Linear epitopes in vaccinia virus A27 are targets of protective antibodies induced by vaccination against smallpox

Thomas Kaever, Michael H. Matho, Xiangzhi Meng, Lindsay Crickard, Andrew Schlossman, Yan Xiang, Shane Crotty, Bjoern Peters, Dirk M. Zajonc

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Abstract

Vaccinia virus (VACV) A27 is a target for viral neutralization and part of the Dryvax smallpox vaccine. A27 is one of the three glycosaminoglycan (GAG) adhesion molecules and binds to heparan sulfate. To understand the function of anti-A27 antibodies, especially their protective capacity and their interaction with A27, we generated and subsequently characterized 7 murine monoclonal antibodies (MAbs), which fell into 4 distinct epitope groups (groups I to IV). The MAbs in three groups (groups I, III, and IV) bound to linear peptides, while the MAbs in group II bound only to VACV lysate and recombinant A27, suggesting that they recognized a conformational and discontinuous epitope. Only group I antibodies neutralized the mature virion in a complement- dependent manner and protected against VACV challenge, while a group II MAb partially protected against VACV challenge but did not neutralize the mature virion. The epitope for group I MAbs was mapped to a region adjacent to the GAG binding site, a finding which suggests that group I MAbs could potentially interfere with the cellular adhesion of A27. We further determined the crystal structure of the neutralizing group I MAb 1G6, as well as the nonneutralizing group IV MAb 8E3, bound to the corresponding linear epitope-containing peptides. Both the light and the heavy chains of the antibodies are important in binding to their antigens. For both antibodies, the L1 loop seems to dominate the overall polar interactions with the antigen, while for MAb 8E3, the light chain generally appears to make more contacts with the antigen.

Original languageEnglish (US)
Pages (from-to)4334-4345
Number of pages12
JournalJournal of Virology
Volume90
Issue number9
DOIs
StatePublished - May 1 2016

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ASJC Scopus subject areas

  • Immunology
  • Virology

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