EDITORIAL ESPAÑOL
=================
Hola Amigos de la red Hoy les traigo el segundo capítulo de los HANTAVIRUS, LA FIEBRE HEMORRÁGICA CON SÍNDROME RENAL (HFRS) Y EL SÍNDROME CARDIOPULMONAR POR HANTAVIRUS (HSPS). EL tema de estos virus es tan largo que decidí dividirlo en 2 partes: PRIMERO LAS ESPECIES CONOCIDAS, y hoy, LAS DOS PRINCIPALES ENFERMEDADES PRODUCIDAS POR ELLOS Y LOS VIRUS INVOLUCRADOS con algunos aspectos históricos.

Como les mencione en la edición previa, los HANTAVIRUS están involucrados principalmente en dos enfermedades conocidas como FIEBRE HEMORRÁGICA CON SÍNDROME RENAL (HFRS) o NEFROPATÍA EPIDÉMICA, que es más frecuente en Europa, Africa y Asia y el SÍNDROME PULMONAR O CARDIOPULMONAR POR HANTAVIRUS (HPS), más frecuente en las Américas, pero ambas se pueden presentar en los países involucrados.

LA FIEBRE HEMORRÁGICA CON SÍNDROME RENAL (HFRS):
=================================================

Conocida también como NEFROPATÍA EPIDÉMICA, FIEBRE HEMORRÁGICA COREANA O FIEBRE HEMORRAGICA EPIDEMICA es transmitida por cinco (6) especies de HANTAVIRUS: RIO HANTAAN VIRUS, DOVRABA-BELGRADO VIRUS, SAAREMA VIRUS, SEUL VIRUS, AMUR VIRUS Y PUUMALA VIRUS.

Estas especies circulan principalmente en EUROPA, ASIA y AFRICA, Siendo la más peligrosa el DOBRAVA-BELGRADO quien causa la forma mis severa de la enfermedad y tiene la mayor mortalidad.

1.) DOBRAVA-BELGRADO VIRUS (DOVB):
==================================

Descrito por primera vez en la villa de DOBRAVA, Eslovenia, YUGOSLAVIA, posteriormente en Rusia, Alemania y el Este de Europa. El reservorio del virus Drovava es el rat�n de campo cuello amarillo. Este virus tiene tres variantes genot�picas de patogenicidad:

A.) VIRUS GENOTIPO DOBRAVA: Encontrado en el ratón de cuello amarillo (Apodemus flavicollis)
B.) VIRUS GENOTIPO KURKINO: Encontrado en el ratón rayado de campo (Apodemus agrarius)
C: VIRUS GENOTIPO SOCHI: Encontrado en el Ratón de campo del Mar Negro (Apodemus ponticus).

La fatalidad por el VIRUS DOBRAVA alcanza el 12% y 16%- 48% de los pacientes afectados renalmente requieren diálisis.

2.) SEUL VIRUS (SEOV):
===================

Descrito por primera vez en SEUL Corea por el Virologista Dr. Lee Ho-Wang, encontrado en ratones de campo del genero Apodemus, y posteriormente fue encontrado en ratas en Noruega (Rattus norvegicus) o rata marrón.

En 2.015 se produjo un brote de FIEBRE HEMORRÁGICA EPIDÉMICA por este virus en HOLANDA, INGLATERRA, GALES, FRANCIA Y SUECIA.

En 2.016-2.017 apareció en Estados Unidos Estado de Illinois, Wisconsin infectando 11 personas, todas se recuperaron, posteriormente el CDC, hizo una investigación y encontró que las ratas diseminaron el VIRUS SEUL (SEOV) a los Estados: Alabama, Arkansas, Colorado, Illinois, Indiana, Iowa, Luisiana, Michigan, Minnesota, Misuri, Dakota del Norte, Carolina del Sur, Tennessee, y Utah.

3.) PUUMALA VIRUS (PUUV):
=======================

Encontrado por primera vez en FINLANDIA en 1.980, El reservorio es el ratón topillo rojo(bank vole).También se ha encontrado en el Norte de Europa, Polonia y Rusia en el roedor (Myodes glareolus) quien es el reservorio del virus, el cual vive en bosques madereros de Europa y Asia.

El porcentaje de mortalidad del PUUMALA VIRUS es menor del 0.5%, y el 5% de los pacientes afectados renalmente requiere de diálisis. El VIRUS PUUMALA (PUUV), es el agente etiológico mas común de la HFRS en EUROPA.

4.) SAAREMAA VIRUS (SAV): 
========================

Encontrado en Eslovaquia en. 2.006 también es responsable de la forma más leve de FIEBRE HEMORRÁGICA CON SÍNDROME RENAL. (HFRS). El reservorio es el ratón rayado de campo..

5.) HAANTAN RIVER VIRUS (HNTV):
=============================

Fue aislado del ratón rayado de campo en el año de 1.976 por los ya mencionados el Virologistas Coreano Lee Ho Wnag y El Americano Karl M Johnson. Es de larga data pues los primeros casos Fueron vistos en la guerra de COREA, 1.951-1.953 cuando algunos soldados presentaron hemorragia fiebre, fallo renal y shock.

La mortalidad de esta especie HAANTAN VIRUS (HNTV): Es del 10-12% al igual que el DOBRAVA VIRUS.

Además de esta especie HAANTAN RIVER VIRUS (HNTV) Y EL SEUL VIRUS (SEOV) ya descrito existen otras 2 especies de HANTAVIRUS responsables de la FIEBRE HEMORRÁGICA CON SÍNDROME RENAL (HFRS) en COREA y son: el SOOCHONG VIRUS (SOO), aislado en 1.997 del Ratón Apodemus peninsulae (ratón coreano de campo) y EL MUJU VIRUS (MUV)

6.) AMUR VIRUS (AMRV:
====================

HANTAVIRUS también agente causal de LA FIEBRE HEMORRÁGICA CON SÍNDROME RENAL (HFRS), aislado por primera vez del ratón Apodemus península en China también conocido en Corea como el ratón Coreano de Campo o ratón de la Madera. Se encuentra distribuido en Asia Nororiental, incluyendo el Lejano Oriente de Rusia, el norte de China, y la península Coreana.

SÍNTOMAS DE LA ENFERMEDAD:
===========================

El periodo de incubación de la enfermedad varia entre dos (2) y cuatro (4) semanas y la enfermedad presenta varias FASES, que incluyen 1.) HIPOTENSIÓN, disminución de las plaquetas, fiebre, taquicardia, hipoxemia, 2.) OLIGURIA, inicio de la insuficiencia renal, luego una fase 3.) DIURÉTICA donde el paciente presenta diuresis de 3 a 6 litros por día, y 4.) CONVALECENCIA, que representa la mejoría del paciente. En algunos casos el paciente queda con insuficiencia renal permanente o muere

La mortalidad por LA FIEBRE HEMORRÁGICA CON SÍNDROME RENAL (HFRS) o NEFROPATÍA EPIDÉMICA, como les dije oscila entre en 10 y 12 %. En los pacientes que se recuperan, en algunos casos quedan con insuficiencia renal permanente.

NO EXISTE VACUNA actualmente para la FIEBRE HEMORRÁGICA CON SÍNDROME RENAL (HFRS).

HANTAVIRUS SÍNDROME PULMONAR O CARDIOPULMONAR (HSP-HCPS):
============================================================
Este síndrome fue primeramente descrito en el año de 1.993 en SURESTE de Los Estados Unidos en la Región denominada "LAS CUATRO ESQUINAS", que comprenden los Estados de Arizona, New México, Colorado y Utah posteriormente el nombre fue cambiado a el SIN NOMBRE VIRUS debido una queja de los nativos Americanos por estigmatizar el nombre de "CUATRO ESQUINAS". El mismo ha sido descrito en otros estados del continente Americano.

El virus es trasmitido en los Estados Unidos por los siguientes ROEDORES: La rata algodonera (Sigmodon hispidus), la rata del arroz (Oryzomys palustris), el ratón del Venado (Peromyscus maniculatus) y el ratón de patas blancas (Peromyscus Leucopus)

El medio de contagio: el contacto con heces, orina saliva y mordedura de estos ratones, o inhalación de excremento pulverizado en el aire que contiene las partículas virales. No se ha descrito transmisión HUMANO-HUMANO, pero recientemente se comprobó este hecho con una de las especies transmisoras del SÍNDROME CARDIOPULMONAR (HPS), EL ANDES VIRUS (ANDV) en Sur América.

Las especies de HANTAVIRUS transmisoras del S�NDROME CARDIOPULMONAR POR HANTAVIRUS (HCSP) son: EL SIN NOMBRE VIRUS (SNV), BAYOU VIRUS (BAYV) y el ANDES VIRUS (ANV), principalmente en América,

1.) SIN NOMBRE VIRUS (SNV):
========================
Hantavirus de la ya conocida familia BUYAVIRIDAE, descrito por primera vez en la región de los Estados Unidos conocida como las "CUATRO ESQUINAS" en el año de 1.993 en un paciente que presento el SÍNDROME PULMONAR POR HANTAVIRUS (HPS).

El principal reservorio del SIN NOMBRE VIRUS (SNV) es el ratón del venado (Peromyscus maniculatus), pero además de este roedor se ha encontrado en otros tres (3) roedores que ya les mencione.

El SIN NOMBRE VIRUS (SNV) se encuentra prácticamente en todo el Territorio Norteamericano con la excepción de sudeste de Texas, La florida y Norte de Canadá, y se encuentra más comúnmente en los estados occidentales Nuevo México, Arizona y California estados con poblaciones rurales donde hay mayor contacto del ratón con los humanos.

La letalidad del SÍNDROME PULMONAR (HPS) POR HANTAVIRUS fue reseñada por el CDC en 1.993 en un 63 %, hoy da 2.017 ha disminuido a un 35%

3.) BAYOU VIRUS (BAYV):
====================
El HANTAVIRUS BAYOU VIRUS (BAYV), fue descrito por primera vez en el Estado de Luisiana Estados Unidos en el año 1.996 siendo aislado en la rata del arroz del plátano, siendo esta el reservorio natural, del VIRUS el cual se encuentra diseminado en el Sureste de Los Estados Unidos y es el SEGUNDO HANTAVIRUS MAS COMÚN en ese país después del VIRUS SIN NOMBRE (SNV), y también es agente etiológico del SÍNDROME PULMONAR POR HANTAVIRUS (HPS).

3.) ANDES VIRUS (ANV):
====================
El HANTAVIRUS ANDES VIRUS (ANDV): fue descrito en Sur América en por primera vez en Abril, Junio de 1.997 en Argentina en un brote de SÍNDROME CARDIOPULMONAR (HCPS) por Hantavirus, y posteriormente en Chile en 1.998.

El reservorio de este virus en Argentina y Chile es la rata de arroz de cola larga (Oligoryzomys longicaudatus) y representa el UNICO HANTAVIRUS QUE SE LE HA DESCRITO TRANSMISIÓN DE HUMANO-HUMANO.

Se han encontrado varias cepas de este virus en Argentina: BERMEJO, LECHIGUANAS, MACIEL, ORAN Y PERGAMINO VIRUS.

También han sido reportado casos en Bolivia, Uruguay, Paraguay y Brasil casos de SÍNDROME PULMONAR (HPS)

La mortalidad del ANDES VIRUS (ANDV) en Argentina es del 25-35% y en Chile del 37%

En Brasil han estado circulando los HANTAVIRUS JUQUITIBA VIRUS posible linaje del ARARAQUARA VIRUS, y los ya mencionados BERMEJO, LECHIGUANAS, LAGUNA NEGRA, PERGAMINO, MEARIM, MACIEL, Y ORAN VIRUS de los roedores Oligoryzomys mattogrossae y Oligoryzomys nigripes, TODOS ESTOS son considerados CEPAS DEL ANDES VIRUS responsables también del SÍNDROME PULMONAR (HPS).

En Venezuela esta circulando en la zona de los Llanos el HANTAVIRUS CAÑOO DELGADITO VIRUS, descubierto en roedores en 1.990

SÍNTOMAS DE LA ENFERMEDAD:
===========================
Los síntomas del SÍNDROME PULMONAR POR HANTAVIRUS (HPS) inicialmente son similares a una gripe con FIEBRE, TOS, DOLOR DE CABEZA, MALESTAR GENERAL, DECAIMIENTO Y DOLOR MUSCULAR, también DOLOR ABDOMINAL , VÓMITOS Y DIARREA. Luego en la fase tardía, 4 a 10 días después de los síntomas iniciales HAY UN INICIO SÚBITO DE FALTA DE ALIENTO con EDEMA PULMONAR, que produce un fallo en la VENTILACIÓN el cual evoluciona rápidamente y aun con asistencia mecánica respiratoria y diuréticos potentes puede ocasionarte la muerte.

El porcentaje de mortalidad por esta enfermedad es del 35-36%.

 

LA VACUNA PARA LOS HANTAVIRUS
============================
La primera vacuna que se desarrollo contra los HANTAVIRUS se denomina HANTAVAX y fue creada en el año de 1.990 para prevenir el HANTAAN RIVER VIRUS que ocasiona la forma más severa de la FIEBRE HEMORRÁGICA CON SÍNDROME RENAL (HFRS), y puesta en práctica en China, produciendo una disminución NOTABLE de los casos anuales.

La vacuna esta compuesta por partículas virales del VIRUS HANTAAN VIRUS inactivadas en formalina, son 3 dosis que se colocan en los meses: O, 1 y 13.

Otros hantavirus para los que se utiliza la vacuna incluyen el VIRUS SEUL (SEOV). Sin embargo, se cree que la vacuna no es eficaz contra los hantavirus Europeos, incluidos los virus Puumala (PUUV) y Dobrava-Belgrade (DOBV)

Actualmente hay en estudio otras VACUNAS pero NO HAN SIDO APROBADAS EN EUROPA NI LOS ESTADOS UNIDOS. HANTAVAX tampoco ha sido aprobada por la FDA hoy día 2.017

De modo que, Tenemos a LAS RATAS portadoras prácticamente en todo el mundo, y la mejor manera de PREVENIR INFECCIÓN POR HANTAVIRUS, es evitar el contacto con ellas, y sus fluidos, bien sea heces, orina saliva y mordeduras.

En las graficas te puse 8 roedores involucrados en las enfermedades que te describo, pero hay muchos mas..De modo que si ves una Rata o Un ratón en los alrededores tienes que hacer algo por ti y tu familia, derríbalos, acábalos, evítalos !!! 

Los HANTAVIRUS hoy día están considerados entre los 10 VIRUS mas peligrosos en el mundo.

Saludos a todos.

Dr. José Lapenta. 

 

=======================================================================

REFERENCIAS BIBLIOGRAFICAS/ BIBLIOGRAPHICAL REFERENCES

=======================================================================

1.) A Fatal Hantavirus Pulmonary Syndrome Misdiagnosed as Dengue: An Investigation into the First Reported Case in Rio de Janeiro State, Brazil.

2) Serum levels of interleukin-6 are linked to the severity of the disease caused by Andes Virus.

3.) Hantavirus pulmonary syndrome, Southern Chile, 1995-2012.

4.) Differential lymphocyte and antibody responses in deer mice infected with Sin Nombre hantavirus or Andes hantavirus.

5.) What Do We Know about How Hantaviruses Interact with Their Different Hosts?

6.) First human isolate of Hantavirus (Andes virus) in the Americas.

7.) Hantavirus infections.

8.) Antiviral therapy and prevention against hantavirus infections.

9.) Becoming an International Scientist in South Korea: Ho Wang Lee's Research Activity about Epidemic Hemorrhagic Fever.

10.) A novel Sin Nombre virus DNA vaccine and its inclusion in a candidate pan-hantavirus vaccine against hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS).

11.) [Puumala and Dobrava viruses in the northeastern and central regions of Bosnia].

12.) Puumala and Dobrava viruses cause hemorrhagic fever with renal syndrome in Bosnia-Herzegovina: evidence of highly cross-neutralizing antibody responses in early patient sera.

13.) Dobrava hantavirus causes hemorrhagic fever with renal syndrome in central Europe and is carried by two different Apodemus mice species.

14.) Co-circulation of three pathogenic hantaviruses: Puumala, Dobrava, and Saaremaa in Hungary.

15.) Long-term immunogenicity and safety of inactivated Hantaan virus vaccine (Hantavax™) in healthy adults.

16.) Antibody responses in humans to an inactivated hantavirus vaccine (Hantavax).

17.) Preliminary human trial of inactivated golden hamster kidney cell (GHKC) vaccine against haemorrhagic fever with renal syndrome (HFRS).

======================================================================

======================================================================

 1.) A Fatal Hantavirus Pulmonary Syndrome Misdiagnosed as Dengue: An Investigation into the First Reported Case in Rio de Janeiro State, Brazil.
 =======================================================================
 Am J Trop Med Hyg. 2017 Jul;97(1):125-129. doi: 10.4269/ajtmh.16-0845.
 
 de Oliveira RC1, Guterres A1, Teixeira BR2, Fernandes J1, Júnior JMP3, de Jesus Oliveira Júnior R3, Pereira LS1, Júnior JB3, Meneguete PS4, Dias CMG4, Bonvicino CR2, D'Andrea PS2, de Lemos ERS1.
 Author information
 
 1
 Laboratório de Hantaviroses e Rickettsioses, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Rio de Janeiro, Brasil.
 2
 Laboratório de Biologia e Parasitologia de Mamíferos Silvestres Reservatórios, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Rio de Janeiro, Brasil.
 3
 Secretaria Municipal de Saúde, Setor de Vigilância Epidemiológica Rio Claro, Rio de Janeiro, Brasil.
 4
 Secretaria de Saúde do Estado do Rio de Janeiro, Setor de Vigilância Epidemiológica, Rio de Janeiro, Rio de Janeiro, Brasil.
 
 Abstract
 
 We report the results of an investigation into a fatal case of hantavirus pulmonary syndrome (HPS) in Rio de Janeiro State, Brazil, where the disease had not been reported previous to 2015. Following the notification of an HPS case, serum samples were collected from the household members and work contacts of the HPS patient and tested for antibody to hantaviruses. Seroprevalence of 22% (10/45) was indicated for hantavirus out of 45 human samples tested. Blood and tissue samples were collected from 72 rodents during fieldwork to evaluate the prevalence of hantavirus infection, by using enzyme-linked immunosorbent assay IgG, and to characterize the rodent hantavirus reservoir(s), by reverse transcription polymerase chain reaction and sequencing. Antibody prevalence was 6.9%. The circulation of a single genotype, the Juquitiba hantavirus, carried by two rodent species, black-footed pigmy rice rat (Oligoryzomys nigripes) and cursor grass mouse (Akodon cursor), was shown by analysis of the nucleotide sequences of the S segment. Juquitiba hantavirus circulates in rodents of various species, but mainly in the black-footed pigmy rice rat. HPS is a newly recognized clinical entity in Rio de Janeiro State and should be considered in patients with febrile illness and acute respiratory distress.
 ======================================================================
 2.) Serum levels of interleukin-6 are linked to the severity of the disease caused by Andes Virus.
 ======================================================================
 PLoS Negl Trop Dis. 2017 Jul 14;11(7):e0005757. doi: 10.1371/journal.pntd.0005757. eCollection 2017 Jul.
 
 Angulo J1, Martínez-Valdebenito C2, Marco C2, Galeno H3, Villagra E3, Vera L3, Lagos N3, Becerra N3, Mora J3, Bermúdez A4, Díaz J4, Ferrés M2, López-Lastra M1.
 Author information
 
 1
 Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia (IMII), Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, División de Pediatría, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
 2
 Laboratorio de Infectología, Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, División de Pediatría, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
 3
 Subdepartamento de Virología Clínica, Departamento Laboratorio Biomédico Nacional y de Referencia, Instituto de Salud Pública de Chile, Santiago, Chile.
 4
 Departamento de Asuntos Científicos, Instituto de Salud Pública de Chile, Santiago, Chile.
 
 Abstract
 
 Andes virus (ANDV) is the etiological agent of hantavirus cardiopulmonary syndrome in Chile. In this study, we evaluated the profile of the pro-inflammatory cytokines IL-1β, IL-12p70, IL-21, TNF-α, IFN-γ, IL-10 and IL-6 in serum samples of ANDV-infected patients at the time of hospitalization. The mean levels of circulating cytokines were determined by a Bead-Based Multiplex assay coupled with Luminex detection technology, in order to compare 43 serum samples of healthy controls and 43 samples of ANDV-infected patients that had been categorized according to the severity of disease. When compared to the controls, no significant differences in IL-1β concentration were observed in ANDV-infected patients (p = 0.9672), whereas levels of IL-12p70 and IL-21 were significantly lower in infected cases (p = <0.0001). Significantly elevated levels of TNF-α, IFN-γ, IL-10, and IL-6 were detected in ANDV-infected individuals (p = <0.0001, 0.0036, <0.0001, <0.0001, respectively). Notably, IL-6 levels were significantly higher (40-fold) in the 22 patients with severe symptoms compared to the 21 individuals with mild symptoms (p = <0.0001). Using multivariate regression models, we show that IL-6 levels has a crude OR of 14.4 (CI: 3.3-63.1). In conclusion, the serum level of IL-6 is a significant predictor of the severity of the clinical outcome of ANDV-induced disease.
 ======================================================================
 3.) Hantavirus pulmonary syndrome, Southern Chile, 1995-2012.
 ======================================================================
 Emerg Infect Dis. 2015 Apr;21(4):562-8. doi: 10.3201/eid2104.141437.
 
 Riquelme R, Rioseco ML, Bastidas L, Trincado D, Riquelme M, Loyola H, Valdivieso F.
 Abstract
 
 Hantavirus is endemic to the Region de Los Lagos in southern Chile; its incidence is 8.5 times higher in the communes of the Andean area than in the rest of the region. We analyzed the epidemiologic aspects of the 103 cases diagnosed by serology and the clinical aspects of 80 hospitalized patients during 1995-2012. Cases in this region clearly predominated during winter, whereas in the rest of the country, they occur mostly during summer. Mild, moderate, and severe disease was observed, and the case-fatality rate was 32%. Shock caused death in 75% of those cases; high respiratory frequency and elevated creatinine plasma level were independent factors associated with death. Early clinical suspicion, especially in rural areas, should prompt urgent transfer to a hospital with an intensive care unit and might help decrease the high case-fatality rate.
 ======================================================================
 4.) Differential lymphocyte and antibody responses in deer mice infected with Sin Nombre hantavirus or Andes hantavirus.
 ======================================================================
 J Virol. 2014 Aug;88(15):8319-31. doi: 10.1128/JVI.00004-14. Epub 2014 May 14.
 
 Schountz T1, Quackenbush S2, Rovnak J2, Haddock E3, Black WC 4th4, Feldmann H3, Prescott J3.
 Author information
 
 1
 Arthropod-borne and Infectious Diseases Laboratory, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA [email protected].
 2
 Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA.
 3
 Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA.
 4
 Arthropod-borne and Infectious Diseases Laboratory, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA.
 
 Abstract
 
 Hantavirus cardiopulmonary syndrome (HCPS) is a rodent-borne disease with a high case-fatality rate that is caused by several New World hantaviruses. Each pathogenic hantavirus is naturally hosted by a principal rodent species without conspicuous disease and infection is persistent, perhaps for life. Deer mice (Peromyscus maniculatus) are the natural reservoirs of Sin Nombre virus (SNV), the etiologic agent of most HCPS cases in North America. Deer mice remain infected despite a helper T cell response that leads to high-titer neutralizing antibodies. Deer mice are also susceptible to Andes hantavirus (ANDV), which causes most HCPS cases in South America; however, deer mice clear ANDV. We infected deer mice with SNV or ANDV to identify differences in host responses that might account for this differential outcome. SNV RNA levels were higher in the lungs but not different in the heart, spleen, or kidneys. Most ANDV-infected deer mice had seroconverted 14 days after inoculation, but none of the SNV-infected deer mice had. Examination of lymph node cell antigen recall responses identified elevated immune gene expression in deer mice infected with ANDV and suggested maturation toward a Th2 or T follicular helper phenotype in some ANDV-infected deer mice, including activation of the interleukin 4 (IL-4) pathway in T cells and B cells. These data suggest that the rate of maturation of the immune response is substantially higher and of greater magnitude during ANDV infection, and these differences may account for clearance of ANDV and persistence of SNV.
 IMPORTANCE:
 
 Hantaviruses persistently infect their reservoir rodent hosts without pathology. It is unknown how these viruses evade sterilizing immune responses in the reservoirs. We have determined that infection of the deer mouse with its homologous hantavirus, Sin Nombre virus, results in low levels of immune gene expression in antigen-stimulated lymph node cells and a poor antibody response. However, infection of deer mice with a heterologous hantavirus, Andes virus, results in a robust lymph node cell response, signatures of T and B cell maturation, and production of antibodies. These findings suggest that an early and aggressive immune response to hantaviruses may lead to clearance in a reservoir host and suggest that a modest immune response may be a component of hantavirus ecology.
 ======================================================================
 5.) What Do We Know about How Hantaviruses Interact with Their Different Hosts?
 ======================================================================
 Viruses. 2016 Aug 11;8(8). pii: E223. doi: 10.3390/v8080223.
 
 Ermonval M1, Baychelier F2, Tordo N3.
 Author information
 
 1
 Unité des Stratégies Antivirales, Département de Virologie, Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France. [email protected].
 2
 Unité des Stratégies Antivirales, Département de Virologie, Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France. [email protected].
 3
 Unité des Stratégies Antivirales, Département de Virologie, Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France. [email protected].
 
 Abstract
 
 Hantaviruses, like other members of the Bunyaviridae family, are emerging viruses that are able to cause hemorrhagic fevers. Occasional transmission to humans is due to inhalation of contaminated aerosolized excreta from infected rodents. Hantaviruses are asymptomatic in their rodent or insectivore natural hosts with which they have co-evolved for millions of years. In contrast, hantaviruses cause different pathologies in humans with varying mortality rates, depending on the hantavirus species and its geographic origin. Cases of hemorrhagic fever with renal syndrome (HFRS) have been reported in Europe and Asia, while hantavirus cardiopulmonary syndromes (HCPS) are observed in the Americas. In some cases, diseases caused by Old World hantaviruses exhibit HCPS-like symptoms. Although the etiologic agents of HFRS were identified in the early 1980s, the way hantaviruses interact with their different hosts still remains elusive. What are the entry receptors? How do hantaviruses propagate in the organism and how do they cope with the immune system? This review summarizes recent data documenting interactions established by pathogenic and nonpathogenic hantaviruses with their natural or human hosts that could highlight their different outcomes.
 ======================================================================
 6.) First human isolate of Hantavirus (Andes virus) in the Americas.
 ======================================================================
 Emerg Infect Dis. 2002 Jul;8(7):657-61.
 
 Galeno H1, Mora J, Villagra E, Fernandez J, Hernandez J, Mertz GJ, Ramirez E.
 Author information
 
 1
 Public Health Institute of Chile, Santiago.
 
 Abstract
 
 We isolated Andes virus (formal name: Andes virus [ANDV], a species in the genus Hantavirus), from serum of an asymptomatic 10-year-old Chilean boy who died 6 days later of hantavirus pulmonary syndrome (HPS). The serum was obtained 12 days after his grandmother died from HPS and 2 days before he became febrile. No hantavirus immunoglobulin (Ig) G or IgM antibodies were detected in the serum sample. After three blind passages, ANDV antigens were detected in Vero E6 cells by immunofluorescence assay and enzyme-linked immunosorbent assay, and ANDV RNA was detected by reverse transcription-polymerase chain reaction. A fragment of the virus genome showed 96.2% nucleotide identity with that of prototype ANDV. To our knowledge, this is the first isolation of any agent of hemorrhagic fever with HPS from a human and the first such isolation of hantavirus before symptoms of that syndrome or HPS began.
 ======================================================================
 7.) Hantavirus infections.
 ======================================================================
 Clin Microbiol Infect. 2015 Jun 22. pii: S1198-743X(15)00536-4. doi: 10.1111/1469-0691.12291. [Epub ahead of print]
 
 Avšič-Županc T1, Saksida A2, Korva M2.
 Author information
 
 1
 Institute of Microbiology and Immunology, Faculty of Medicine, Ljubljana, Slovenia. Electronic address: [email protected].
 2
 Institute of Microbiology and Immunology, Faculty of Medicine, Ljubljana, Slovenia.
 
 Abstract
 
 Over the past few decades understanding and recognition of hantavirus infection has greatly improved worldwide, but both the amplitude and the magnitude of hantavirus outbreaks have been increasing. Several novel hantaviruses with unknown pathogenic potential have been identified in a variety of insectivore hosts. With the new hosts, new geographical distributions of hantaviruses have also been discovered and several new species were found in Africa. Hantavirus infection in humans can result in two clinical syndromes: haemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) caused by Old World and New World hantaviruses, respectively. The clinical presentation of HFRS varies from subclinical, mild, and moderate to severe, depending in part on the causative agent of the disease. In general, HFRS caused by Hantaan virus, Amur virus and Dobrava virus are more severe with mortality rates from 5 to 15%, whereas Seoul virus causes moderate and Puumala virus and Saaremaa virus cause mild forms of disease with mortality rates <1%. The central phenomena behind the pathogenesis of both HFRS and HCPS are increased vascular permeability and acute thrombocytopenia. The pathogenesis is likely to be a complex multifactorial process that includes contributions from immune responses, platelet dysfunction and the deregulation of endothelial cell barrier functions. Also a genetic predisposition, related to HLA type, seems to be important for the severity of the disease. As there is no effective treatment or vaccine approved for use in the USA and Europe, public awareness and precautionary measures are the only ways to minimize the risk of hantavirus disease.
 ======================================================================
 8.) Antiviral therapy and prevention against hantavirus infections.
 ======================================================================
 Acta Virol. 2017;61(1):3-12. doi: 10.4149/av_2017_01_3.
 
 Szabó R.
 Abstract
 
 Hantaviruses are emerging zoonoses hosted by small mammals. In humans, they cause two diseases. Hemorrhagic fever with renal syndrome is mainly caused by Dobrava-Belgrade virus, Puumala virus, Seoul virus and Hantaan virus in Asia and Europe. On the other hand, the most important causes of hantavirus cardiopulmonary syndrome are Sin Nombre virus and Andes virus in Americas. Ribavirin yet remains the only licensed drug against the hantavirus infections, but its sufficient antiviral activity remains an issue under discussion. There are still no available vaccines against hantaviruses except of some inactivated virus vaccines licensed only in East-Asian countries. Some of the vaccines are under development in pre-clinical stages. The review discuses about specific compounds with approved antiviral activity against hantaviruses. Other approaches such as development of vaccines, are compiled as well.
 ======================================================================
 9.) Becoming an International Scientist in South Korea: Ho Wang Lee's Research Activity about Epidemic Hemorrhagic Fever.
 ======================================================================
 Uisahak. 2017 Apr;26(1):95-124. doi: 10.13081/kjmh.2017.26.95.
 
 Shin M1.
 Author information
 
 1
 Dept. of Science Studies, Chonbuk National University, Jeonju-si, Jeollabuk-do, KOREA.
 
 Abstract
 
 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.
 ======================================================================
 10.) A novel Sin Nombre virus DNA vaccine and its inclusion in a candidate pan-hantavirus vaccine against hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS).
 ========================================================================
 Vaccine. 2013 Sep 13;31(40):4314-21. doi: 10.1016/j.vaccine.2013.07.025. Epub 2013 Jul 24.
 
 Hooper JW1, Josleyn M, Ballantyne J, Brocato R.
 Author information
 
 1
 Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA. [email protected]
 
 Abstract
 
 Sin Nombre virus (SNV; family Bunyaviridae, genus Hantavirus) causes a hemorrhagic fever known as hantavirus pulmonary syndrome (HPS) in North America. There have been approximately 200 fatal cases of HPS in the United States since 1993, predominantly in healthy working-age males (case fatality rate 35%). There are no FDA-approved vaccines or drugs to prevent or treat HPS. Previously, we reported that hantavirus vaccines based on the full-length M gene segment of Andes virus (ANDV) for HPS in South America, and Hantaan virus (HTNV) and Puumala virus (PUUV) for hemorrhagic fever with renal syndrome (HFRS) in Eurasia, all elicited high-titer neutralizing antibodies in animal models. HFRS is more prevalent than HPS (>20,000 cases per year) but less pathogenic (case fatality rate 1-15%). Here, we report the construction and testing of a SNV full-length M gene-based DNA vaccine to prevent HPS. Rabbits vaccinated with the SNV DNA vaccine by muscle electroporation (mEP) developed high titers of neutralizing antibodies. Furthermore, hamsters vaccinated three times with the SNV DNA vaccine using a gene gun were completely protected against SNV infection. This is the first vaccine of any kind that specifically elicits high-titer neutralizing antibodies against SNV. To test the possibility of producing a pan-hantavirus vaccine, rabbits were vaccinated by mEP with an HPS mix (ANDV and SNV plasmids), or HFRS mix (HTNV and PUUV plasmids), or HPS/HFRS mix (all four plasmids). The HPS mix and HFRS mix elicited neutralizing antibodies predominantly against ANDV/SNV and HTNV/PUUV, respectively. Furthermore, the HPS/HFRS mix elicited neutralizing antibodies against all four viruses. These findings demonstrate a pan-hantavirus vaccine using a mixed-plasmid DNA vaccine approach is feasible and warrants further development.
 ======================================================================
 11.) [Puumala and Dobrava viruses in the northeastern and central regions of Bosnia].
 ======================================================================
 Acta Med Croatica. 2003;57(5):373-80.
 
 [Article in Croatian]
 Hukić M1, Muzaferović S, Tulumović D, Calkić L, Sabović S, Karakas S, Sabitović D, Pavić G, Osmancević E.
 Author information
 
 1
 Zavod za mikrobiologiju Univerzitetski klinicki centar Tuzla Trnovac bb 75000 Tuzla, Bosna i Hercegovina.
 
 Abstract
 
 Bosnia and Herzegovina has been known as a highly endemic region for Hantavirus infections for more than 50 years. Previous studies have shown that at least two different hantaviruses, the murine Dobrava (DOB) and avricoline Puumala (PUU) viruses, each carried by a different rodent species, have been circulating in the area. However, there is little information on rodent population density fluctuations in Bosnia over the past years as well as on the ratio of Puumala to Dobrava infection in humans.
 THE AIMS:
 
 THE AIMS OF OUR STUDY WERE:
 
 to identify the rodent species which may serve as hantavirus reservoirs in the north-east and central Bosnia; to assess the geographical distribution, density and population dynamics of rodent species in the area; to assess the influence of climatic conditions on the size of rodent population; and to determine the ratio of Puumala to Dobrava infection in humans.
 METHODS:
 
 The epidemiologic and epizootic study in the north-east and central Bosnia was conducted during the 8-year period (1995-2003). The average yearly and monthly temperatures, air humidity and precipitation during the study period were analyzed. A total of 381 small rodents were caught during the epidemic years (1995 and 2002), and in-between the epidemic periods (1999 and 2000). The animals were caught by live-traps and identified by morphometric methods. The density of animals was estimated by counting the number of holes per 1000 m2. Sera of 311 patients with clinical signs and symptoms of hemorrhagic fever with renal syndrome (HFRS) were tested for the presence of antibodies reactive to the Dobrava, Puumala and Seoul viruses by using indirect immunofluorescence test (IIF), and IgG and IgM ELIS. Sera of 84 patients were tested using only IIF, and 227 sera were tested by IIF and -capture IgM ELIS tests.
 RESULTS:
 
 During the epidemic years, the average monthly temperatures in February were by 4.3 times higher than the average temperatures during the nonepidemic years, which may have influenced the early reproduction of rodents and development of "mouse years". The rodents were identified as: Apodemus flavicollis (n = 139), Apodemus sylvaticus (n = 89), Apodemus agrarius (n = 4), Clethrionomys glareolus (n = 117), Sorex araneus (n = 5), Pytimus subterraneus (n = 23), Mus musculus (n = 1), Mycrotus arvalis (n = 1) and Rattus norvegicus (n = 2). Clethrionomys glareolus was predominant in the regions with the altitude higher than 1160 meters and Apodemus species in the regions with the altitude lower than 670 meters. The rodent population density changes seasonally and cyclically. During the epidemic years, the rodent population density was marked as very high, whereas during the nonepidemic years it was designated from low to moderate. Well-known natural hosts of Hantaviruses (A. flavicolis and C. glareolus) are most widely spread species of small rodents, and the increase in their population is closely related with outbreaks of epidemics of HVBS-a. Puumala virus caused HVBS-a in 49.84% (155/311); Dobrava virus in 23.15% (72/311) of cases, whereas Hantaviruses serotype was not identified in 27.00% (84/311) of cases. Infections caused by Puumala virus were more frequent than the infections caused by Dobrava virus during both epidemic and nonepidemic periods. The proportion of humans infected with Puumala and Dobrava viruses correlated with the number of natural hosts of Hantaviruses in the areas of HVBS outbreaks. The study of the prevalence of hantavirus antibodies in the populations of rodents and humans, which had been under way, should elucidate these relationships.
 ======================================================================
 12.) Puumala and Dobrava viruses cause hemorrhagic fever with renal syndrome in Bosnia-Herzegovina: evidence of highly cross-neutralizing antibody responses in early patient sera.
 ======================================================================
 Lundkvist A1, Hukic M, Hörling J, Gilljam M, Nichol S, Niklasson B.
 Author information
 
 1
 Swedish Institute for Infectious Disease Control, Stockholm. [email protected]
 
 Abstract
 
 Hantavirus infection was diagnosed serologically by mu-capture IgM and IgG ELISAs in hemorrhagic fever with renal syndrome (HFRS) patients admitted to Tuzla Hospital, Bosnia-Herzegovina. The results indicated that more than one hantavirus caused the outbreak. To address the question of which hantavirus serotypes were involved, sequentially drawn sera were analyzed by focus reduction neutralization test (FRNT) for antibodies against Puumala, Hantaan, Dobrava, and Seoul hantaviruses. The data revealed that acute- or early convalescent-phase sera, even when drawn as late as 3 weeks after the onset of disease, could not be used for typing of the causative hantavirus; a significant number of these samples showed similar reactivity of neutralizing antibodies to several different hantavirus serotypes. Moreover, although several acute-phase sera showed the highest FRNT titer to Hantaan virus, convalescent sera from these patients in all cases showed high specificity for Puumala or Dobrava viruses. This phenomenon, interpreted as a cross-neutralizing primary antibody response, makes several earlier reports concerning causative agents of HFRS questionable. Serological examination of small rodents trapped in the endemic area identified Puumala- and Dobrava-like virus infections. RT-PCR and sequencing of rodent lung samples identified Dobrava virus in one yellow-necked field mouse (Apodemus flavicollis). Cross-FRNT data, using polyclonal rabbit antibodies, clearly confirmed Dobrava virus as a unique hantavirus serotype. In conclusion, the results revealed that both Puumala- and Dobrava-like viruses caused HFRS in Bosnia-Herzegovina, whereas no signs of Hantaan or Seoul virus involvement were found.
 ======================================================================
 13.) Dobrava hantavirus causes hemorrhagic fever with renal syndrome in central Europe and is carried by two different Apodemus mice species.
 ======================================================================
 J Med Virol. 2001 Feb;63(2):158-67.
 
 Sibold C1, Ulrich R, Labuda M, Lundkvist A, Martens H, Schütt M, Gerke P, Leitmeyer K, Meisel H, Krüger DH.
 Author information
 
 1
 Institute of Virology, Charité School of Medicine, Humboldt University, Berlin, Germany.
 
 Abstract
 
 In central Europe, hemorrhagic fevers with renal syndrome (HFRS) in humans are caused by the hantavirus species Puumala (transmitted by voles) and a second, Hantaan-related species (transmitted by mice). The second virus could be identified as Dobrava virus. To date, 19 clinical cases of Dobrava infection have been found in Germany and Slovakia. All patients exhibited a mild/moderate clinical course and no case fatality occurred. Screening for infected rodents revealed that the striped field mouse (Apodemus agrarius) represents the main reservoir for Dobrava virus in central Europe. Nucleotide sequence comparisons and phylogenetic analysis based on complete and partial genomic S segment nucleotide sequences placed the Slovakian A. agrarius-derived hantavirus strains within the Dobrava species, forming a cluster on the Dobrava phylogenetic tree. In east Slovakia, a single Dobrava virus-infected yellow-necked mouse (Apodemus flavicollis) was trapped in a locality that predominantly showed Dobrava-infected A. agrarius. Comparison of the S segment sequence (nucleotides 381-935) revealed that the Dobrava strain from A. flavicollis shows only 84.3% nucleotide homology to A. agrarius-derived strains from this location but 96.3% homology to A. flavicollis-derived Dobrava strains from the Balkans (southeast Europe). Phylogenetic analysis of the partial S segment placed the A. flavicollis-derived Dobrava strain from Slovakia on a distinct Dobrava lineage (DOB-Af) together with the south-east European A. flavicollis-derived strains. The results indicate that Dobrava strains from A. agrarius (DOB-Aa) vs. A. flavicollis (DOB-Af) could develop different degrees of virulence in humans.
 =======================================================================
 14.) Co-circulation of three pathogenic hantaviruses: Puumala, Dobrava, and Saaremaa in Hungary.
 =======================================================================
 J Med Virol. 2009 Dec;81(12):2045-52. doi: 10.1002/jmv.21635.
 
 Plyusnina A1, Ferenczi E, Rácz GR, Nemirov K, Lundkvist A, Vaheri A, Vapalahti O, Plyusnin A.
 Author information
 
 1
 Department of Virology, Infection Biology Research Program, Haartman Institute, University of Helsinki, Helsinki, Finland.
 
 Abstract
 
 Hantaviruses (Bunyaviridae) cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus (cardio)pulmonary syndrome (HCPS) in the Americas. HFRS is caused by Hantaan virus (HTNV), Seoul virus (SEOV), Dobrava virus (DOBV), Saaremaa virus (SAAV), and Puumala virus (PUUV). Of those, only HTNV is not present in Europe. In recent years, hantaviruses, described in other parts of Europe, were also detected at various locations in Hungary. To study the genetic properties of Hungarian hantaviruses in detail, sequences of the viral S and M segments were recovered from bank voles (Myodes glareolus), yellow-necked mice (Apodemus flavicollis), and striped field mice (Apodemus agrarius) trapped in the Transdanubian region. As expected, the sequences recovered belonged, respectively, to PUUV (two strains), DOBV (one strain), and SAAV (one strain). On phylogenetic trees two new Hungarian PUUV strains located within the well- supported Alpe-Adrian (ALAD) genetic lineage that included also Austrian, Slovenian, and Croatian strains. Analysis of the Hungarian SAAV and DOBV genetic variants showed host-specific clustering and also geographical clustering within each of these hantavirus species. Hungarian SAAV and DOBV strains were related most closely to strains from Slovenia (Prekmurje region). This study confirms that multiple hantaviruses can co-circulate in the same locality and can be maintained side-by-side in different rodent species.
 =================================================================
 15.) Long-term immunogenicity and safety of inactivated Hantaan virus vaccine (Hantavax™) in healthy adults.
 ==================================================================
 Vaccine. 2016 Mar 4;34(10):1289-95. doi: 10.1016/j.vaccine.2016.01.031. Epub 2016 Jan 28.
 
 Song JY1, Woo HJ2, Cheong HJ1, Noh JY1, Baek LJ3, Kim WJ4.
 Author information
 
 1
 Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
 2
 Division of Infectious Diseases, Department of Internal Medicine, Hallym University College of Medicine, Seoul, Republic of Korea.
 3
 Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul, Republic of Korea.
 4
 Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea. Electronic address: [email protected].
 
 Abstract
 BACKGROUND:
 
 Hemorrhagic fever with renal syndrome is a serious health problem in Eurasian countries, including Korea and China. This study evaluated the long-term immunogenicity and safety of formalin-inactivated Hantaan virus vaccine (Hantavax™).
 METHODS:
 
 A phase III, multi-center clinical trial was undertaken to evaluate the immunogenicity and safety of Hantavax™ (three-dose schedule at 0, 1, and 13 months) among healthy adults. Immune response was assessed using the plaque reduction neutralizing antibody test (PRNT) and immunofluorescent antibody assay (IFA). Antibody levels were measured pre-vaccination and at 2, 13, 14, 25, 37, and 49 months after the initial vaccination. Systemic and local adverse events were assessed.
 RESULTS:
 
 A total of 226 healthy subjects aged 19-75 years were enrolled. Following two primary doses of Hantavax™, the seroconversion rate was 90.14% by IFA, but it was only 23.24% by PRNT50. With booster administration, seropositive rates were 87.32% and 45.07% at one month post-vaccination according to IFA and PRNT50, respectively. In young adults (19-39 years), the seropositive rate according to PRNT50 reached about 60% after booster vaccination. The mean duration of seropositive response was 735 days for PRNT50 and 845 days for IFA. Solicited local and systemic adverse events occurred in 47.79% and 25.22% of study subjects, respectively, and most were grade 1.
 CONCLUSION:
 
 Hantavax™ showed a booster effect and immunogenicity lasting two years with a three-dose schedule. The neutralizing antibody response was quite poor with two primary doses, so an early booster vaccination at 2-6 months might be warranted to provide timely protection to high-risk subjects.
 ======================================================================
 16.) Antibody responses in humans to an inactivated hantavirus vaccine (Hantavax).
 ======================================================================
 Vaccine. 1999 Jun 4;17(20-21):2569-75.
 
 Cho HW1, Howard CR.
 Author information
 
 1
 Department of Virology, National Institute of Health, Eunpyung Gu, Seoul, South Korea.
 
 Abstract
 
 Hantaviruses cause haemorrhagic fever with renal syndrome (HFRS) and result in severe human morbidity and mortality. Safe and effective vaccines are needed urgently in order to reduce the incidence of human illness. Hitherto studies of hantavirus vaccine efficiency have been limited to individuals at low risk of infection. In this study the immune response to an inactivated hantavirus vaccine was measured in 64 human volunteers at high risk of infection by virtue of residence and occupation. 30 d after vaccination, 79% of subjects developed a significant hantavirus antibody titre as measured by immunofluorescence (IFA) and 62% by enzyme linked immunosorbent assay (ELISA). Seroconversion rates increased to 97% one month after the booster dose. Neutralising antibody titres paralleled this trend with 13% of vaccine recipients producing neutralising antibody one month after the first dose and 75% of vaccine recipients responding one month after boosting. Antibody titres had declined by one year, however, with only 37% and 43% of sera positive by IFA and ELISA, respectively. Re-vaccination at this time produced a vigorous anamnestic response with 94% and 100% of vaccine recipients yielding positive antibody titres. Only 50% of the sampled population, however, produced neutralising antibodies following the booster dose one year later. The vaccine was well tolerated and there were no apparent differences in the responses of males and females. However, further improvement of this vaccine is necessary in order to induce a more longlasting humoral immune response.
 ======================================================================
 17.) Preliminary human trial of inactivated golden hamster kidney cell (GHKC) vaccine against haemorrhagic fever with renal syndrome (HFRS).
 ======================================================================
 Vaccine. 1992;10(4):214-6.
 
 Song G1, Huang YC, Hang CS, Hao FY, Li DX, Zheng XL, Liu WM, Li SL, Huo ZW, Huei LJ, et al.
 Author information
 
 1
 Institute of Virology, Chinese Academy of Preventive Medicine, Beiming.
 
 Abstract
 
 An inactivated golden hamster kidney cell culture (GHKC) vaccine against haemorrhagic fever with renal syndrome (HFRS) has been developed in recent years. A monovalent GHKC vaccine (lot 88-17) was prepared with L99 strain of the rat-type hantavirus, adapted in suckling mouse brain, cultivated in GHKC, and inactivated with 0.025% formalin, and a preliminary trial of the vaccine was carried out in a small number of human volunteers with the approval of the Ministry of Public Health, PRC, in order to identify safety and antibody response of the vaccine. Three inoculations were made on days 0, 7 and 28 respectively, by the intramuscular route with 1 ml vaccine each time for every volunteer. No obvious side effect was observed in vaccinees within 3 days after each inoculation. All 12 vaccinees (10 received three inoculations, and two received two inoculations of the vaccine) showed positive seroconversion of IgG antibody (by IFAT and ELISA) and neutralizing antibody (by enzyme focus reduction neutralization test, EFRNT), and 10 of them were still seropositive 180 and 360 days after the first inoculation. These results suggest that this vaccine would be safe for human use, and could effectively induce IgG and neutralizing antibody responses.