Smallpox is a top bioterrorism concern. Smallpox is a highly lethal viral infection of humans (30% mortality), which can spread rapidly through a population. Furthermore, there is an active smallpox vaccination campaign in the USA military, and VIG (Vaccinia Immune Globulin) is used to treat rare severe side effects of vaccination. VIG can also be used to treat smallpox infections. Problems with VIG-particularly the small number of VIG doses available and their limited potency-have led to great interest in the development of a better anti-vaccinia and anti-smallpox immunotherapy. Indeed, the NIAID High Priority Biodefense Products list includes """"""""High titer/concentrated Vaccinia Immune Globulin (VIG) or replacement product based on monoclonal antibodies (mAbs)"""""""" as the first desired biodefense product. Our project goal is to develop a highly efficacious, highly standardized mAb replacement of VIG that can be produced in large quantities and stored long term. Fully human mAbs are the best possible form of mAbs for use in humans, eliminating all xeno / rejection issues. Gemini Science, Inc. has transgenic mice possessing the human immunoglobulin loci and thereby produce fully human antibodies. We have used these mice to develop fully human anti-poxvirus monoclonal antibodies that neutralize vaccinia virus in vitro and are protective in vivo in preliminary experiments. We will now fully demonstrate efficacy of these anti-poxvirus monoclonal antibodies in vitro and in vivo, and scale up production of sufficient mAbs to complete all preclinical testing and IND filing. Licensure of a mAb VIG replacement therapeutic product should be based on a demonstration of equal or better activity (""""""""noninferiority"""""""") of the mAbs in the same in vivo and in vitro assays used to validate VIG for licensure, and a demonstration of superiority to VIG in safety, dosing, and product manufacturing features (e.g., ability to standardize the mAb product and produce it in large quantities). Our human anti-poxvirus mAbs are likely to succeed by all of these criteria.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1-TP-M (J1))
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Challberg, Mark D
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La Jolla Institute
La Jolla
United States
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Benhnia, Mohammed Rafii-El-Idrissi; Maybeno, Matthew; Blum, David et al. (2013) Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine. J Virol 87:1569-85
Crickard, Lindsay; Babas, Tahar; Seth, Sidharth et al. (2012) Protection of rabbits and immunodeficient mice against lethal poxvirus infections by human monoclonal antibodies. PLoS One 7:e48706
Tomimori, Yoshiaki; Kawakami, Yuko; McCausland, Megan M et al. (2011) Protective murine and human monoclonal antibodies against eczema vaccinatum. Antivir Ther 16:67-75
McCausland, Megan M; Benhnia, Mohammed Rafii-El-Idrissi; Crickard, Lindsay et al. (2010) Combination therapy of vaccinia virus infection with human anti-H3 and anti-B5 monoclonal antibodies in a small animal model. Antivir Ther 15:661-75
Benhnia, Mohammed Rafii-El-Idrissi; McCausland, Megan M; Moyron, Juan et al. (2009) Vaccinia virus extracellular enveloped virion neutralization in vitro and protection in vivo depend on complement. J Virol 83:1201-15
Benhnia, Mohammed Rafii-El-Idrissi; McCausland, Megan M; Laudenslager, John et al. (2009) Heavily isotype-dependent protective activities of human antibodies against vaccinia virus extracellular virion antigen B5. J Virol 83:12355-67
Moyron-Quiroz, Juan E; McCausland, Megan M; Kageyama, Robin et al. (2009) The smallpox vaccine induces an early neutralizing IgM response. Vaccine 28:140-7
Kawakami, Yuko; Tomimori, Yoshiaki; Yumoto, Kenji et al. (2009) Inhibition of NK cell activity by IL-17 allows vaccinia virus to induce severe skin lesions in a mouse model of eczema vaccinatum. J Exp Med 206:1219-25
Sette, Alessandro; Moutaftsi, Magdalini; Moyron-Quiroz, Juan et al. (2008) Selective CD4+ T cell help for antibody responses to a large viral pathogen: deterministic linkage of specificities. Immunity 28:847-58