Cross-Protective Potential of a Novel Monoclonal Antibody Directed against Antigenic Site B of the Hemagglutinin of Influenza A Viruses

Autor: Ayato Takada, Noriko Kishida, Reiko Yoshida, Daisuke Tomabechi, Hiroshi Kida, Kimihito Ito, Manabu Igarashi, Hiroichi Ozaki
Jazyk: angličtina
Rok vydání: 2009
Předmět:
Zdroj: PLoS Pathogens, Vol 5, Iss 3, p e1000350 (2009)
PLoS Pathogens
ISSN: 1553-7374
Popis: The hemagglutinin (HA) of influenza A viruses has been classified into sixteen distinct subtypes (H1–H16) to date. The HA subtypes of influenza A viruses are principally defined as serotypes determined by neutralization or hemagglutination inhibition tests using polyclonal antisera to the respective HA subtypes, which have little cross-reactivity to the other HA subtypes. Thus, it is generally believed that the neutralizing antibodies are not broadly cross-reactive among HA subtypes. In this study, we generated a novel monoclonal antibody (MAb) specific to HA, designated MAb S139/1, which showed heterosubtypic cross-reactive neutralization and hemagglutination inhibition of influenza A viruses. This MAb was found to have broad reactivity to many other viruses (H1, H2, H3, H5, H9, and H13 subtypes) in enzyme-linked immunosorbent assays. We further found that MAb S139/1 showed neutralization and hemagglutination-inhibition activities against particular strains of H1, H2, H3, and H13 subtypes of influenza A viruses. Mutant viruses that escaped neutralization by MAb S139/1 were selected from the A/Aichi/2/68 (H3N2), A/Adachi/2/57 (H2N2), and A/WSN/33 (H1N1) strains, and sequence analysis of the HA genes of these escape mutants revealed amino acid substitutions at positions 156, 158, and 193 (H3 numbering). A molecular modeling study showed that these amino acids were located on the globular head of the HA and formed a novel conformational epitope adjacent to the receptor-binding domain of HA. Furthermore, passive immunization of mice with MAb S139/1 provided heterosubtypic protection. These results demonstrate that MAb S139/1 binds to a common antigenic site shared among a variety of HA subtypes and neutralizes viral infectivity in vitro and in vivo by affecting viral attachment to cells. The present study supports the notion that cross-reactive antibodies play some roles in heterosubtypic immunity against influenza A virus infection, and underscores the potential therapeutic utility of cross-reactive antibodies against influenza.
Author Summary Neutralizing antibodies play a critical role in protection from influenza A virus infection. Most neutralizing antibodies recognize hemagglutinin (HA), which is the major surface glycoprotein of influenza viruses. The HA has been classified into sixteen antigenically distinct subtypes. Since HA subtypes of influenza A viruses are principally defined as serotypes determined by neutralization or hemagglutination inhibition tests using polyclonal antisera to the respective HA subtypes, which have little cross-reactivity to the other HA subtypes, it is generally believed that the neutralizing antibodies are not broadly cross-reactive among HA subtypes. Herein we present a novel cross-neutralizing monoclonal antibody that reacts with a variety of HA subtypes in vitro and provides heterosubtypic protection against influenza A virus infections in mice. We demonstrate that this antibody recognizes a common epitope adjacent to the receptor binding region of HA and inhibits virus binding to the cells. The present study supports the notion that cross-reactive antibodies, as well as cytotoxic T lymphocytes, play some roles in heterosubtypic immunity against influenza A virus infection, and underscores the potential therapeutic utility of cross-reactive monoclonal antibodies for multivalent prophylaxis and treatment against infection with influenza A viruses, including the hypothetical new pandemic influenza viruses.
Databáze: OpenAIRE
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