Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine

Mohammed Rafii El Idrissi Benhnia, Matthew Maybeno, David Blum, Rowena Aguilar-Sino, Michael Matho, Xiangzhi Meng, Steven Head, Philip L. Felgner, Dirk M. Zajonc, Lilia Koriazova, Shinichiro Kato, Dennis R. Burton, Yan Xiang, James E. Crowe, Bjoern Peters, Shane Crotty

Research output: Contribution to journalArticle

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Abstract

The extracellular virion form (EV) of vaccinia virus (VACV) is essential for viral pathogenesis and is difficult to neutralize with antibodies. Why this is the case and how the smallpox vaccine overcomes this challenge remain incompletely understood. We previously showed that high concentrations of anti-B5 antibodies are insufficient to directly neutralize EV (M. R. Benhnia, et al., J. Virol. 83:1201-1215, 2009). This allowed for at least two possible interpretations: covering the EV surface is insufficient for neutralization, or there are insufficient copies of B5 to allow anti-B5 IgG to cover the whole surface of EV and another viral receptor protein remains active. We endeavored to test these possibilities, focusing on the antibody responses elicited by immunization against smallpox. We tested whether human monoclonal antibodies (MAbs) against the three major EV antigens, B5, A33, and A56, could individually or together neutralize EV. While anti-B5 or anti-A33 (but not anti-A56) MAbs of appropriate isotypes were capable of neutralizing EV in the presence of complement, a mixture of anti-B5, anti-A33, and anti-A56 MAbs was incapable of directly neutralizing EV, even at high concentrations. This remained true when neutralizing the IHD-J strain, which lacks a functional version of the fourth and final known EV surface protein, A34. These immunological data are consistent with the possibility that viral proteins may not be the active component of the EV surface for target cell binding and infectivity. We conclude that the protection afforded by the smallpox vaccine anti-EV response is predominantly mediated not by direct neutralization but by isotype-dependent effector functions, such as complement recruitment for antibodies targeting B5 and A33.

Original languageEnglish (US)
Pages (from-to)1569-1585
Number of pages17
JournalJournal of Virology
Volume87
Issue number3
DOIs
StatePublished - Feb 2013

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Smallpox Vaccine
Vaccinia virus
virion
neutralization
Virion
Antibody Formation
vaccines
antibodies
losigame
monoclonal antibodies
Monoclonal Antibodies
Viral Proteins
complement
Smallpox
Antibodies
viral proteins
surface proteins
Anti-Idiotypic Antibodies
Immunization
immunization

ASJC Scopus subject areas

  • Immunology
  • Virology

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Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine. / Benhnia, Mohammed Rafii El Idrissi; Maybeno, Matthew; Blum, David; Aguilar-Sino, Rowena; Matho, Michael; Meng, Xiangzhi; Head, Steven; Felgner, Philip L.; Zajonc, Dirk M.; Koriazova, Lilia; Kato, Shinichiro; Burton, Dennis R.; Xiang, Yan; Crowe, James E.; Peters, Bjoern; Crotty, Shane.

In: Journal of Virology, Vol. 87, No. 3, 02.2013, p. 1569-1585.

Research output: Contribution to journalArticle

Benhnia, MREI, Maybeno, M, Blum, D, Aguilar-Sino, R, Matho, M, Meng, X, Head, S, Felgner, PL, Zajonc, DM, Koriazova, L, Kato, S, Burton, DR, Xiang, Y, Crowe, JE, Peters, B & Crotty, S 2013, 'Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine', Journal of Virology, vol. 87, no. 3, pp. 1569-1585. https://doi.org/10.1128/JVI.02152-12
Benhnia, Mohammed Rafii El Idrissi ; Maybeno, Matthew ; Blum, David ; Aguilar-Sino, Rowena ; Matho, Michael ; Meng, Xiangzhi ; Head, Steven ; Felgner, Philip L. ; Zajonc, Dirk M. ; Koriazova, Lilia ; Kato, Shinichiro ; Burton, Dennis R. ; Xiang, Yan ; Crowe, James E. ; Peters, Bjoern ; Crotty, Shane. / Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine. In: Journal of Virology. 2013 ; Vol. 87, No. 3. pp. 1569-1585.
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abstract = "The extracellular virion form (EV) of vaccinia virus (VACV) is essential for viral pathogenesis and is difficult to neutralize with antibodies. Why this is the case and how the smallpox vaccine overcomes this challenge remain incompletely understood. We previously showed that high concentrations of anti-B5 antibodies are insufficient to directly neutralize EV (M. R. Benhnia, et al., J. Virol. 83:1201-1215, 2009). This allowed for at least two possible interpretations: covering the EV surface is insufficient for neutralization, or there are insufficient copies of B5 to allow anti-B5 IgG to cover the whole surface of EV and another viral receptor protein remains active. We endeavored to test these possibilities, focusing on the antibody responses elicited by immunization against smallpox. We tested whether human monoclonal antibodies (MAbs) against the three major EV antigens, B5, A33, and A56, could individually or together neutralize EV. While anti-B5 or anti-A33 (but not anti-A56) MAbs of appropriate isotypes were capable of neutralizing EV in the presence of complement, a mixture of anti-B5, anti-A33, and anti-A56 MAbs was incapable of directly neutralizing EV, even at high concentrations. This remained true when neutralizing the IHD-J strain, which lacks a functional version of the fourth and final known EV surface protein, A34. These immunological data are consistent with the possibility that viral proteins may not be the active component of the EV surface for target cell binding and infectivity. We conclude that the protection afforded by the smallpox vaccine anti-EV response is predominantly mediated not by direct neutralization but by isotype-dependent effector functions, such as complement recruitment for antibodies targeting B5 and A33.",
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