Active vaccination with vaccinia virus A33 protects mice against lethal vaccinia and ectromelia viruses but not against cowpoxvirus; elucidation of the specific adaptive immune response

Virology Journal

Udy Olshevsky²  Reuven Levin²  Dana Stein¹  Ofir Israeli¹  Batel Lachmi²  Paula Schneider²  David Ben-Nathan²  Boaz Politi²  Sharon Melamed²  Tomer Israely²  Noam Erez²  Anat Zvi¹  Shlomo Lustig²  Nir Paran² 

[1] Department of Biochemistry and Molecular Biology, Israel Institute for Biological Research, P.O. box 19, Ness-Ziona 74100, Israel;Department of Infectious Diseases, Israel Institute for Biological Research, P.O. box 19, Ness-Ziona 74100, Israel

关键词: In-vivo protection;    Sindbis;    Alphavirus;    1G10;    Monkeypox;    Vaccinia;    Cowpox;    A33;    Subunit vaccine;    Smallpox;   

Others  :  829221
DOI  :  10.1186/1743-422X-10-229

 received in 2013-05-16, accepted in 2013-07-05,  发布年份 2013

【 摘 要 】

Vaccinia virus protein A33 (A33^VACV) plays an important role in protection against orthopoxviruses, and hence is included in experimental multi-subunit smallpox vaccines. In this study we show that single-dose vaccination with recombinant Sindbis virus expressing A33^VACV, is sufficient to protect mice against lethal challenge with vaccinia virus WR (VACV-WR) and ectromelia virus (ECTV) but not against cowpox virus (CPXV), a closely related orthopoxvirus. Moreover, a subunit vaccine based on the cowpox virus A33 ortholog (A33^CPXV) failed to protect against cowpox and only partially protected mice against VACV-WR challenge. We mapped regions of sequence variation between A33^VACV and A33^CPXVand analyzed the role of such variations in protection. We identified a single protective region located between residues 104–120 that harbors a putative H-2Kd T cell epitope as well as a B cell epitope - a target for the neutralizing antibody MAb-1G10 that blocks spreading of extracellular virions. Both epitopes in A33^CPXV are mutated and predicted to be non-functional. Whereas vaccination with A33^VACV did not induce in-vivo CTL activity to the predicted epitope, inhibition of virus spread in-vitro, and protection from lethal VACV challenge pointed to the B cell epitope highlighting the critical role of residue L118 and of adjacent compensatory residues in protection. This epitope’s critical role in protection, as well as its modifications within the orthopoxvirus genus should be taken in context with the failure of A33 to protect against CPXV as demonstrated here. These findings should be considered when developing new subunit vaccines and monoclonal antibody based therapeutics against orthopoxviruses, especially variola virus, the etiologic agent of smallpox.

【 授权许可】

   
2013 Paran et al.; licensee BioMed Central Ltd.

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