Abstract
BackgroundThe virus-specific cytotoxic T lymphocyte (CTL) induction is an important target for the development of a broadly protective human influenza vaccine, since most CTL epitopes are found on internal viral proteins and relatively conserved. In this study, the possibility of developing a strain/subtype-independent human influenza vaccine was explored by taking a bioinformatics approach to establish an immunogenic HLA-A24 restricted CTL epitope screening system in HLA-transgenic mice.Methodology/Principal FindingsHLA-A24 restricted CTL epitope peptides derived from internal proteins of the H5N1 highly pathogenic avian influenza A virus were predicted by CTL epitope peptide prediction programs. Of 35 predicted peptides, six peptides exhibited remarkable cytotoxic activity in vivo. More than half of the mice which were subcutaneously vaccinated with the three most immunogenic and highly conserved epitopes among three different influenza A virus subtypes (H1N1, H3N2 and H5N1) survived lethal influenza virus challenge during both effector and memory CTL phases. Furthermore, mice that were intranasally vaccinated with these peptides remained free of clinical signs after lethal virus challenge during the effector phase.Conclusions/SignificanceThis CTL epitope peptide selection system can be used as an effective tool for the development of a cross-protective human influenza vaccine. Furthermore this vaccine strategy can be applicable to the development of all intracellular pathogens vaccines to induce epitope-specific CTL that effectively eliminate infected cells.
Highlights
Influenza A viruses are highly contagious and cause respiratory tract infection associated with a marked disease burden
While the induction of neutralizing antibody production against a particular viral strain with a matching inactivated vaccine is generally effective for reducing the intensity of clinical -signs [2], the effects of these vaccines are limited due to their inability to stimulate mucosal immunity and cytotoxic T lymphocyte (CTL) responses, both of which are indispensable for the suppression of initial viral replication in the respiratory epithelium [3,4]
While the selective pressure from neutralizing antibodies induces a high frequency of antigenic drift in influenza A virus surface proteins, HA and NA, the amino acid sequences of internal proteins, such as matrix (M), nonstructural (NS), nucleocapsid (NP), polymerase acidic (PA), polymerase basic 1(PB1) and polymerase basic 2 (PB2), are relatively well-conserved
Summary
Influenza A viruses are highly contagious and cause respiratory tract infection associated with a marked disease burden. While the induction of neutralizing antibody production against a particular viral strain with a matching inactivated vaccine is generally effective for reducing the intensity of clinical -signs [2], the effects of these vaccines are limited due to their inability to stimulate mucosal immunity and cytotoxic T lymphocyte (CTL) responses, both of which are indispensable for the suppression of initial viral replication in the respiratory epithelium [3,4]. In contrast to inactivated vaccines, live attenuated influenza vaccines (LAIV) which are currently licensed in the United States are administered intranasally (i.n.) and induce cross-protective immunity by stimulating mucosal immunity and CTL responses. The possibility of developing a strain/subtype-independent human influenza vaccine was explored by taking a bioinformatics approach to establish an immunogenic HLA-A24 restricted CTL epitope screening system in HLAtransgenic mice
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