Limits...
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

(A) Protective immune responses induced by m8∆ and derivative viruses in mice. (A–F) Average body weight of mice immunized (intramuscularly) with (104–106 PFU) vaccinia viruses (VVs) and then challenged intranasally with the Western Reserve (WR) strain. Crosses denote mice that either died or were sacrificed because they lost >30% of their body weight. Figure modified from Kidokoro et al. [34].
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4494248&req=5

vaccines-02-00755-f003: (A) Protective immune responses induced by m8∆ and derivative viruses in mice. (A–F) Average body weight of mice immunized (intramuscularly) with (104–106 PFU) vaccinia viruses (VVs) and then challenged intranasally with the Western Reserve (WR) strain. Crosses denote mice that either died or were sacrificed because they lost >30% of their body weight. Figure modified from Kidokoro et al. [34].

Mentions: The protective immune response elicited by LC16m8∆ was compared with that elicited by Dryvax, MVA, LC16m8 and LC16m8 derivatives (m8B5R and m8dTM, both of which express the B5 ectodomain at high levels) in a mouse model. This model, in which the immunized mice are challenged with a highly pathogenic VV (the Western Reserve (WR) strain), is one of the most popular methods of evaluating the efficacy of smallpox vaccines [62] (Figure 3). We immunized each group of mice with a single dose (104, 105 or 106 PFU) of each VV via the intramuscular (i.m.) route. We found that the level of protective immunity elicited by LCm8∆ was comparable with that elicited by Dryvax and superior to that elicited by MVA. For example, the minimal dose (104 PFU) of LC16m8∆ or Dryvax fully protected mice from lethal infection with WR, whereas mice immunized with MVA, LC16m8, m8B5R or m8dTM, lost weight and, in some cases, died. The maximum dose (106 PFU) of MVA resulted in prominent weight loss after WR challenge. It is noteworthy that immunization with LCm8∆ was more efficient than that with m8B5R or m8dTM when compared at their minimal dose. In particular, m8B5R was significantly inferior to LC16m8∆ (t-test, p = 0.005). These results suggest that B5R does not play a major role in eliciting protective immune responses in these mice. In addition, LC16m8∆ elicited protective immune responses in cynomolgus monkeys and fully protected them against lethal infection with monkeypox virus [63]. Taken together, these data suggest that LC16m8∆ is as effective as the first-generation smallpox vaccine, Dryvax. Although several studies report that the B5 protein is the major target of EEV-neutralizing antibodies, which are significant for protection against smallpox infection, immunization with B5-deficient vaccine viruses protects animals against lethal challenge by pathogenic orthopoxviruses [58,64,65,66,67]. In addition, some reports show that smallpox vaccines do not always induce anti-B5 antibodies, and antibody response profiles against each viral protein are highly heterologous in humans [68,69,70]. They also concluded that the key to inducing a strong neutralizing antibody response is to elicit antibodies that recognize multiple viral proteins; these antibodies then act synergistically to provide better protection.


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

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

(A) Protective immune responses induced by m8∆ and derivative viruses in mice. (A–F) Average body weight of mice immunized (intramuscularly) with (104–106 PFU) vaccinia viruses (VVs) and then challenged intranasally with the Western Reserve (WR) strain. Crosses denote mice that either died or were sacrificed because they lost >30% of their body weight. 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-f003: (A) Protective immune responses induced by m8∆ and derivative viruses in mice. (A–F) Average body weight of mice immunized (intramuscularly) with (104–106 PFU) vaccinia viruses (VVs) and then challenged intranasally with the Western Reserve (WR) strain. Crosses denote mice that either died or were sacrificed because they lost >30% of their body weight. Figure modified from Kidokoro et al. [34].
Mentions: The protective immune response elicited by LC16m8∆ was compared with that elicited by Dryvax, MVA, LC16m8 and LC16m8 derivatives (m8B5R and m8dTM, both of which express the B5 ectodomain at high levels) in a mouse model. This model, in which the immunized mice are challenged with a highly pathogenic VV (the Western Reserve (WR) strain), is one of the most popular methods of evaluating the efficacy of smallpox vaccines [62] (Figure 3). We immunized each group of mice with a single dose (104, 105 or 106 PFU) of each VV via the intramuscular (i.m.) route. We found that the level of protective immunity elicited by LCm8∆ was comparable with that elicited by Dryvax and superior to that elicited by MVA. For example, the minimal dose (104 PFU) of LC16m8∆ or Dryvax fully protected mice from lethal infection with WR, whereas mice immunized with MVA, LC16m8, m8B5R or m8dTM, lost weight and, in some cases, died. The maximum dose (106 PFU) of MVA resulted in prominent weight loss after WR challenge. It is noteworthy that immunization with LCm8∆ was more efficient than that with m8B5R or m8dTM when compared at their minimal dose. In particular, m8B5R was significantly inferior to LC16m8∆ (t-test, p = 0.005). These results suggest that B5R does not play a major role in eliciting protective immune responses in these mice. In addition, LC16m8∆ elicited protective immune responses in cynomolgus monkeys and fully protected them against lethal infection with monkeypox virus [63]. Taken together, these data suggest that LC16m8∆ is as effective as the first-generation smallpox vaccine, Dryvax. Although several studies report that the B5 protein is the major target of EEV-neutralizing antibodies, which are significant for protection against smallpox infection, immunization with B5-deficient vaccine viruses protects animals against lethal challenge by pathogenic orthopoxviruses [58,64,65,66,67]. In addition, some reports show that smallpox vaccines do not always induce anti-B5 antibodies, and antibody response profiles against each viral protein are highly heterologous in humans [68,69,70]. They also concluded that the key to inducing a strong neutralizing antibody response is to elicit antibodies that recognize multiple viral proteins; these antibodies then act synergistically to provide better protection.

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