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Journal of Virology, February 2009, p. 1201-1215, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01797-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Vaccinia Virus Extracellular Enveloped Virion Neutralization In Vitro and Protection In Vivo Depend on Complement{triangledown}

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

Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037,1 Kirin Pharma USA, La Jolla, California 920372

Received 27 August 2008/ Accepted 5 November 2008

Antibody neutralization is an important component of protective immunity against vaccinia virus (VACV). Two distinct virion forms, mature virion and enveloped virion (MV and EV, respectively), possess separate functions and nonoverlapping immunological properties. In this study we examined the mechanics of EV neutralization, focusing on EV protein B5 (also called B5R). We show that neutralization of EV is predominantly complement dependent. From a panel of high-affinity anti-B5 monoclonal antibodies (MAbs), the only potent neutralizer in vitro (90% at 535 ng/ml) was an immunoglobulin G2a (IgG2a), and neutralization was complement mediated. This MAb was the most protective in vivo against lethal intranasal VACV challenge. Further studies demonstrated that in vivo depletion of complement caused a >50% loss of anti-B5 IgG2a protection, directly establishing the importance of complement for protection against the EV form. However, the mechanism of protection is not sterilizing immunity via elimination of the inoculum as the viral inoculum consisted of a purified MV form. The prevention of illness in vivo indicated rapid control of infection. We further demonstrate that antibody-mediated killing of VACV-infected cells expressing surface B5 is a second protective mechanism provided by complement-fixing anti-B5 IgG. Cell killing was very efficient, and this effector function was highly isotype specific. These results indicate that anti-B5 antibody-directed cell lysis via complement is a powerful mechanism for clearance of infected cells, keeping poxvirus-infected cells from being invisible to humoral immune responses. These findings highlight the importance of multiple mechanisms of antibody-mediated protection against VACV and point to key immunobiological differences between MVs and EVs that impact the outcome of infection.

* Corresponding author. Mailing address: La Jolla Institute for Allergy and Immunology, 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 19 November 2008.

{dagger} M.R.B. and M.M.M. contributed equally to this work.

Journal of Virology, February 2009, p. 1201-1215, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01797-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Benhnia, M. R.-E.-I., McCausland, M. M., Laudenslager, J., Granger, S. W., Rickert, S., Koriazova, L., Tahara, T., Kubo, R. T., Kato, S., Crotty, S. (2009). Heavily Isotype-Dependent Protective Activities of Human Antibodies against Vaccinia Virus Extracellular Virion Antigen B5. J. Virol. 83: 12355-12367 [Abstract] [Full Text]  
  • Liszewski, M. K., Leung, M. K., Hauhart, R., Fang, C. J., Bertram, P., Atkinson, J. P. (2009). Smallpox Inhibitor of Complement Enzymes (SPICE): Dissecting Functional Sites and Abrogating Activity. J. Immunol. 183: 3150-3159 [Abstract] [Full Text]  


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