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Expression of CCL20 and granulocyte-macrophage colony-stimulating factor, but not Flt3-L, from modified vaccinia virus ankara enhances antiviral cellular and humoral immune responses.
J Virol. 2006 Aug; 80(15):7676-87.JV

Abstract

While modified vaccinia virus Ankara (MVA) is currently in clinical development as a safe vaccine against smallpox and heterologous infectious diseases, its immunogenicity is likely limited due to the inability of the virus to replicate productively in mammalian hosts. In light of recent data demonstrating that vaccinia viruses, including MVA, preferentially infect antigen-presenting cells (APCs) that play crucial roles in generating antiviral immunity, we hypothesized that expression of specific cytokines and chemokines that mediate APC recruitment and activation from recombinant MVA (rMVA) vectors would enhance the immunogenicity of these vectors. To test this hypothesis, we generated rMVAs that express murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), human CCL20/human macrophage inflammatory protein 3alpha (hCCL20/hMIP-3alpha), or human fms-like tyrosine kinase 3 ligand (hFlt3-L), factors predicted to increase levels of dendritic cells (DCs), to recruit DCs to sites of immunization, or to promote maturation of DCs in vivo, respectively. These rMVAs also coexpress the well-characterized, immunodominant lymphocytic choriomeningitis virus nucleoprotein (NP) antigen that enabled sensitive and quantitative assessment of antigen-specific CD8(+) T-cell responses following immunization of BALB/c mice. Our results demonstrate that immunization of mice with rMVAs expressing mGM-CSF or hCCL20, but not hFlt3-L, results in two- to fourfold increases of cellular immune responses directed against vector-encoded antigens and 6- to 17-fold enhancements of MVA-specific antibody titers, compared to those responses elicited by nonadjuvanted rMVA. Of note, cytokine augmentation of cellular immune responses occurs when rMVAs are given as primary immunizations but not when they are used as booster immunizations, suggesting that these APC-modulating proteins, when used as poxvirus-encoded adjuvants, are more effective at stimulating naïve T-cell responses than in promoting recall of preexisting memory T-cell responses. Our results demonstrate that a strategy to express specific genetic adjuvants from rMVA vectors can be successfully applied to enhance the immunogenicity of MVA-based vaccines.

Authors+Show Affiliations

Emory University Vaccine Center, 954 Gatewood Road NE, Atlanta, GA 30329, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16840346

Citation

Chavan, R, et al. "Expression of CCL20 and Granulocyte-macrophage Colony-stimulating Factor, but Not Flt3-L, From Modified Vaccinia Virus Ankara Enhances Antiviral Cellular and Humoral Immune Responses." Journal of Virology, vol. 80, no. 15, 2006, pp. 7676-87.
Chavan R, Marfatia KA, An IC, et al. Expression of CCL20 and granulocyte-macrophage colony-stimulating factor, but not Flt3-L, from modified vaccinia virus ankara enhances antiviral cellular and humoral immune responses. J Virol. 2006;80(15):7676-87.
Chavan, R., Marfatia, K. A., An, I. C., Garber, D. A., & Feinberg, M. B. (2006). Expression of CCL20 and granulocyte-macrophage colony-stimulating factor, but not Flt3-L, from modified vaccinia virus ankara enhances antiviral cellular and humoral immune responses. Journal of Virology, 80(15), 7676-87.
Chavan R, et al. Expression of CCL20 and Granulocyte-macrophage Colony-stimulating Factor, but Not Flt3-L, From Modified Vaccinia Virus Ankara Enhances Antiviral Cellular and Humoral Immune Responses. J Virol. 2006;80(15):7676-87. PubMed PMID: 16840346.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Expression of CCL20 and granulocyte-macrophage colony-stimulating factor, but not Flt3-L, from modified vaccinia virus ankara enhances antiviral cellular and humoral immune responses. AU - Chavan,R, AU - Marfatia,K A, AU - An,I C, AU - Garber,D A, AU - Feinberg,M B, PY - 2006/7/15/pubmed PY - 2006/8/19/medline PY - 2006/7/15/entrez SP - 7676 EP - 87 JF - Journal of virology JO - J Virol VL - 80 IS - 15 N2 - While modified vaccinia virus Ankara (MVA) is currently in clinical development as a safe vaccine against smallpox and heterologous infectious diseases, its immunogenicity is likely limited due to the inability of the virus to replicate productively in mammalian hosts. In light of recent data demonstrating that vaccinia viruses, including MVA, preferentially infect antigen-presenting cells (APCs) that play crucial roles in generating antiviral immunity, we hypothesized that expression of specific cytokines and chemokines that mediate APC recruitment and activation from recombinant MVA (rMVA) vectors would enhance the immunogenicity of these vectors. To test this hypothesis, we generated rMVAs that express murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), human CCL20/human macrophage inflammatory protein 3alpha (hCCL20/hMIP-3alpha), or human fms-like tyrosine kinase 3 ligand (hFlt3-L), factors predicted to increase levels of dendritic cells (DCs), to recruit DCs to sites of immunization, or to promote maturation of DCs in vivo, respectively. These rMVAs also coexpress the well-characterized, immunodominant lymphocytic choriomeningitis virus nucleoprotein (NP) antigen that enabled sensitive and quantitative assessment of antigen-specific CD8(+) T-cell responses following immunization of BALB/c mice. Our results demonstrate that immunization of mice with rMVAs expressing mGM-CSF or hCCL20, but not hFlt3-L, results in two- to fourfold increases of cellular immune responses directed against vector-encoded antigens and 6- to 17-fold enhancements of MVA-specific antibody titers, compared to those responses elicited by nonadjuvanted rMVA. Of note, cytokine augmentation of cellular immune responses occurs when rMVAs are given as primary immunizations but not when they are used as booster immunizations, suggesting that these APC-modulating proteins, when used as poxvirus-encoded adjuvants, are more effective at stimulating naïve T-cell responses than in promoting recall of preexisting memory T-cell responses. Our results demonstrate that a strategy to express specific genetic adjuvants from rMVA vectors can be successfully applied to enhance the immunogenicity of MVA-based vaccines. SN - 0022-538X UR - https://www.unboundmedicine.com/medline/citation/16840346/Expression_of_CCL20_and_granulocyte_macrophage_colony_stimulating_factor_but_not_Flt3_L_from_modified_vaccinia_virus_ankara_enhances_antiviral_cellular_and_humoral_immune_responses_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=16840346 DB - PRIME DP - Unbound Medicine ER -