Abstract
Studies of influenza virus evolution under controlled experimental conditions can provide a better understanding of the consequences of evolutionary processes with and without immunological pressure. Characterization of evolved strains assists in the development of predictive algorithms for both the selection of subtypes represented in the seasonal influenza vaccine and the design of novel immune refocused vaccines. To obtain data on the evolution of influenza in a controlled setting, naïve and immunized Guinea pigs were infected with influenza A/Wyoming/2003 (H3N2). Virus progeny from nasal wash samples were assessed for variation in the dominant and other epitopes by sequencing the hemagglutinin (HA) gene to quantify evolutionary changes. Viral RNA from the nasal washes from infection of naïve and immune animals contained 6% and 24.5% HA variant sequences, respectively. Analysis of mutations relative to antigenic epitopes indicated that adaptive immunity played a key role in virus evolution. HA mutations in immunized animals were associated with loss of glycosylation and changes in charge and hydrophobicity in and near residues within known epitopes. Four regions of HA-1 (75–85, 125–135, 165–170, 225–230) contained residues of highest variability. These sites are adjacent to or within known epitopes and appear to play an important role in antigenic variation. Recognition of the role of these sites during evolution will lead to a better understanding of the nature of evolution which help in the prediction of future strains for selection of seasonal vaccines and the design of novel vaccines intended to stimulated broadened cross-reactive protection to conserved sites outside of dominant epitopes.
Highlights
Influenza is responsible for 250,000 to 500,000 deaths annually and is considered one of the most important respiratory pathogens of humans [1,2,3]
According to the results of antigenic surveillance done by Centers for Disease Control and Prevention (CDC), 91% of the H1N1 viruses circulating in 2007–8 were similar to the vaccine strain, but only 29% of the H3N2 strains were characterized as A/ Wisconsin-like virus
The present study examines the variations in the HA of A/Wyoming/2003 (H3N2) that occur in both naıve and immune animals for the dual purposes of assessing the model for recapitulation of virus evolution in humans and identifying evolutionary trends which can be used for prediction of future strains and subsequent design of novel vaccine candidates
Summary
Influenza is responsible for 250,000 to 500,000 deaths annually and is considered one of the most important respiratory pathogens of humans [1,2,3]. Due to the antigenic evolution of the virus and strain-specific immune responses of the host, the vaccine requires reformulation every year or two to offer significant protection against circulating strains not represented in the vaccine. According to the results of antigenic surveillance done by CDC, 91% of the H1N1 viruses circulating in 2007–8 were similar to the vaccine strain, but only 29% of the H3N2 strains were characterized as A/ Wisconsin-like virus. The vaccine was not a good match against circulating strains in 2007–8, causing larger than normal numbers morbidity and mortality predominantly due to Brisbane/2007 like viruses. Improvements in predictive capabilities could lead to more effective vaccines
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