=======================================================================
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.
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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.
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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.
======================================================================
6.) 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.
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7.) 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.