Yellow fever vaccine-associated viscerotropic disease and death in Spain.
ABSTRACT Yellow fever vaccine-associated viscerotropic disease (YEL-AVD) is a recently described severe adverse event after yellow fever vaccination, and some cases have been reported in different countries [Anonymous. Effects of yellow fever and vaccination. Lancet 2001;358(9296):1907-9]. Herein we describe a YEL-AVD case in a young woman, who died after vaccination with 17D-204 strain. Clinical, serological and immunochemical analysis as well as virus detection, quantification, sequence analysis and cytokine release, were performed. Further investigations on yellow fever vaccine adverse events, and carefully analysis of the immune response elicited are important tasks for the future.
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ABSTRACT: The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viruses inserted into the backbone of another virus (so-called "chimeric virus vaccines"). Many viral vector vaccines are in advanced clinical trials. The first such vaccine to be approved for marketing (to date in Australia, Thailand, Malaysia, and the Philippines) is a vaccine against the flavivirus, Japanese encephalitis (JE), which employs a licensed vaccine (yellow fever 17D) as a vector. In this vaccine, two envelope proteins (prM-E) of YF 17D virus were exchanged for the corresponding genes of JE virus, with additional attenuating mutations incorporated into the JE gene inserts. Similar vaccines have been constructed by inserting prM-E genes of dengue and West Nile into YF 17D virus and are in late stage clinical studies. The dengue vaccine is, however, more complex in that it requires a mixture of four live vectors each expressing one of the four dengue serotypes. This vaccine has been evaluated in multiple clinical trials. No significant safety concerns have been found. The Phase 3 trials met their endpoints in terms of overall reduction of confirmed dengue fever, and, most importantly a significant reduction in severe dengue and hospitalization due to dengue. However, based on results that have been published so far, efficacy in preventing serotype 2 infection is less than that for the other three serotypes. In the development of these chimeric vaccines, an important series of comparative studies of safety and efficacy were made using the parental YF 17D vaccine virus as a benchmark. In this paper, we use a standardized template describing the key characteristics of the novel flavivirus vaccine vectors, in comparison to the parental YF 17D vaccine. The template facilitates scientific discourse among key stakeholders by increasing the transparency and comparability of information. The Brighton Collaboration V3SWG template may also be useful as a guide to the evaluation of other recombinant viral vector vaccines. Copyright © 2014. Published by Elsevier Ltd.Vaccine. 10/2014;
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ABSTRACT: Yellow fever (YF) vaccine is considered safe; however, severe illness and death following vaccination have been reported. Vaccine Safety Datalink (VSD) and US Department of Defense (DoD) data were used to identify adverse reactions following YF vaccination. Within the VSD, YF-vaccine-exposed subjects were compared to age-, site-, and gender-matched unexposed subjects. YF-vaccine-exposed DoD subjects were studied using a risk-interval design. For both cohorts, ICD-9 codes were analyzed for allergic and local reactions, mild systemic reactions, and possible visceral and neurologic adverse events (AEs). The VSD cohort received 47,159 doses from 1991 through 2006. The DoD cohort received 1.12 million doses from 1999 through 2007. Most subjects received other vaccines simultaneously. In the VSD cohort, rates of allergic, local, and mild systemic reactions were not statistically different between YF-vaccine-exposed and -unexposed subjects. In the DoD, there was an increased risk for outpatient allergic events in the period following vaccination with YF and other vaccines rate ratios [RR 3.85, 95% confidence interval (CI) 3.35-4.41] but with no increased risk for inpatient allergic reactions. In both cohorts, inpatient ICD-9 codes for visceral events were significantly less common following vaccination; inpatient codes for neurologic events were less common in the VSD YF-vaccine-exposed adult cohort, but did not differ between exposed and unexposed periods in the DoD. In the DoD, one fatal case of YF-vaccine-associated viscerotropic disease (YF-vaccine-AVD) was detected. The estimated death rate was 0.89 for 1,000,000 YF vaccine doses (95% CI 0.12-6.31/1,000,000 doses). No YF vaccine-associated deaths occurred in the VSD. In these closed cohorts we did not detect increased risk for visceral or neurologic events following YF vaccination. The death rate following YF vaccine was consistent with previous reports. These data support current recommendations for use of YF vaccine in young healthy individuals. These data are inadequate to judge safety of YF vaccines in elderly patients.Journal of Travel Medicine 10/2013; · 1.68 Impact Factor
Journal of Clinical Virology 36 (2006) 156–158
Yellow fever vaccine-associated viscerotropic
disease and death in Spain
A. Doblasa,1, C. Domingob,∗,1, H.G. Baec,1, C.L. Boh´ orquezd, F de Oryb,
M. Niedrigc, D. Moraa, F.J. Carrascoa, A. Tenoriob
aEmergency and Critical Care Department, Juan Ram´ on Jim´ enez Hospital, Huelva, Spain
bNational Center for Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
cRobert Koch Institute, Berlin, Germany
dPathology Department, Juan Ram´ on Jim´ enez Hospital, Huelva, Spain
Received 15 November 2005; received in revised form 3 February 2006; accepted 5 February 2006
Yellow fever vaccine-associated viscerotropic disease (YEL-AVD) is a recently described severe adverse event after yellow fever
vaccination, and some cases have been reported in different countries [Anonymous. Effects of yellow fever and vaccination. Lancet
2001;358(9296):1907–9]. Herein we describe a YEL-AVD case in a young woman, who died after vaccination with 17D-204 strain. Clinical,
serological and immunochemical analysis as well as virus detection, quantification, sequence analysis and cytokine release, were performed.
Further investigations on yellow fever vaccine adverse events, and carefully analysis of the immune response elicited are important tasks for
© 2006 Elsevier B.V. All rights reserved.
Keywords: Yellow fever vaccine; Viscerotropic adverse event
On 14 October 2004, a 26-year-old Caucasian woman
from Huelva (Spain) received single doses of diphtheria, and
tetanus vaccine and was primary vaccinated against yellow
travel counselling. She had no pathologies, no known risk
Abbreviations: YF, yellow fever; YFV, yellow fever virus; YF-AVD,
yellow fever vaccine-associated viscerotropic disease; HIV, human immun-
odeficiency virus; RT-PCR, reverse transcription polimerase chain reaction;
IgM, immunoglobulin M; IgG, immunoglobulin G; GE, genome equiva-
lents; ml, millilitres; g, grammes; Nt Ab, neutralising antibodies; GRO;
GRO-?; IL-6, interlekin-6; IL-8, interlekin-8; IL-10, interlekin-10; MCP-1;
GCSF; GM-CSF; IL-1?, interleukin-1?; IL-13, interleukin-13; MIG; TGF-
?1, tumor growth factor ?1
∗Corresponding author at: Laboratory of Arboviruses and Imported Viral
Diseases, Diagnostic Microbiology Service, National Center for Microbiol-
ogy, Instituto de Salud Carlos III, Carretera de Majadahonda a Pozuelo km
2, Majadahonda 28220, Madrid, Spain. Tel.: +34 918 223 954;
fax: +34 915 097 919.
E-mail address: email@example.com (C. Domingo).
1These authors contributed equally to this work.
factors, and did not receive regular medication at the time of
Three days later, she developed pain and signs of inflam-
scribed. On 21 October she returned to the emergency room
tent fever. Chest and abdominal radiographies were normal.
Laboratory tests showed thrombocytopaenia and increased
levels of creatinine, aminotranferases, and bilirubin (Fig. 1).
The patient was admitted to the intensive care unit, where a
developed multiorgan failure and respiratory distress that
could not be controlled, and finally deteriorated to refractory
shock and death on 24 October 2004. Bacterial cultures from
samples of the patient’s blood, faeces and urine were nega-
A, B or C, influenza A or B, varicella-zoster, parainfluenza,
1386-6532/$ – see front matter © 2006 Elsevier B.V. All rights reserved.
A. Doblas et al. / Journal of Clinical Virology 36 (2006) 156–158
Fig. 1. Clinical presentation and analytical data. The figure presents clinical manifestations and biochemical data against the time course of YFV infection.
or respiratory sincytial viruses, nor by Leptospira inter-
rogans, Rickettsia conorii, Coxiella burnetti or Legionella
pneumophila. YF virus (YFV) growth was detected by RT-
PCR (S´ anchez-Seco et al., 2005) in VeroE6 cells 4 days after
inoculation with liver and kidney tissue homogenates, and
plasma. No virus could be cultured from serum.
microvesicular steatosis and hepatocellular necrosis affect-
ing lobular zone 2. Small haemorrhagic areas were observed
in the spleen, kidneys, heart and lungs. Vacuolar degenera-
tion of tubular epithelial cells in the kidneys, scarce areas
of muscle fibre vacuolation in the heart, and white pulp
depletion and histiocytic aggregates in the spleen were also
observed. Cytoplasmatic immunostaining of YFV-antigen
was observed in many hepatocytes and few cardiac muscle
fibre and renal tubular cells; no immunostaining was
observed in the spleen, lung, skin or gastrointestinal tract.
Serum obtained 8 days after vaccination showed specific
anti-YFV IgM, but no IgG, by indirect immunefluorescence
using YFV-infected cells, and a high titre (1:512) of neu-
tralising antibodies in a microneutralisation assay. RT-PCR
showed the presence of flavivirus RNA (S´ anchez-Seco et al.,
2005) in the liver, kidney, plasma and serum. No amplifica-
tion was detected in whole blood due to the presence of PCR
Virus load was determined by real-time PCR (Bae
et al., 2003). High amounts of YFV were detected
in the liver (6.2×109genome equivalents/g) and kid-
4×105GE/ml were detected in serum, plasma and whole
The complete consensus sequence (GenBank accession
number DQ118157) for the YFV present in liver and kidney
was compared to the sequence of the YFV 17D Stamaril®
vaccine strain. Only two silent nucleotide substitutions and
no base insertions or deletions were detected (Fig. 2).
CSF, IL-1?, IL-13, MIG and TGF-?1 showed weak signals,
production compartments of immune response.
The time elapsing from vaccination to onset of symptoms
association between YF vaccine and the clinical manifesta-
tions leading to death in this patient.
In contrast to typical wild-type YF, the patient showed
no bradycardia, haemorrhage was not prominent, hepatic
2001; Gerasimon and Lowry, 2005).
Fig. 2. Virological study. Results on the virological investigation in serum samples obtained 8 days after vaccination and in post-mortem tissues recovered 10
days after vaccination are tabulated.
A. Doblas et al. / Journal of Clinical Virology 36 (2006) 156–158
No adverse events associated with the same vaccine batch
have been reported by others. It is unclear whether other
factors such as host susceptibility may have led to the fatal
and a careful analysis of virological and immunological
markers are important tasks for the future.
The authors thank Dr. Yves Girerd-Chambaz (Sanofi-
(Stamaril®),Dr.F.J.Garc´ ıaPe˜ naforexcludingLeptospirasp.
infection, and Dr. M. Cabrerizo, F. Molero, and N. Reyes for
their helpful assistance in the laboratory work. The authors
are grateful to Dr. J.E. Mej´ ıa for assisting in manuscript
preparation. Dr. C. Domingo is supported by an agreement
between the Public Health Division of the Spanish Ministry
of Health (DGSP-MSC) and the Instituto de Salud Carlos
III (ISCIII) for the development of the Haemorrhagic Viral
Fevers Surveillance and Control Programme in Spain. The
collaboration between the National Centre for Microbiology
Network for Imported Viral Diseases (ENIVD).
Anonymous. Effects of yellow fever vaccination. Lancet 2001;358(9296):
Bae HG, Nitsche A, Teichmann A, Biel SS, Niedrig M. Detection of
yellow fever virus: a comparison of quantitative real-time PCR and
plaque assay. J Virol Meth 2003;110(2):185–91.
Gerasimon G, Lowry K. Rare case of fatal yellow fever vaccine
associated viscerotropic disease. Southern Med J 2005;98(6):653–
S´ anchez-Seco MP, Rosario D, Domingo C, et al. Generic RT-nested-PCR
for detection of flaviviruses using degenerated primers and internal
control followed by sequencing for specific identification. J Virol Meth