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      Vaccine Efficacy in Senescent Mice Challenged with Recombinant SARS-CoV Bearing Epidemic and Zoonotic Spike Variants

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          Abstract

          Background

          In 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) was identified as the etiological agent of severe acute respiratory syndrome, a disease characterized by severe pneumonia that sometimes results in death. SARS-CoV is a zoonotic virus that crossed the species barrier, most likely originating from bats or from other species including civets, raccoon dogs, domestic cats, swine, and rodents. A SARS-CoV vaccine should confer long-term protection, especially in vulnerable senescent populations, against both the 2003 epidemic strains and zoonotic strains that may yet emerge from animal reservoirs. We report the comprehensive investigation of SARS vaccine efficacy in young and senescent mice following homologous and heterologous challenge.

          Methods and Findings

          Using Venezuelan equine encephalitis virus replicon particles (VRP) expressing the 2003 epidemic Urbani SARS-CoV strain spike (S) glycoprotein (VRP-S) or the nucleocapsid (N) protein from the same strain (VRP-N), we demonstrate that VRP-S, but not VRP-N vaccines provide complete short- and long-term protection against homologous strain challenge in young and senescent mice. To test VRP vaccine efficacy against a heterologous SARS-CoV, we used phylogenetic analyses, synthetic biology, and reverse genetics to construct a chimeric virus (icGDO3-S) encoding a synthetic S glycoprotein gene of the most genetically divergent human strain, GDO3, which clusters among the zoonotic SARS-CoV. icGD03-S replicated efficiently in human airway epithelial cells and in the lungs of young and senescent mice, and was highly resistant to neutralization with antisera directed against the Urbani strain. Although VRP-S vaccines provided complete short-term protection against heterologous icGD03-S challenge in young mice, only limited protection was seen in vaccinated senescent animals. VRP-N vaccines not only failed to protect from homologous or heterologous challenge, but resulted in enhanced immunopathology with eosinophilic infiltrates within the lungs of SARS-CoV–challenged mice. VRP-N–induced pathology presented at day 4, peaked around day 7, and persisted through day 14, and was likely mediated by cellular immune responses.

          Conclusions

          This study identifies gaps and challenges in vaccine design for controlling future SARS-CoV zoonosis, especially in vulnerable elderly populations. The availability of a SARS-CoV virus bearing heterologous S glycoproteins provides a robust challenge inoculum for evaluating vaccine efficacy against zoonotic strains, the most likely source of future outbreaks.

          Abstract

          Experiments in mice suggest challenges in vaccine design for controlling future SARS-CoV zoonosis, especially in vulnerable elderly populations.

          Abstract

          Editors' Summary
          Background.

          Severe acute respiratory syndrome (SARS) is a flu-like illness and was first recognized in China in 2002, after which the disease rapidly spread around the world. SARS was associated with high death rates, much higher than those for flu. Around 10% of people recognized as being infected with SARS died, and the death rate approached 50% among elderly people. The virus causing SARS was identified as a member of the coronavirus family; it is generally thought that this virus “jumped” to humans from bats, which harbor related viruses. Although SARS was declared eradicated by the World Health Organization in May 2005, there is still the possibility that similar viruses will again cross the species barrier and infect humans, with potentially serious consequences. As a result, many groups are working to develop vaccines that will protect against SARS infection.

          Why Was This Study Done?

          A SARS vaccine should be effective in people of all ages, including the elderly who are more likely to get seriously ill or die if they become infected. In addition, potential vaccines should protect against different variants of the virus, because there are different types of the virus that could potentially cross the species barrier from animals to humans. Of the different proteins that make up the SARS coronavirus, the spike glycoprotein is thought to elicit an immune response in humans that can protect against future infection. The researchers therefore examined vaccine candidates based on this particular protein (termed SARS-CoV S), as well as a second one called SARS-CoV N, in mice. Specifically, they tested whether the vaccines would protect against SARS infection in both young and older mice, and whether they would protect against infection by different strains of the SARS virus.

          What Did the Researchers Do and Find?

          The researchers created vaccines based on SARS-CoV S and SARS-CoV N by taking the genes coding for those proteins and inserting them into another type of virus particle that acted as a delivery vehicle. They injected mice with these vaccines and then tested whether the mice generated an immune response against the specific SARS proteins, which they did. The next step was to work out whether mice injected with the vaccines would be protected against later infection with SARS-CoV. The researchers found that mice injected with vaccine based on SARS-CoV S were protected against later infection with a standard SARS-CoV strain, both in the short term (eight weeks after vaccination) and the long term (54 weeks after vaccination). However, the vaccine based on SARS-CoV N did not seem to result in protection, and, worryingly, caused pathological changes in the lungs of mice following virus challenge. To find out if their candidate vaccines would protect against different strains of SARS, the researchers made a synthetic test virus that contained a mixture of genetic material from different natural variants of the virus. This test virus was used to “challenge” mice that had been immunized with the two different vaccines. The researchers found that the vaccine based on SARS-CoV S protected against infection by the test virus when mice were vaccinated young, but it failed to efficiently protect when administered to older mice.

          What Do These Findings Mean?

          The findings confirm others suggesting that vaccines based on the SARS-CoV S protein are more effective than those based on SARS-CoV N. They also suggest that the former can provide long-term protection in animals vaccinated young against closely related viruses. However, protection against more distantly related viruses remains a challenge, especially when vaccinating older animals. The differences seen between young and older mice suggest that older mice might provide a useful model for animal testing of candidate vaccines for diseases like SARS, flu, and West Nile virus that pose a particular threat to elderly people. Overall, these results provide useful lessons toward future SARS vaccine development in animals. The synthetic virus strain generated here, and others like it, are likely to be useful tools for such future studies.

          Additional Information.

          Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030525.

          • The World Health Organization provides guidance, archives, and other information resources on SARS

          • Information from the US Centers for Disease Control on SARS

          • Wikipedia (an internet encyclopedia anyone can edit) has an entry on SARS

          • Collected resources from MedLinePlus about SARS

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          Most cited references59

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          Identification of a Novel Coronavirus in Patients with Severe Acute Respiratory Syndrome

          The severe acute respiratory syndrome (SARS) has recently been identified as a new clinical entity. SARS is thought to be caused by an unknown infectious agent. Clinical specimens from patients with SARS were searched for unknown viruses with the use of cell cultures and molecular techniques. A novel coronavirus was identified in patients with SARS. The virus was isolated in cell culture, and a sequence 300 nucleotides in length was obtained by a polymerase-chain-reaction (PCR)-based random-amplification procedure. Genetic characterization indicated that the virus is only distantly related to known coronaviruses (identical in 50 to 60 percent of the nucleotide sequence). On the basis of the obtained sequence, conventional and real-time PCR assays for specific and sensitive detection of the novel virus were established. Virus was detected in a variety of clinical specimens from patients with SARS but not in controls. High concentrations of viral RNA of up to 100 million molecules per milliliter were found in sputum. Viral RNA was also detected at extremely low concentrations in plasma during the acute phase and in feces during the late convalescent phase. Infected patients showed seroconversion on the Vero cells in which the virus was isolated. The novel coronavirus might have a role in causing SARS. Copyright 2003 Massachusetts Medical Society
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            A worldwide outbreak of severe acute respiratory syndrome (SARS) has been associated with exposures originating from a single ill health care worker from Guangdong Province, China. We conducted studies to identify the etiologic agent of this outbreak. We received clinical specimens from patients in seven countries and tested them, using virus-isolation techniques, electron-microscopical and histologic studies, and molecular and serologic assays, in an attempt to identify a wide range of potential pathogens. None of the previously described respiratory pathogens were consistently identified. However, a novel coronavirus was isolated from patients who met the case definition of SARS. Cytopathological features were noted in Vero E6 cells inoculated with a throat-swab specimen. Electron-microscopical examination revealed ultrastructural features characteristic of coronaviruses. Immunohistochemical and immunofluorescence staining revealed reactivity with group I coronavirus polyclonal antibodies. Consensus coronavirus primers designed to amplify a fragment of the polymerase gene by reverse transcription-polymerase chain reaction (RT-PCR) were used to obtain a sequence that clearly identified the isolate as a unique coronavirus only distantly related to previously sequenced coronaviruses. With specific diagnostic RT-PCR primers we identified several identical nucleotide sequences in 12 patients from several locations, a finding consistent with a point-source outbreak. Indirect fluorescence antibody tests and enzyme-linked immunosorbent assays made with the new isolate have been used to demonstrate a virus-specific serologic response. This virus may never before have circulated in the U.S. population. A novel coronavirus is associated with this outbreak, and the evidence indicates that this virus has an etiologic role in SARS. Because of the death of Dr. Carlo Urbani, we propose that our first isolate be named the Urbani strain of SARS-associated coronavirus. Copyright 2003 Massachusetts Medical Society
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              MRBAYES: Bayesian inference of phylogenetic trees.

              The program MRBAYES performs Bayesian inference of phylogeny using a variant of Markov chain Monte Carlo. MRBAYES, including the source code, documentation, sample data files, and an executable, is available at http://brahms.biology.rochester.edu/software.html.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Med
                pmed
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                1549-1277
                1549-1676
                December 2006
                26 December 2006
                : 3
                : 12
                : e525
                Affiliations
                [1 ] Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [2 ] Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [3 ] Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [4 ] Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                [5 ] Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America
                [6 ] United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America
                The University of Hong Kong, People's Republic of China
                Author notes
                * To whom correspondence should be addressed. E-mail: rbaric@ 123456email.unc.edu
                Article
                06-PLME-RA-0214R3 plme-03-12-30
                10.1371/journal.pmed.0030525
                1716185
                17194199
                54b6a59e-f94c-4875-acdc-dc3349d3659a
                Copyright: © 2006 Deming, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 16 March 2006
                : 31 October 2006
                Page count
                Pages: 17
                Categories
                Research Article
                Evolutionary Biology
                Genetics and Genomics
                Immunology
                Microbiology
                Molecular Biology
                Pathology
                Virology
                Virology
                Infectious Diseases
                Microbiology
                Geriatric Medicine
                Respiratory Medicine
                Immunology and Allergy
                Custom metadata
                Deming D, Sheahan T, Heise M, Yount B, Davis N, et al. (2006) Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants. PLoS Med 3(12): e525. doi: 10.1371/journal.pmed.0030525

                Medicine
                Medicine

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