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Vaccinia Virus LC16m8∆ as a Vaccine Vector for Clinical Applications.

Kidokoro M, Shida H - Vaccines (Basel) (2014)

Bottom Line: Moreover, LC16m8∆ is >500-fold more effective than the non-replicating vaccinia virus (VV), Modified Vaccinia Ankara (MVA), at inducing murine immune responses against pathogenic VV.Moreover, LC16m8∆ expressing HIV-1 Env in combination with a Sendai virus vector induced the production of anti-Env antibodies and CD8⁺ T-cells.Thus, the safety and efficacy of LC16m8∆ mean that it represents an outstanding platform for the development of human vaccine vectors.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology III, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan. kidokoro@nih.go.jp.

ABSTRACT
The LC16m8 strain of vaccinia virus, the active ingredient in the Japanese smallpox vaccine, was derived from the Lister/Elstree strain. LC16m8 is replication-competent and has been administered to over 100,000 infants and 3,000 adults with no serious adverse reactions. Despite this outstanding safety profile, the occurrence of spontaneously-generated large plaque-forming virulent LC16m8 revertants following passage in cell culture is a major drawback. We identified the gene responsible for the reversion and deleted the gene (B5R) from LC16m8 to derive LC16m8Δ. LC16m8∆ is non-pathogenic in immunodeficient severe combined immunodeficiency (SCID) mice, genetically-stable and does not reverse to a large-plaque phenotype upon passage in cell culture, even under conditions in which most LC16m8 populations are replaced by revertants. Moreover, LC16m8∆ is >500-fold more effective than the non-replicating vaccinia virus (VV), Modified Vaccinia Ankara (MVA), at inducing murine immune responses against pathogenic VV. LC16m8∆, which expresses the SIV gag gene, also induced anti-Gag CD8⁺ T-cells more efficiently than MVA and another non-replicating VV, Dairen I minute-pock variants (DIs). Moreover, LC16m8∆ expressing HIV-1 Env in combination with a Sendai virus vector induced the production of anti-Env antibodies and CD8⁺ T-cells. Thus, the safety and efficacy of LC16m8∆ mean that it represents an outstanding platform for the development of human vaccine vectors.

No MeSH data available.


Related in: MedlinePlus

Pathogenicity of B5R-defective viruses in severe combined immunodeficiency (SCID) mice. Figure modified from Kidokoro et al. [34].
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vaccines-02-00755-f001: Pathogenicity of B5R-defective viruses in severe combined immunodeficiency (SCID) mice. Figure modified from Kidokoro et al. [34].

Mentions: To prevent the generation of LC16m8 revertants, we decided to delete the entire B5R gene from the LC16m8 genome by homologous recombination to yield LC16m8∆ [34]. The phenotype of LC16m8∆ (plaque size and dermal reaction in rabbits) was similar to that of LC16m8. Intraperitoneal (i.p.) injection of 107 PFU of LC16m8∆ (a dose three logs higher than that needed to elicit protective immunity in BALB/c mice) did not cause any symptoms in SCID mice over an eight-week period (Figure 1). MVA and plaque-purified LC16m8 (which contains a very low level of revertants) were also nonpathogenic; however, LC16mO and m8B5R (a derivative constructed by reintroducing the intact B5R gene into LC16m8) caused severe rashes and death in SCID mice, even when administered at a dose two logs lower than LC16m8∆ (Figure 1).


Vaccinia Virus LC16m8∆ as a Vaccine Vector for Clinical Applications.

Kidokoro M, Shida H - Vaccines (Basel) (2014)

Pathogenicity of B5R-defective viruses in severe combined immunodeficiency (SCID) mice. Figure modified from Kidokoro et al. [34].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494248&req=5

vaccines-02-00755-f001: Pathogenicity of B5R-defective viruses in severe combined immunodeficiency (SCID) mice. Figure modified from Kidokoro et al. [34].
Mentions: To prevent the generation of LC16m8 revertants, we decided to delete the entire B5R gene from the LC16m8 genome by homologous recombination to yield LC16m8∆ [34]. The phenotype of LC16m8∆ (plaque size and dermal reaction in rabbits) was similar to that of LC16m8. Intraperitoneal (i.p.) injection of 107 PFU of LC16m8∆ (a dose three logs higher than that needed to elicit protective immunity in BALB/c mice) did not cause any symptoms in SCID mice over an eight-week period (Figure 1). MVA and plaque-purified LC16m8 (which contains a very low level of revertants) were also nonpathogenic; however, LC16mO and m8B5R (a derivative constructed by reintroducing the intact B5R gene into LC16m8) caused severe rashes and death in SCID mice, even when administered at a dose two logs lower than LC16m8∆ (Figure 1).

Bottom Line: Moreover, LC16m8∆ is >500-fold more effective than the non-replicating vaccinia virus (VV), Modified Vaccinia Ankara (MVA), at inducing murine immune responses against pathogenic VV.Moreover, LC16m8∆ expressing HIV-1 Env in combination with a Sendai virus vector induced the production of anti-Env antibodies and CD8⁺ T-cells.Thus, the safety and efficacy of LC16m8∆ mean that it represents an outstanding platform for the development of human vaccine vectors.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology III, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan. kidokoro@nih.go.jp.

ABSTRACT
The LC16m8 strain of vaccinia virus, the active ingredient in the Japanese smallpox vaccine, was derived from the Lister/Elstree strain. LC16m8 is replication-competent and has been administered to over 100,000 infants and 3,000 adults with no serious adverse reactions. Despite this outstanding safety profile, the occurrence of spontaneously-generated large plaque-forming virulent LC16m8 revertants following passage in cell culture is a major drawback. We identified the gene responsible for the reversion and deleted the gene (B5R) from LC16m8 to derive LC16m8Δ. LC16m8∆ is non-pathogenic in immunodeficient severe combined immunodeficiency (SCID) mice, genetically-stable and does not reverse to a large-plaque phenotype upon passage in cell culture, even under conditions in which most LC16m8 populations are replaced by revertants. Moreover, LC16m8∆ is >500-fold more effective than the non-replicating vaccinia virus (VV), Modified Vaccinia Ankara (MVA), at inducing murine immune responses against pathogenic VV. LC16m8∆, which expresses the SIV gag gene, also induced anti-Gag CD8⁺ T-cells more efficiently than MVA and another non-replicating VV, Dairen I minute-pock variants (DIs). Moreover, LC16m8∆ expressing HIV-1 Env in combination with a Sendai virus vector induced the production of anti-Env antibodies and CD8⁺ T-cells. Thus, the safety and efficacy of LC16m8∆ mean that it represents an outstanding platform for the development of human vaccine vectors.

No MeSH data available.


Related in: MedlinePlus