Heavily isotype-dependent protective activities of human antibodies against vaccinia virus extracellular virion antigen B5.
Antibodies against the extracellular virion (EV or EEV) form of vaccinia virus are an important component of protective immunity in animal models and likely contribute to the protection of immunized humans against poxviruses. Using fully human monoclonal antibodies (MAbs), we now have shown that the protective attributes of the human anti-B5 antibody response to the smallpox vaccine (vaccinia virus) are heavily dependent on effector functions. By switching Fc domains of a single MAb, we have definitively shown that neutralization in vitro--and protection in vivo in a mouse model--by the human anti-B5 immunoglobulin G MAbs is isotype dependent, thereby demonstrating that efficient protection by these antibodies is not simply dependent on binding an appropriate vaccinia virion antigen with high affinity but in fact requires antibody effector function. The complement components C3 and C1q, but not C5, were required for neutralization. We also have demonstrated that human MAbs against B5 can potently direct complement-dependent cytotoxicity of vaccinia virus-infected cells. Each of these results was then extended to the polyclonal human antibody response to the smallpox vaccine. A model is proposed to explain the mechanism of EV neutralization. Altogether these findings enhance our understanding of the central protective activities of smallpox vaccine-elicited antibodies in immunized humans.
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
Mohammed Rafii-El-Idrissi
MR
Benhnia
Megan M
MM
McCausland
John
J
Laudenslager
Steven W
SW
Granger
Sandra
S
Rickert
Lilia
L
Koriazova
Tomoyuki
T
Tahara
Ralph T
RT
Kubo
Shinichiro
S
Kato
Shane
S
Crotty
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D001835:Body Weight; D015922:Complement C1q / Q000276:immunology; D003176:Complement C3 / Q000276:immunology; D005260:Female; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009500:Neutralization Tests; D012899:Smallpox / Q000517:prevention & control*; D016019:Survival Analysis; D014616:Vaccinia virus / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; C534336:B5 protein, vaccinia virus; D003176:Complement C3; D007132:Immunoglobulin Isotypes; D014763:Viral Matrix Proteins; D015922:Complement C1q