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Journal of Virology, December 2009, p. 12355-12367, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01593-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Heavily Isotype-Dependent Protective Activities of Human Antibodies against Vaccinia Virus Extracellular Virion Antigen B5{triangledown}

Mohammed Rafii-El-Idrissi Benhnia,1 Megan M. McCausland,1,{dagger} John Laudenslager,2 Steven W. Granger,2 Sandra Rickert,2,{ddagger} Lilia Koriazova,2 Tomoyuki Tahara,2 Ralph T. Kubo,1,2 Shinichiro Kato,2,§ and Shane Crotty1*

Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology (LIAI), La Jolla, California 92037,1 Kyowa Hakko Kirin California, La Jolla, California 920372

Received 31 July 2009/ Accepted 17 September 2009

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.

* Corresponding author. Mailing address: La Jolla Institute for Allergy and Immunology, Division of Vaccine Discovery, 9420 Athena Circle, La Jolla, CA 92037. Phone: (858) 752-6816. Fax: (858) 752-6993. E-mail: shane{at}liai.org

{triangledown} Published ahead of print on 30 September 2009.

{dagger} Present address: Emory University School of Medicine, Atlanta, Georgia 3032.

{ddagger} Present address: Vertex Pharmaceuticals Ltd., La Jolla, CA 92121.

§ Present address: Kyowa Hakko Kirin, Tokyo, Japan.

Journal of Virology, December 2009, p. 12355-12367, Vol. 83, No. 23
0022-538X/09/$08.00+0     doi:10.1128/JVI.01593-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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