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2.  Advances in influenza vaccination 
F1000Prime Reports  2014;6:47.
Influenza virus infections yearly cause high morbidity and mortality burdens in humans, and the development of a new influenza pandemic continues to threaten mankind as a Damoclean sword. Influenza vaccines have been produced by using egg-based virus growth and passaging techniques that were developed more than 60 years ago, following the identification of influenza A virus as an etiological agent of seasonal influenza. These vaccines aimed mainly at eliciting neutralizing antibodies targeting antigenically variable regions of the hemagglutinin (HA) protein, which requires regular updates to match circulating seasonal influenza A and B virus strains. Given the relatively limited protection induced by current seasonal influenza vaccines, a more universal influenza vaccine that would protect against more—if not all—influenza viruses is among the largest unmet medical needs of the 21st century. New insights into correlates of protection from influenza and into broad B- and T-cell protective anti-influenza immune responses offer promising avenues for innovative vaccine development as well as manufacturing strategies or platforms, leading to the development of a new generation of vaccines. These aim at the rapid and massive production of influenza vaccines that provide broad protective and long-lasting immunity. Recent advances in influenza vaccine research demonstrate the feasibility of a wide range of approaches and call for the initiation of preclinical proof-of-principle studies followed by clinical trials in humans.
doi:10.12703/P6-47
PMCID: PMC4047948  PMID: 24991424
3.  Genetic Relatedness of Dolphin Rhabdovirus with Fish Rhabdoviruses 
Emerging Infectious Diseases  2014;20(6):1081-1082.
doi:10.3201/eid2006.131880
PMCID: PMC4036773  PMID: 24857764
rhabdovirus; viruses; dolphin; fish; marine mammal; genetic relatedness; genome organization; phylogenetic analysis
4.  Bioinformatics in New Generation Flavivirus Vaccines 
Flavivirus infections are the most prevalent arthropod-borne infections world wide, often causing severe disease especially among children, the elderly, and the immunocompromised. In the absence of effective antiviral treatment, prevention through vaccination would greatly reduce morbidity and mortality associated with flavivirus infections. Despite the success of the empirically developed vaccines against yellow fever virus, Japanese encephalitis virus and tick-borne encephalitis virus, there is an increasing need for a more rational design and development of safe and effective vaccines. Several bioinformatic tools are available to support such rational vaccine design. In doing so, several parameters have to be taken into account, such as safety for the target population, overall immunogenicity of the candidate vaccine, and efficacy and longevity of the immune responses triggered. Examples of how bio-informatics is applied to assist in the rational design and improvements of vaccines, particularly flavivirus vaccines, are presented and discussed.
doi:10.1155/2010/864029
PMCID: PMC2867002  PMID: 20467477
5.  Middle East Respiratory Syndrome Coronavirus Spike Protein Delivered by Modified Vaccinia Virus Ankara Efficiently Induces Virus-Neutralizing Antibodies 
Journal of Virology  2013;87(21):11950-11954.
Middle East respiratory syndrome coronavirus (MERS-CoV) has recently emerged as a causative agent of severe respiratory disease in humans. Here, we constructed recombinant modified vaccinia virus Ankara (MVA) expressing full-length MERS-CoV spike (S) protein (MVA-MERS-S). The genetic stability and growth characteristics of MVA-MERS-S make it a suitable candidate vaccine for clinical testing. Vaccinated mice produced high levels of serum antibodies neutralizing MERS-CoV. Thus, MVA-MERS-S may serve for further development of an emergency vaccine against MERS-CoV.
doi:10.1128/JVI.01672-13
PMCID: PMC3807317  PMID: 23986586
6.  Determinants of virulence of influenza A virus 
Influenza A viruses cause yearly seasonal epidemics and occasional global pandemics in humans. In the last century, four human influenza A virus pandemics have occured. Ocasionally, influenza A viruses that circulate in other species, cross the species barrier and infect humans. Virus re-assortment (i.e. mixing of gene segments of multiple viruses) and the accumulation of mutations contribute to the emergence of new influenza A virus variants. Fortunately, most of these variants do not have the ability to spread among humans and subsequently cause a pandemic. In this review we focus on the threat of animal influenza A viruses which have shown the ability to infect humans. In addition, genetic factors which could alter the virulence of influenza A viruses are discussed. Identification and characterization of these factors may provide insights into genetic traits which change virulence and help us to understand which genetic determinants are of importance for the pandemic potential of animal influenza A viruses.
doi:10.1007/s10096-013-1984-8
PMCID: PMC3969785  PMID: 24078062
Influenza A viruses; virulence factors; pandemic threat; transmission
7.  Cowpox Virus Transmission from Rats to Monkeys, the Netherlands 
Emerging Infectious Diseases  2006;12(6):1005-1007.
We report an outbreak of cowpox virus among monkeys at a sanctuary for exotic animals. Serologic analysis and polymerase chain reaction were performed on blood and swab samples from different rodent species trapped at the sanctuary during the outbreak. Sequence comparison and serologic results showed that brown rats (Rattus norvegicus) transmitted the virus to monkeys.
doi:10.3201/eid1206.051513
PMCID: PMC3373046  PMID: 16707063
Poxvirus; zoonosis; nonhuman primates; transmission; rodents; dispatch
8.  Nonhuman Primate Models for SARS 
PLoS Medicine  2006;3(5):e194.
Osterhaus and Haagmans discuss a new study in PLoS Medicine that supports the use of the cynomolgus macaque model to study SARS pathogenesis and to test intervention strategies.
doi:10.1371/journal.pmed.0030194
PMCID: PMC1435785  PMID: 16608385
10.  In Vitro Assessment of the Immunological Significance of a Human Monoclonal Antibody Directed to the Influenza A Virus Nucleoprotein 
Influenza A viruses cause annual epidemics and occasionally pandemics. Antibodies directed to the conserved viral nucleoprotein (NP) may play a role in immunity against various influenza A virus subtypes. Here, we assessed the immunological significance of a human monoclonal antibody directed to NP in vitro. This antibody bound to virus-infected cells but did not display virus-neutralizing activity, complement-dependent cell cytotoxicity, or opsonization of viral antigen for improved antigen presentation to CD8+ T cells by dendritic cells.
doi:10.1128/CVI.00339-13
PMCID: PMC3754521  PMID: 23761662
11.  Identification of Multiple Novel Viruses, Including a Parvovirus and a Hepevirus, in Feces of Red Foxes 
Journal of Virology  2013;87(13):7758-7764.
Red foxes (Vulpes vulpes) are the most widespread members of the order of Carnivora. Since they often live in (peri)urban areas, they are a potential reservoir of viruses that transmit from wildlife to humans or domestic animals. Here we evaluated the fecal viral microbiome of 13 red foxes by random PCR in combination with next-generation sequencing. Various novel viruses, including a parvovirus, bocavirus, adeno-associated virus, hepevirus, astroviruses, and picobirnaviruses, were identified.
doi:10.1128/JVI.00568-13
PMCID: PMC3700315  PMID: 23616657
12.  Epidemiology of Influenza A Virus among Black-headed Gulls, the Netherlands, 2006–2010 
Emerging Infectious Diseases  2014;20(1):138-141.
We sampled 7,511 black-headed gulls for influenza virus in the Netherlands during 2006–2010 and found that subtypes H13 and H16 caused annual epidemics in fledglings on colony sites. Our findings validate targeted surveillance of wild waterbirds and clarify underlying factors for influenza virus emergence in other species.
doi:10.3201/eid2001.130984
PMCID: PMC3884729  PMID: 24377955
influenza A virus; viruses; influenza; avian influenza; Charadriiformes; epidemics; virulence; disease reservoirs; zoonoses; black-headed gulls; the Netherlands
13.  Measles Virus Infection of Epithelial Cells in the Macaque Upper Respiratory Tract Is Mediated by Subepithelial Immune Cells 
Journal of Virology  2013;87(7):4033-4042.
Measles virus (MV), one of the most contagious viruses infecting humans, causes a systemic infection leading to fever, immune suppression, and a characteristic maculopapular rash. However, the specific mechanism or mechanisms responsible for the spread of MV into the respiratory epithelium in the late stages of the disease are unknown. Here we show the crucial role of PVRL4 in mediating the spread of MV from immune to epithelial cells by generating a PVRL4 “blind” recombinant wild-type MV and developing a novel in vitro coculture model of B cells with primary differentiated normal human bronchial epithelial cells. We utilized the macaque model of measles to analyze virus distribution in the respiratory tract prior to and at the peak of MV replication. Expression of PVRL4 was widespread in both the lower and upper respiratory tract (URT) of macaques, indicating MV transmission can be facilitated by more than only epithelial cells of the trachea. Analysis of tissues collected at early time points after experimental MV infection demonstrated the presence of MV-infected lymphoid and myeloid cells contacting respiratory tract epithelium in the absence of infected epithelial cells, suggesting that these immune cells seed the infection in vivo. Thereafter, lateral cell-to-cell spread of MV led to the formation of large foci of infected cells in the trachea and high levels of MV infection in the URT, particularly in the nasal cavity. These novel findings have important implications for our understanding of the high transmissibility of measles.
doi:10.1128/JVI.03258-12
PMCID: PMC3624209  PMID: 23365435
14.  Infection of the Upper Respiratory Tract with Seasonal Influenza A(H3N2) Virus Induces Protective Immunity in Ferrets against Infection with A(H1N1)pdm09 Virus after Intranasal, but Not Intratracheal, Inoculation 
Journal of Virology  2013;87(8):4293-4301.
The clinical symptoms caused by infection with influenza A virus vary widely and depend on the strain causing the infection, the dose and route of inoculation, and the presence of preexisting immunity. In most cases, seasonal influenza A viruses cause relatively mild upper respiratory tract disease, while sometimes patients develop an acute severe pneumonia. Heterosubtypic immunity induced by previous infections with influenza A viruses may dampen the development of clinical symptoms caused by infection with influenza A viruses of another subtype, as is the case during influenza pandemics. Here we show that ferrets acquire protective immunity after infection of the upper respiratory tract with a seasonal influenza A(H3N2) virus against subsequent infection with influenza A(H1N1)pdm09 virus inoculated by the intranasal route. However, protective heterosubtypic immunity was afforded locally, since the prior infection with the A(H3N2) virus did not provide protection against the development of pneumonia induced after intratracheal inoculation with the A(H1N1)pdm09 virus. Interestingly, some of these animals developed more severe disease than that observed in naïve control animals. These findings are of interest in light of the development of so-called universal influenza vaccines that aim at the induction of cross-reactive T cell responses.
doi:10.1128/JVI.02536-12
PMCID: PMC3624397  PMID: 23365444
15.  Characterization of the Mouse Neuroinvasiveness of Selected European Strains of West Nile Virus 
PLoS ONE  2013;8(9):e74575.
West Nile virus (WNV) has caused outbreaks and sporadic infections in Central, Eastern and Mediterranean Europe for over 45 years. Most strains responsible for the European and Mediterranean basin outbreaks are classified as lineage 1. In recent years, WNV strains belonging to lineage 1 and 2 have been causing outbreaks of neuroinvasive disease in humans in countries such as Italy, Hungary and Greece, while mass mortality among birds was not reported. This study characterizes three European strains of WNV isolated in Italy (FIN and Ita09) and Hungary (578/10) in terms of in vitro replication kinetics on neuroblastoma cells, LD50 values in C57BL/6 mice, median day mortality, cumulative mortality, concentration of virus in the brain and spinal cord, and the response to infection in the brain. Overall, the results indicate that strains circulating in Europe belonging to both lineage 1 and 2 are highly virulent and that Ita09 and 578/10 are more neurovirulent compared to the FIN strain.
doi:10.1371/journal.pone.0074575
PMCID: PMC3776840  PMID: 24058590
16.  T-Cell Infiltration Correlates with CXCL10 Expression in Ganglia of Cynomolgus Macaques with Reactivated Simian Varicella Virus 
Journal of Virology  2013;87(5):2979-2982.
Ganglia of monkeys with reactivated simian varicella virus (SVV) contained more CD8 than CD4 T cells around neurons. The abundance of CD8 T cells was greater less than 2 months after reactivation than that at later times and correlated with that of CXCL10 RNA but not with those of SVV protein or open reading frame 61 (ORF61) antisense RNA. CXCL10 RNA colocalized with T-cell clusters. After SVV reactivation, transient T-cell infiltration, possibly mediated by CXCL10, parallels varicella zoster virus (VZV) reactivation in humans.
doi:10.1128/JVI.03181-12
PMCID: PMC3571377  PMID: 23269790
17.  Novel Cyclovirus in Human Cerebrospinal Fluid, Malawi, 2010–2011 
Emerging Infectious Diseases  2013;19(9):1511-1513.
To identify unknown human viruses, we analyzed serum and cerebrospinal fluid samples from patients with unexplained paraplegia from Malawi by using viral metagenomics. A novel cyclovirus species was identified and subsequently found in 15% and 10% of serum and cerebrospinal fluid samples, respectively. These data expand our knowledge of cyclovirus diversity and tropism.
doi:10.3201/eid1909.130404
PMCID: PMC3810929  PMID: 23968557
Paraplegia; virus; cyclovirus; random amplification; cerebrospinal fluid; serum; viruses; Malawi
18.  Identification and Characterization of Two Novel Viruses in Ocular Infections in Reindeer 
PLoS ONE  2013;8(7):e69711.
A thorough understanding of virus diversity in wildlife provides epidemiological baseline information about pathogens. In this study, eye swab samples were obtained from semi-domesticated reindeer (Rangifertarandustarandus) in Norway during an outbreak of infectious eye disease, possibly a very early stage of infectious keratoconjunctivitis (IKC). Large scale molecular virus screening, based on host nucleic acid depletion, sequence-independent amplification and next-generation sequencing of partially purified viral nucleic acid, revealed the presence of a new papillomavirus in 2 out of 8 eye swab samples and a new betaherpesvirus in 3 out of 8 eye swab samples collected from animals with clinical signs and not in similar samples in 9 animals without clinical signs. Whether either virus was responsible for causing the clinical signs or in any respect was associated to the disease condition remains to be determined.
doi:10.1371/journal.pone.0069711
PMCID: PMC3713034  PMID: 23874987
19.  Complete Genome Sequence of Phocine Distemper Virus Isolated from a Harbor Seal (Phoca vitulina) during the 1988 North Sea Epidemic 
Genome Announcements  2013;1(3):e00291-13.
Phocine distemper virus (PDV) was identified as the cause of a large morbillivirus outbreak among harbor seals in the North Sea in 1988. PDV is a member of the family Paramyxoviridae, genus Morbillivirus. Until now, no full-genome sequence of PDV has been available.
doi:10.1128/genomeA.00291-13
PMCID: PMC3695424  PMID: 23814028
20.  The Future of Research and Publication on Altered H5N1 Viruses 
The Journal of Infectious Diseases  2012;205(11):1628-1631.
Recently, we and others obtained experimental evidence that highly pathogenic avian influenza virus subtype H5 can acquire the ability to transmit via aerosols between ferrets. Upon submission of manuscripts describing the results of these studies, the US National Science Advisory Board for Biosecurity was consulted and recommended that the main conclusions of the work be published but without the experimental details and mutation data that would enable replication of the experiments. Over the past few months, these events have led to intense discussions. Should this type of experiment be conducted? If so, under what conditions? Do the scientific and public health benefits of the work and its publication outweigh the potential risks? In February 2012, public health and influenza experts discussed these issues during a World Health Organization–organized technical consultation. This perspective article reviews the current state of the field and the recommendations made during the meeting.
doi:10.1093/infdis/jis257
PMCID: PMC3415850  PMID: 22454474
21.  Restricted Varicella-Zoster Virus Transcription in Human Trigeminal Ganglia Obtained Soon after Death 
Journal of Virology  2012;86(18):10203-10206.
We analyzed the varicella-zoster virus (VZV) transcriptome in 43 latently infected human trigeminal ganglia (TG) with postmortem intervals (PMIs) ranging from 3.7 to 24 h. Multiplex reverse transcriptase PCR (RT-PCR) revealed no VZV transcripts with a PMI of <9 h. Real-time PCR indicated a significant increase (P = 0.02) in VZV ORF63 transcript levels but not the virus DNA burden with longer PMI. Overall, both the breadth of the VZV transcriptome and the VZV ORF63 transcript levels in human cadaver TG increased with longer PMI.
doi:10.1128/JVI.01331-12
PMCID: PMC3446590  PMID: 22740396
22.  Recurring Influenza B Virus Infections in Seals  
Emerging Infectious Diseases  2013;19(3):511-512.
doi:10.3201/eid1903.120965
PMCID: PMC3647654  PMID: 23750359
influenza B virus; seals; serology; viruses; influenza; Suggested citation for this article: Bodewes R; Morick D; de Mutsert G; Osinga N; Bestebroer T; van der Vliet S; et al. Recurring influenza B virus infections in seals [letter]. Emerg Infect Dis [Internet]. 2013 Mar [date cited]. http://dx.doi.org/10.3201/eid1903.120965
23.  Evaluation of the 2009 WHO Dengue Case Classification in an Indonesian Pediatric Cohort 
The classification of dengue virus-infected patients continues to be a challenge to researchers and clinicians in the field. The accuracy of the 1997 World Health Organization (WHO) dengue case definition has been debated for a decade, because the definition was very stringent, for instance, several researchers showed that apparently severe cases were misclassified as not severe. Therefore the WHO issued revised guidelines in 2009. Here, we retrospectively compared the performance of the WHO case definition of 2009 with the WHO case definition of 1997 in a detailed documented pediatric cohort from Indonesia. Intensive treatment intervention was used as an indicator of severity of disease. In line with our expectations, the 2009 WHO case classification proved to be significantly more specific, albeit less sensitive than the WHO case classification of 1997. We conclude that the revised classification is promising both from research and clinical perspectives, but validation of the classification criteria still needs to be addressed.
doi:10.4269/ajtmh.2012.11-0491
PMCID: PMC3247126  PMID: 22232468
24.  Genomic Characterization of a Newly Discovered Coronavirus Associated with Acute Respiratory Distress Syndrome in Humans 
mBio  2012;3(6):e00473-12.
ABSTRACT
A novel human coronavirus (HCoV-EMC/2012) was isolated from a man with acute pneumonia and renal failure in June 2012. This report describes the complete genome sequence, genome organization, and expression strategy of HCoV-EMC/2012 and its relation with known coronaviruses. The genome contains 30,119 nucleotides and contains at least 10 predicted open reading frames, 9 of which are predicted to be expressed from a nested set of seven subgenomic mRNAs. Phylogenetic analysis of the replicase gene of coronaviruses with completely sequenced genomes showed that HCoV-EMC/2012 is most closely related to Tylonycteris bat coronavirus HKU4 (BtCoV-HKU4) and Pipistrellus bat coronavirus HKU5 (BtCoV-HKU5), which prototype two species in lineage C of the genus Betacoronavirus. In accordance with the guidelines of the International Committee on Taxonomy of Viruses, and in view of the 75% and 77% amino acid sequence identity in 7 conserved replicase domains with BtCoV-HKU4 and BtCoV-HKU5, respectively, we propose that HCoV-EMC/2012 prototypes a novel species in the genus Betacoronavirus. HCoV-EMC/2012 may be most closely related to a coronavirus detected in Pipistrellus pipistrellus in The Netherlands, but because only a short sequence from the most conserved part of the RNA-dependent RNA polymerase-encoding region of the genome was reported for this bat virus, its genetic distance from HCoV-EMC remains uncertain. HCoV-EMC/2012 is the sixth coronavirus known to infect humans and the first human virus within betacoronavirus lineage C.
IMPORTANCE
Coronaviruses are capable of infecting humans and many animal species. Most infections caused by human coronaviruses are relatively mild. However, the outbreak of severe acute respiratory syndrome (SARS) caused by SARS-CoV in 2002 to 2003 and the fatal infection of a human by HCoV-EMC/2012 in 2012 show that coronaviruses are able to cause severe, sometimes fatal disease in humans. We have determined the complete genome of HCoV-EMC/2012 using an unbiased virus discovery approach involving next-generation sequencing techniques, which enabled subsequent state-of-the-art bioinformatics, phylogenetics, and taxonomic analyses. By establishing its complete genome sequence, HCoV-EMC/2012 was characterized as a new genotype which is closely related to bat coronaviruses that are distant from SARS-CoV. We expect that this information will be vital to rapid advancement of both clinical and vital research on this emerging pathogen.
doi:10.1128/mBio.00473-12
PMCID: PMC3509437  PMID: 23170002
25.  The Multibasic Cleavage Site in H5N1 Virus Is Critical for Systemic Spread along the Olfactory and Hematogenous Routes in Ferrets 
Journal of Virology  2012;86(7):3975-3984.
The route by which highly pathogenic avian influenza (HPAI) H5N1 virus spreads systemically, including the central nervous system (CNS), is largely unknown in mammals. Especially, the olfactory route, which could be a route of entry into the CNS, has not been studied in detail. Although the multibasic cleavage site (MBCS) in the hemagglutinin (HA) of HPAI H5N1 viruses is a major determinant of systemic spread in poultry, the association between the MBCS and systemic spread in mammals is less clear. Here we determined the virus distribution of HPAI H5N1 virus in ferrets in time and space—including along the olfactory route—and the role of the MBCS in systemic replication. Intranasal inoculation with wild-type H5N1 virus revealed extensive replication in the olfactory mucosa, from which it spread to the olfactory bulb and the rest of the CNS, including the cerebrospinal fluid (CSF). Virus spread to the heart, liver, pancreas, and colon was also detected, indicating hematogenous spread. Ferrets inoculated intranasally with H5N1 virus lacking an MBCS demonstrated respiratory tract infection only. In conclusion, HPAI H5N1 virus can spread systemically via two different routes, olfactory and hematogenous, in ferrets. This systemic spread was dependent on the presence of the MBCS in HA.
doi:10.1128/JVI.06828-11
PMCID: PMC3302532  PMID: 22278228

Results 1-25 (161)