Immunization with Modified Vaccinia Virus Ankara-Based Recombinant Vaccine against Severe Acute Respiratory Syndrome Is Associated with Enhanced Hepatitis in Ferrets

Weingartl, Hana M.; Czub, Markus; Czub, Stefanie; Neufeld, James; Marszal, Peter; Gren, Jason; Smith, Greg; Jones, Shane; Proulx, Roxanne; Deschambault, Yvonne; Grudeski, Elsie; Andonov, Anton; He, Runtao; Li, Yan; Copps, John; Grolla, Allen; Dick, Daryl; Berry, Jody D.; Ganske, Shelley; Manning, Lisa; Cao, Jingxin

doi:10.1128/jvi.78.22.12672-12676.2004

Cited by 354 publications

(341 citation statements)

References 19 publications

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“…There was some change in appearance of the liver in six of the 46 animals in the six groups, namely a pale or tan colour in two animals in each of the PBS, WKV and WKV+alum groups. There was no apparent evidence of enhanced liver pathology in SARS-antigen-vaccinated groups as was reported previously for the modified vaccinia virus (MVA)-vectored SARS vaccines (Czub et al, 2005;Weingartl et al, 2004). Gross pathology indicated frequent significant haemorrhage in lung and mediastinum (the area between the lungs containing the heart, trachea, oesophagus, thymus and lymph nodes), specifically the thymus (Fig.…”

mentioning

confidence: 54%

“…One ferret study indicated that, upon intranasal (i.n.) administration of SARS-CoV Toronto 2 (Tor2) strain, no clinical signs were observed up to 29 days post-challenge, although viral RNA could be detected in pharyngeal swabs (Czub et al, 2005;Weingartl et al, 2004). Our preliminary studies showed clinical signs, viral replication and lung pathology in ferrets infected with SARS-CoV reflecting pathogenesis in humans ; we therefore decided to evaluate and compare our two SARS vaccine candidates (WKV and Ad expressing S and N protein) in a single trial in the ferret model (Kobinger et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Severe acute respiratory syndrome vaccine efficacy in ferrets: whole killed virus and adenovirus-vectored vaccines

See

Petric

Lawrence

et al. 2008

Journal of General Virology

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Although the 2003 severe acute respiratory syndrome (SARS) outbreak was controlled, repeated transmission of SARS coronavirus (CoV) over several years makes the development of a SARS vaccine desirable. We performed a comparative evaluation of two SARS vaccines for their ability to protect against live SARS-CoV intranasal challenge in ferrets. Both the whole killed SARS-CoV vaccine (with and without alum) and adenovirus-based vectors encoding the nucleocapsid (N) and spike (S) protein induced neutralizing antibody responses and reduced viral replication and shedding in the upper respiratory tract and progression of virus to the lower respiratory tract. The vaccines also diminished haemorrhage in the thymus and reduced the severity and extent of pneumonia and damage to lung epithelium. However, despite high neutralizing antibody titres, protection was incomplete for all vaccine preparations and administration routes. Our data suggest that a combination of vaccine strategies may be required for effective protection from this pathogen. The ferret may be a good model for SARS-CoV infection because it is the only model that replicates the fever seen in human patients, as well as replicating other SARS disease features including infection by the respiratory route, clinical signs, viral replication in upper and lower respiratory tract and lung damage. INTRODUCTIONSevere acute respiratory syndrome (SARS) caused 8098 reported cases and 774 deaths in 26 countries (WHO, 2004a) in a single autumn-to-spring period from 2002 to 2003, and had significant effects on the global economy. Serological evidence suggests zoonotic transmission of SARS coronavirus (CoV) into the human population for several years before this outbreak (Zheng et al., 2004); transmission to humans has continued, resulting in at least four independent non-laboratory associated cases in (Che et al., 2006Fleck, 2004; Guan et al., 2005; WHO, 2004b). The aetiological agent of SARS has been identified as a novel human CoV by sequencing of its genome (Marra et al., 2003;Rota et al., 2003) and by experimental infection of macaques to fulfil Koch's postulates (Fouchier et al., 2003). It is of particular concern as a zoonosis because it can replicate in a large number of animals including cats, pigs, ferrets, foxes, monkeys and rats (Chen et al., 2005; et al., 1996;Olsen, 1993). Although antibodies to CoV N proteins have no virus-neutralizing activity, there is evidence that the protein may provide protection in vivo by induction of cell-mediated immunity, although it has also been suggested to induce eosinophilic infiltrates resulting in immunopathology (Deming et al., 2006;Enjuanes et al., 1995; Stohlman et al., 1995;Wesseling et al., 1993). N protein has been shown to generate CoV-specific CD8 + T cells (Boots et al., 1991;Seo et al., 1997; Stohlman et al., 1993 Stohlman et al., , 1995; it also provides protection in animals in response to infection by animal CoV (Collisson et al., 2000;Seo et al., 1997). In addition, vaccination with SARS N protein decre...

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confidence: 54%

Section: Introductionmentioning

confidence: 99%

Severe acute respiratory syndrome vaccine efficacy in ferrets: whole killed virus and adenovirus-vectored vaccines

See

Petric

Lawrence

et al. 2008

Journal of General Virology

View full text Add to dashboard Cite

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“…However, recombinant vaccinia viruses expressing different foreign viral antigens, including the HA of influenza virus, have been shown to induce protective immunity in ferrets (Jakeman et al, 1989). A recombinant MVA expressing the spike or nucleocapsid protein of severe acute respiratory syndrome (SARS) coronavirus also proved to be immunogenic (Czub et al, 2005;Weingartl et al, 2004). It is therefore unlikely that the differences in protective effectiveness in monkeys and ferrets were related to the species that was used.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a modified vaccinia virus Ankara (MVA)-based candidate pandemic influenza A/H1N1 vaccine in the ferret model

Kreijtz¹,

Süzer

Bodewes³

et al. 2010

Journal of General Virology

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“…Thus, the reduced production of both anti-inflammatory cytokines in the mOrVV-NHis-immunized mice after SARS-CoV infection may be related to the severity of the pulmonary inflammation in these mice. Weingartl et al (47) and Czub et al (48) reported that immunization with S protein expressing-recombinant modified VV Ankara (rMVA-S) induced stronger inflammatory responses and focal necrosis in liver tissues after SARSCoV challenge than in control animals. However, the precise mechanism underlying this liver inflammation has not been clarified.…”

Section: Discussionmentioning

confidence: 99%

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

Yasui¹,

Kai

Kitabatake³

et al. 2008

The Journal of Immunology

251

240

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The details of the mechanism by which severe acute respiratory syndrome-associated coronavirus (SARS-CoV) causes severe pneumonia are unclear. We investigated the immune responses and pathologies of SARS-CoV-infected BALB/c mice that were immunized intradermally with recombinant vaccinia virus (VV) that expressed either the SARS-CoV spike (S) protein (LC16m8rVV-S) or simultaneously all the structural proteins, including the nucleocapsid (N), membrane (M), envelope (E), and S proteins (LC16m8rVV-NMES) 7–8 wk before intranasal SARS-CoV infection. The LC16m8rVV-NMES-immunized group exhibited as severe pneumonia as the control groups, although LC16m8rVV-NMES significantly decreased the pulmonary SARS-CoV titer to the same extent as LC16m8rVV-S. To identify the cause of the exacerbated pneumonia, BALB/c mice were immunized with recombinant VV that expressed the individual structural proteins of SARS-CoV (LC16mOrVV-N, -M, -E, -S) with or without LC16mOrVV-S (i.e., LC16mOrVV-N, LC16mOrVV-M, LC16mOrVV-E, or LC16mOrVV-S alone or LC16mOrVV-N + LC16mOrVV-S, LC16mOrVV-M + LC16mOrVV-S, or LC16mOrVV-E + LC16mOrVV-S), and infected with SARS-CoV more than 4 wk later. Both LC16mOrVV-N-immunized mice and LC16mOrVV-N + LC16mOrVV-S-immunized mice exhibited severe pneumonia. Furthermore, LC16mOrVV-N-immunized mice upon infection exhibited significant up-regulation of both Th1 (IFN-γ, IL-2) and Th2 (IL-4, IL-5) cytokines and down-regulation of anti-inflammatory cytokines (IL-10, TGF-β), resulting in robust infiltration of neutrophils, eosinophils, and lymphocytes into the lung, as well as thickening of the alveolar epithelium. These results suggest that an excessive host immune response against the nucleocapsid protein of SARS-CoV is involved in severe pneumonia caused by SARS-CoV infection. These findings increase our understanding of the pathogenesis of SARS.

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Immunization with Modified Vaccinia Virus Ankara-Based Recombinant Vaccine against Severe Acute Respiratory Syndrome Is Associated with Enhanced Hepatitis in Ferrets

Cited by 354 publications

References 19 publications

Severe acute respiratory syndrome vaccine efficacy in ferrets: whole killed virus and adenovirus-vectored vaccines

Severe acute respiratory syndrome vaccine efficacy in ferrets: whole killed virus and adenovirus-vectored vaccines

Evaluation of a modified vaccinia virus Ankara (MVA)-based candidate pandemic influenza A/H1N1 vaccine in the ferret model

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

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