic hemorrhagic fever. This paper examines how a Korean scientist who was in the periphery of virology could go into the central area of virology. Also this article shows the process through which the virus found by Ho Wang Lee was registered with the international academia and he proceeded with follow-up research based on this progress to reach the level at which he generalized epidemic hemorrhagic fever related studies throughout the world. While he was conducting the studies, experimental methods that he had never experienced encountered him as new difficulties. He tried to solve the new difficulties faced in his changed status through devices of cooperation and connection. Ho Wang Lee's growth as a researcher can be seen as well as a view of a researcher that grew from a regional level to an international level and could advance from the area of non-mainstream into the mainstream. This analytic tool is meaningful in that it can be another method of examining the growth process of scientists in South Korea or developing countries.

Correlación entre criterios clínicos y de laboratorio de casos notificados por sospecha de hantavirosis y el resultado de la técnica de referencia / Correlation between clinical and laboratory criteria of suspected Hantavirus cases and the results of the reference diagnostic technique

Antecedentes: Actualmente en Chile, debido a la elevada sospecha clínica de enfermedad por hantavirus y el alto impacto en salud pública que esto provoca, se hace necesario reforzar al equipo de salud, los criterios de sospecha clínica y epidemiológica de hantavirosis. Objetivo: Analizar la información contenida en las notificaciones de sospecha de infección por hantavirus versus la técnica de referencia para el diagnóstico confirmatorio de casos sospechosos, ELISA IgM de captura anti-hantavirus. Material y Método: Mediante cálculo de precisión diagnóstica se analizó la correlación que existe entre la información entregada en las notificaciones versus el resultado de la confirmación mediante la técnica de referencia. Resultados: De 1.566 pacientes estudiados 3,4% (53 casos) fue confirmado para SCPH. De las notificaciones analizadas 58,6% estaban con datos incompletos. Los porcentajes de positividad de la técnica de referencia asociada a fiebre, mialgia y cefalea, fueron de 80-85%. Destaca que la presencia de inmunoblastos (> 10%), presenta: S: 25%, E: 98%, VPP: 37%, VPN: 97%. Paratrombocitopenia se obtuvo: S: 98%, E: 74%, VPP: 16%, VPN: 100%. Conclusión: Se hace necesario reiterar a nivel del sistema sanitario chileno la importancia de contar con datos completos en los formularios de notificación. La presencia de trombocitopenia e inmunoblastos (> 10%) fue altamente sensible y especifica, respectivamente, en la detección de pacientes con SCPH. Con el fin de optimizar la sospecha de infección por hantavirus, según la definición de caso sospechoso, se plantea la necesidad de desarrollar programas de capacitación para la sospecha clínica y lectura de parámetros de laboratorio, tales como presencia de inmunoblastos en el hemograma, así como incluir un algoritmo con el fin de optimizar la sospecha y el uso adecuado de los recursos sanitarios.

Background: Currently in Chile, due to the frequent clinical suspicion of Hantavirus disease and the high public health impact that this causes, it is necessary to strengthen the criteria for clinical and epidemiological suspicion in the health team. Objective: To analyze the information contained in the reports of suspected Hantavirus infection versus the confirmatory diagnosis with the reference technique, IgM capture ELISA anti-hantavirus. Material andMethods: Correlation between the information provided in notifications versus the result of confirmation was analyzed by calculating diagnostic accuracy. Results: 3.4% of 1,566 patients studied (53 cases) was confirmed as SCPH. 58.6% of the analyzed notifications was incomplete. The percentage of positivity of the reference technique associated with fever, myalgia and headache was 80-85%. The presence of immunoblasts (> 10%) showed 25% sensitivity, 98% specificity, 37% PPV, 97% NPV. Thrombocytopenia exhibited 98% sensitivity, 74% specificity, 16% PPV, 100% NPV. Conclusion: It is necessary to reinforce the importance of comprehensive data reporting at the health system level. The presence of thrombocytopenia and immunoblasts (> 10%) is highly sensitive and specific, respectively, for detecting patients with SCPH. There is a need to develop training programs in order to optimize the suspicion of Hantavirus infection and appropriate use of health resources.

Study on the transmission of Hantaan virus and Orientia tsutsugamushi by naturally dual infected Leptotrombidium scutellare through stinging / 中华预防医学杂志

<p><b>OBJECTIVE</b>To investigate whether Leptotrombidium scutellare could be naturally infected by both Hantaan virus (HV) and Orientia tsutsugamushi (OT) and transmission status by stinging.</p><p><b>METHODS</b>3459 Leptotrombidium scutellares from mice bodies and 3265 which were free were collected in the epidemic area of hemorrhagic fever with renal syndrome (HFRS) and tsutsugamushi disease.15 days later, the suspensions of lung and spleen of mice with 6 in a group stung by 1, 5 or 10 infected mites were injected intra-cerebrally into other mice for the detection of HV and OT in the next 6 generations of the mice, with immunofluorescent antibody technique (IFAT) and Giemsa staining technique. The passages of Vero-E6 cells inoculated on the aseptic filtrations from different number of infected mites were used to detect HV and OT pathogens. HV-RNA and OT-DNA were detected by PCR.</p><p><b>RESULTS</b>After passage, HV positive mouse body mite group out of both 5 and 10 mites in the sixth generation, OT positive mouse body mite group out of the 10 mites in the sixth generation, both HV and OT positive mouse body mite group out of 1 mite in the fifth and sixth generation, both HV and OT positive mouse body mite group out of 5 and 10 mites in the sixth generation, and free mites group out of 1, 5 and 10 mites in the sixth generation, were found one mouse infected by both HV and OT, respectively. Out of the fourth generation of Vero-E6 cells, one sample was found both HV and OT positive out of 5 and 10 HV and OT mouse body mite group, respectively. In the sixth generation, both HV and OT positive cells were detected in one mouse mite group and the 1, 5, 10 free mite groups, respectively. HV-RNA and OT-DNA were all detected by PCR.</p><p><b>CONCLUSION</b>Both HV and OT could be coexisted in wild Leptotrombidium scutellare and transmitted by stinging.</p>

Reversible Splenium Lesion of the Corpus Callosum in Hemorrhagic Fever with Renal Failure Syndrome

This is the first case of virus-associated encephalitis/encephalopathy in which the pathogen was Hantaan virus. A 53-yr-old man presented fever, renal failure and a hemorrhagic tendency and he was diagnosed with hemorrhagic fever with renal failure syndrome (HFRS). In the course of his illness, mild neurologic symptoms such as dizziness and confusion developed and magnetic resonance images revealed a reversible lesion in the splenium of the corpus callosum. This case suggests that HFRS patients with neurologic symptoms like dizziness and mental slowing should be considered to have structural brain lesions and to require brain imaging studies.

Hemorrhagic Fever with Renal Syndrome

Hemorrhagic fever with renal syndrome (HFRS) is an acute febrile illness caused by Eurasian hantaviruses and characterized by renal insufficiency, hemorrhage, thrombocytopenia, and shock. Each hantavirus is primarily associated with a single rodent host species or genus, and is transmitted to human via aerosols of rodent excreta. During the last decades, clinical features of HFRS in Korea have changed with mild degree of hypotension and very low prevalence of oliguria. Treatment of HFRS is mainly supportive. Recently, however, treatment of HFRS patients with ribavirin in China and Korea, within 7 days after the onset of fever, resulted in a reduced mortality as well as shortened course of illness. Although a commercial inactivated Hantaan virus vaccine has been on the market in Korea for more than 15 years, the effect of vaccination is not clear. Further efforts are necessary to develop safer and more effective hantavirus vaccines.

Hemorrhagic Fever with Renal Syndrome

Hemorrhagic fever with renal syndrome (HFRS) is an acute febrile illness caused by Eurasian hantaviruses and characterized by renal insufficiency, hemorrhage, thrombocytopenia, and shock. Each hantavirus is primarily associated with a single rodent host species or genus, and is transmitted to human via aerosols of rodent excreta. During the last decades, clinical features of HFRS in Korea have changed with mild degree of hypotension and very low prevalence of oliguria. Treatment of HFRS is mainly supportive. Recently, however, treatment of HFRS patients with ribavirin in China and Korea, within 7 days after the onset of fever, resulted in a reduced mortality as well as shortened course of illness. Although a commercial inactivated Hantaan virus vaccine has been on the market in Korea for more than 15 years, the effect of vaccination is not clear. Further efforts are necessary to develop safer and more effective hantavirus vaccines.

The influence of vaccination on the clinical features of hemorrhagic fever with renal syndrome in the last 5 years / 대한내과학회지

BACKGROUND/AIMS: Hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus is an endemic febrile disease in Korea. Although inactivated Hantaan virus vaccine has been introduced, the effect of vaccination is not clear. We evaluated the effect of vaccination on the incidence rate and clinical features of HFRS based on our clinical experience. METHODS: Group I consisted of the patients with confirmed HFRS from a total of 131 patients who were seropositive for Hantaan virus at one tertiary teaching hospital from January 2002 to December 2006. Group II contained 100 patients treated as HFRS at the same hospital from January 1986 to December 1990, before the introduction of the vaccine. Then, we compared the clinical features of the two groups. We confirmed whether the patients had been vaccinated by reviewing their medical records and from telephone interviews. RESULTS: Only 16 (12.2%) of the 131 patients who were seropositive for Hantaan virus were confirmed to have overt HFRS during the most recent 5 years. The incidence of overt HFRS was significantly lower in vaccinees (5%, 3 of 56) than in non-vaccinees (20%, 10 of 50) (p=0.025). The prevalence of renal failure (62.5 vs. 95%, p<0.001) and oliguria (6.25 vs. 46%, p=0.002) was significantly lower in group I than in group II. Three patients were treated with dialysis and none died in group I, versus 17 and 8, respectively, in group II. CONCLUSIONS: It appears that Hantaan virus vaccine has helped to reduce the amount of serious illness and the occurrence of HFRS.

A Case of Graves' Disease Combined with Hantaan Virus Infection

Graves' disease (GD) is generally presented by thyrotoxicosis with hyperthyroidism, and it is an organ-specific autoimmune disease induced by thyroid-stimulating hormone receptor autoantibodies. However, among diverse etiologies, viral infections have been suggested to trigger or to be involved in the pathogenesis of GD. Hantaan virus infection causing hemorrhagic fever with renal syndrome (HFRS) is common in South Korea and its pathogenesis is suggested to be an immunologic mechanism. We have experienced a patient who was diagnosed as HFRS with thyrotoxicosis. So we herein report the case as GD combined with the hantaan virus infection.

The Effects of Hantaan Virus on the Expression of Platelet Activating Factor Receptor and on the Activity of Platelet Activating Factor Acetylhydrolase / 영남의대학술지

BACKGROUND: The central physiological derangement of hemorrhagic fever with renal syndrome (HFRS) caused by hantaan virus (HTNV) is a vascular dysfunction, manifested by hemorrhage, impaired vascular tone and increased vascular permeability. Platelet activating factor (PAF), whose actions are mediated through a specific receptor, is a potent bioactive lipid. PAF has diverse biological functions in the vascular system, such as increasing vascular permeability, adhesion of leukocytes to the endothelium and reduction of cardiac output, which result in hypotension and shock. The goal of the present study was to investigate whether PAF is involved in the pathogenesis of HFRS. For this purpose, we evaluated the effect of HTNV on the expression of PAF receptor (PAF-R) and on the activity of PAF-acetylhydrolase (PAF-AH) instead of PAF because PAF is rapidly degraded by PAF-AH in vivo. MATERIALS AND METHODS: To evaluate the expression of PAF-R, we performed reverse-transcription PCR, western blot and FACS analyses using HTNV-infected human umbilical vein endothelial cells (HUVECs) and non-infected (control) HUVECs. In addition, we measured the activity of plasma PAF-AH in HFRS patients and normal healthy persons. RESULTS: The mRNA and protein expression of PAF-R was increased in HTNV-infected HUVECs compared with control HUVECs at 2 and 3 days post-infection (d.p.i.). FACS analysis showed that HTNV induced the surface expression of PAF-R in HUVECs from 2 d.p.i. The activity of plasma PAF-AH was 2.5-fold lower in HFRS patients than in normal healthy persons. CONCLUSION: Increased PAF-R expression by HTNV might increase the responsiveness to PAF in endothelial cells. Reduced PAF-AH activity in the blood of HFRS patients might delay PAF degradation. These results suggest that changes in PAF-R and PAF-AH by HTNV might influence to PAF activity and might be involved in the vascular dysfunction of HFRS.

A case of hemorrhagic fever with renal syndrome after renal transplantation / 대한내과학회지

Hemorrhagic fever with renal syndrome is an acute disease characterized by fever, headache, bleeding tendency, and anuria. We recently treated a case of hemorrhagic fever in a renal allograft patient with renal syndrome. A 43-year-old woman presented with high fever, headache, and myalgia for 4 days. In February 1998, she had undergone allograft kidney transplantation following treatment with cyclosporine and steroids. Allograft function was stable. Hantaan virus infection was demonstrated by serology during the first hospital week. Her clinical course progressed through febrile, hypotensive, oliguria, polyuria, and recovery phases. The patient was successfully treated with continuous renal replacement therapy and supportive management with maintenance doses of immunosuppressive agents.

Identification of a functional ITAM-like sequence within G1 cytoplasmic tail of Hantaan virus / 病毒学报

The G1 cytoplasmic tail of Hantaan virus (HTNV) harbors a highly conserved region, which is homologous to immunoreceptor tyrosine-based activation motifs (ITAM) and is termed the ITAM-like sequence. To demonstrate the potential signal-transducing activity of G1 ITAM-like sequence resembling the canonical ITAM within immune and endothelial cells, a series of experiments were performed to define its interaction with cellular kinases. The synthesized G1 ITAM-like peptide was shown to coprecipitate with cellular phosphoprotein complexes by an immune-complex kinase assay. Mutational analyses showed that this ITAM-like sequence was a substrate for the Src family kinase Fyn, and two conserved tyrosine residues were required for coprecipitating Lyn, Syk, and ZAP-70 kinases. These findings demonstrated that HTNV envelope glycoprotein G1 contains a functional ITAM-like sequence in its cytoplasmic tail, which can bind critical cellular kinases that regulate immune and endothelial cell functions.

Hantaan Virus Reduces the von Willebrand Factor in Human Umbilical Vein Endothelial Cells

To understand the molecular mechanism of hemorrhagic tendency represented in hemorrhagic fever with renal syndrome (HFRS), the effect of Hantaan virus (HTNV) on the von Willebrand factor (vWF) was observed in human umbilical vein endothelial cells (HuVECs). An immunofluorescence assay (IFA) showed a significant reduction of the vWF in the cytoplasm of HTNV-infected HuVECs. The amount of vWF protein in HTNV-infected HuVECs was reduced to 86, 49, 67, and 42% of those in control HuVECs at 1(st), 3(rd), 5(th), and 7(th) days of post infection (d.p.i.), respectively. However, there were no significant differences in the vWF mRNA expression in both groups at all time courses by reverse transcriptase polymerase chain reaction (RT-PCR). The amounts of secreted vWF in the culture supernatants of the HTNV-infected HuVECs were 79, 87, 83, and 82% of those in control HuVECs at 1(st), 3(rd), 5(th), and 7(th) d.p.i., respectively. These results indicated that the reduction of vWF by HTNV was regulated at post-transcriptional level and this might delay the coagulation process on the site of HTNV infection, thus leading to hemorrhage in HFRS.

Interferon-Stimulated Genes Response in Endothelial Cells Following Hantaan Virus Infection

The regulation mechanism of interferon (IFN) and IFN-stimulated genes is a very complex procedure and is dependent on cell types and virus species. We observed molecular changes related to anti-viral responses in endothelial cells during Hantaan virus (HTNV) infection. We found that there are two patterns of gene expression, the first pattern of gene expression being characterized by early induction and short action, as in that of type I IFNs,' and the other being characterized by delayed induction and long duration, as those of IRF-7, MxA, and TAP-1/2. Even though there are significant differences in their induction folds, we found that all of IFN-alpha/beta , IRF- 3/7, MxA, and TAP-1/2 mRNA expressions reached the peak when the viral replication was most active, which took place 3 days of post infection (d.p.i.). In addition, an interesting phenomenon was observed; only one gene was highly expressed in paired genes such as IFN-alpha/beta??(3/277-folds), IRF-3/7 (2.2/29.4-folds), and TAP- 1/2 (26.2/6.1-folds). Therefore, IFN-beta, IRF-7, and TAP-1 seem to be more important for the anti-viral response in HTNV infection. MxA was increased to 296-folds at 3 d.p.i. and kept continuing 207-folds until 7 d.p.i.. The above results indicate that IFN-beta works for an early anti-viral response, while IRF7, MxA, and TAP-1 work for prolonged anti-viral response in HTNV infection.

Development and evaluation of a double antigen sandwich ELISA for the detection of total antibodies against hemorrhagic fever with renal syndrome virus / 中华实验和临床病毒学杂志

<p><b>OBJECTIVES</b>To develop and evaluate a method for detection of the total antibodies against hemorrhagic fever with renal syndrome (HFRS) virus with improved sensitivity and simplified operation procedure.</p><p><b>METHODS</b>The nucleic proteins of hantavirus were used as coating antigens as well as detection antigens labeled with horse radish peroxidase (HRP). The operation protocol was established, optimized and compared with indirect fluorescence assay (IFA).</p><p><b>RESULTS</b>The specificity of this method was 100 percent in the test of different human sera and 4-8 times more sensitive than IFA. And, it is simpler without requiring any change of the reagents, different sources of samples did not affect the results of the test.</p><p><b>CONCLUSION</b>This method is specific, sensitive and simple for detection of the total antibodies in sera against hantavirus, could be used for the screening of Hantavirus infection in human and host rodent animals.</p>

Nucleotide Sequence and Phylogenetic Analysis of M and L Segment of Soochong Virus

Hantaan virus (HTNV) and Seoul virus (SEOV) have mainly been known as the cause of hemorrhagic fever with renal syndrome (HFRS) in Korea since HTNV has been isolated from Korean field mouse, Apodemus agrarius in 1976 and SEOV has been isolated from Rattus norvegicus in 1980. Soochong virus-1, -2, -3, -4 (SOOVs) were isolated from lung tissues of four Apodemus peninsulae captured on August 1997 at Mt. Gyebang in Hongcheon-gun, Mt. Gachil, Inje-gun, Gangwon Province, and in September 1998 at Mt. Deogyu, Muju-gun, Jeollabuk Province. Apodemus peninsulae is the second-most dominant field rodent species found throughout Korea. To determine phylogenetic analysis of SOOVs, we entirely identified nucleotide sequences of M and L segments. The length of M segment was 3,615 bp and L segment was 6,533 bp. SOOVs were diverged from HTNV by 22.7~23.3% and SEOV by 36.3~37.2%, in M segment. In addition, L segment was diverged from HTNV by 21.8~22.0% and SEOV by 30.3~30.5%. SOOVs sequence compared with Amur virus (AMRV) in M segment showed that SOOVs were different with AMRV about 14.6~16.2% in nucleotide sequences. Neighbor-joining phylogenetic analysis based on entire sequences of the M and L segment indicated that the SOOVs sequences present a separate lineage with HTNV, SEOV and AMRV. SOOVs constituted an individual cluster on the phylogenetic tree and they composed a phylogenic lineage separately. According to these data, SOOVs could be classified as a new hantavirus.

Seroepidemiological Characteristics of Haemorrhagic Fever with Renal Syndrome from 1996 to 2005 in Korea

Haemorrhagic fever with renal syndrome (HFRS) caused by Hantaan viruses has been one of the principal acute febrile disease in Korea. To analysis the sero-epidemiological patterns of HFRS, 4,177 patient sera of acute febrile illness submitted for serological assay to National Institute of Health from Community Health Centers, Institutes of Health and Environment and hospitals from 1996 to 2005 were examined for antibodies against Hantaan virus by indirect immunofluorescent assay (IFA). Serum samples with greater than 1:32 antibody titer were considered positive. The results were analyzed seroepidemiologically by annual, sexual, seasonal, age and regional distribution of HFRS patients. Out of 4,177 serum samples tested, 1,415 samples (33.9%) were positive to Hantaan virus. The ratio of males (48.2%, 682/1,415) to females (38.2%, 541/1,415) was 1.3:1. Seasonal incidence showed that 69.5% (985/1,415) of cases occurred from October to December, resulting with higher prevalence in November (41.3%, 584/1,415). Regionally, seropositive rates of samples collected in Gyenggi, Gangwon and Chungbuk were 39.9% (564/1,415), 19.3% (274/1,415) and 8.5% (120/1,1415), respectively. Age distributions of seropositive of HFRS were detected from 20 to 79 years (78%).