title: Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine.
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.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Mohammed Rafii-El-Idrissi
authors.initials: MR
authors.lastname: Benhnia
authors.forename: Matthew
authors.initials: M
authors.lastname: Maybeno
authors.forename: David
authors.initials: D
authors.lastname: Blum
authors.forename: Rowena
authors.initials: R
authors.lastname: Aguilar-Sino
authors.forename: Michael
authors.initials: M
authors.lastname: Matho
authors.forename: Xiangzhi
authors.initials: X
authors.lastname: Meng
authors.forename: Steven
authors.initials: S
authors.lastname: Head
authors.forename: Philip L
authors.initials: PL
authors.lastname: Felgner
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Zajonc
authors.forename: Lilia
authors.initials: L
authors.lastname: Koriazova
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kato
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiang
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology; D006801:Humans; D009500:Neutralization Tests; D012900:Smallpox Vaccine / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*; D014771:Virion / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D012900:Smallpox Vaccine; D003165:Complement System Proteins