ABSTRACT
BACKGROUND: Examination of the evolutionary dynamics of complete influenza viral genomes reveals that other processes, in conjunction with antigenic drift, play important roles in viral evolution and selection, but there is little biological evidence to support these genomic data. Previous work demonstrated that after the A/Fujian/411/2002-like H3N2 influenza A epidemic during 2003-2004, a preexisting nondominant Fujian-like viral clade gained a small number of changes in genes encoding the viral polymerase complex, along with several changes in the antigenic regions of hemagglutinin, and in a genome-wide selective sweep, it replaced other co-circulating H3N2 clades. METHODS: Representative strains of these virus clades were evaluated in vitro and in vivo. RESULTS: The newly dominant 2004-2005 A/California/7/2004-like H3N2 clade, which featured 2 key amino acid changes in the polymerase PA segment, grew to higher titers in MDCK cells and ferret tissues and caused more-severe disease in ferrets. The polymerase complex of this virus demonstrated enhanced activity in vitro, correlating directly to the enhanced replicative fitness and virulence in vivo. CONCLUSION: These data suggest that influenza strains can be selected in humans through mutations that increase replicative fitness and virulence, in addition to the well-characterized antigenic changes in the surface glycoproteins.
Subject(s)
Antigens, Viral/genetics , Genetic Drift , Influenza A Virus, H3N2 Subtype/genetics , Influenza, Human/virology , Orthomyxoviridae Infections/virology , Selection, Genetic , Animals , Cell Line , Dogs , Ferrets , Humans , Influenza, Human/epidemiology , Lung/pathology , Male , Orthomyxoviridae Infections/pathology , Phylogeny , Virus ReplicationABSTRACT
The immunogenicity and protective efficacy of a live attenuated vaccine consisting of a recombinant severe acute respiratory syndrome (SARS) coronavirus lacking the E gene (rSARS-CoV-DeltaE) were studied using hamsters. Hamsters immunized with rSARS-CoV-DeltaE developed high serum-neutralizing antibody titers and were protected from replication of homologous (SARS-CoV Urbani) and heterologous (GD03) SARS-CoV in the upper and lower respiratory tract. rSARS-CoV-DeltaE-immunized hamsters remained active following wild-type virus challenge, while mock-immunized hamsters displayed decreased activity. Despite being attenuated in replication in the respiratory tract, rSARS-CoV-DeltaE is an immunogenic and efficacious vaccine in hamsters.
Subject(s)
Severe Acute Respiratory Syndrome/prevention & control , Severe acute respiratory syndrome-related coronavirus/immunology , Viral Vaccines/immunology , Animals , Antibodies, Viral/blood , Cricetinae , Gene Deletion , Lung/pathology , Lung/virology , Mesocricetus , Neutralization Tests , Respiratory System/virology , Severe acute respiratory syndrome-related coronavirus/genetics , Severe Acute Respiratory Syndrome/immunology , Vaccines, Attenuated , Viral Envelope Proteins/genetics , Viral Vaccines/genetics , Viroporin ProteinsABSTRACT
We summarize findings of SARS-CoV infections in several animal models each of which support viral replication in lungs accompanied by histopathological changes and/or clinical signs of illness to varying degrees. New findings are reported on SARS-CoV replication and associated pathology in two additional strains (C57BL/6 and 129S6) of aged mice. We also provide new comparative data on viral replication and associated pathology following infection of golden Syrian hamsters with various SARS-CoV strains and report the levels of neutralizing antibody titers following these infections and the cross-protective efficacy of infection with these strains in protecting against heterologous challenge. Finally, we summarize findings of a variety of vaccine approaches and discuss the available in vitro and in vivo data addressing the potential for disease enhancement following re-infection in animals previously vaccinated against or infected with SARS-CoV.