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Immunogenicity, protective efficacy, and non-replicative status of the HSV-2 vaccine candidate HSV529 in mice and guinea pigs.

Bernard MC, Barban V, Pradezynski F, de Montfort A, Ryall R, Caillet C, Londono-Hayes P - PLoS ONE (2015)

Bottom Line: Immunization effectively prevented HSV-2 infection in all three animal models by reducing mortality, acute genital disease severity and frequency, and viral shedding.It also reduced ganglionic viral latency and recurrent disease in naïve and HSV-1 seropositive guinea pigs.These results further support the clinical investigation of HSV529 in human subjects as a prophylactic vaccine.

View Article: PubMed Central - PubMed

Affiliation: Sanofi Pasteur, Research and Development, Marcy-l'Étoile, France.

ABSTRACT
HSV-2 vaccine is needed to prevent genital disease, latent infection, and virus transmission. A replication-deficient mutant virus (dl5-29) has demonstrated promising efficacy in animal models of genital herpes. However, the immunogenicity, protective efficacy, and non-replicative status of the highly purified clinical vaccine candidate (HSV529) derived from dl5-29 have not been evaluated. Humoral and cellular immune responses were measured in mice and guinea pigs immunized with HSV529. Protection against acute and recurrent genital herpes, mortality, latent infection, and viral shedding after vaginal HSV-2 infection was determined in mice or in naïve and HSV-1 seropositive guinea pigs. HSV529 replication and pathogenicity were investigated in three sensitive models of virus replication: severe combined immunodeficient (SCID/Beige) mice inoculated by the intramuscular route, suckling mice inoculated by the intracranial route, and vaginally-inoculated guinea pigs. HSV529 immunization induced HSV-2-neutralizing antibody production in mice and guinea pigs. In mice, it induced production of specific HSV-2 antibodies and splenocytes secreting IFNγ or IL-5. Immunization effectively prevented HSV-2 infection in all three animal models by reducing mortality, acute genital disease severity and frequency, and viral shedding. It also reduced ganglionic viral latency and recurrent disease in naïve and HSV-1 seropositive guinea pigs. HSV529 replication/propagation was not detected in the muscles of SCID/Beige mice, in the brains of suckling mice, or in vaginal secretions of inoculated guinea pigs. These results confirm the non-replicative status, as well as its immunogenicity and efficacy in mice and guinea pigs, including HSV-1 seropositive guinea pigs. In mice, HSV529 produced Th1/Th2 characteristic immune response thought to be necessary for an effective vaccine. These results further support the clinical investigation of HSV529 in human subjects as a prophylactic vaccine.

No MeSH data available.


Related in: MedlinePlus

HSV529 immunization protects HSV-1-primed guinea pigs from effects of HSV-2 vaginal challenge.Guinea pigs were inoculated with HSV-1 (KOS strain; 106 CCID50; n = 30) or PBS (n = 18) by the intranasal route on day 0. All animal inoculated with HSV-1 were positive for HSV-1 at week 5. At weeks 7 and 10, animals inoculated with HSV-1 were immunized with HSV529 (106 CCID50; n = 15) or PBS (n = 14) by the i.m. route. At week 14, all animals except 3 PBS controls were challenged with an intravaginal inoculation of HSV-2 (G strain, 2 x 106 CCID50). (A) Mean body weight change after HSV-2 challenge. (B) Mean vaginal lesion score after HSV-2 challenge. (C) Percent survival after HSV-2 challenge. (D) HSV-2 viral shedding after challenge. (E) Cumulative number of recurrent lesions per animal. *Dead or euthanized animal. Error bars represent standard error of the mean.
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pone.0121518.g005: HSV529 immunization protects HSV-1-primed guinea pigs from effects of HSV-2 vaginal challenge.Guinea pigs were inoculated with HSV-1 (KOS strain; 106 CCID50; n = 30) or PBS (n = 18) by the intranasal route on day 0. All animal inoculated with HSV-1 were positive for HSV-1 at week 5. At weeks 7 and 10, animals inoculated with HSV-1 were immunized with HSV529 (106 CCID50; n = 15) or PBS (n = 14) by the i.m. route. At week 14, all animals except 3 PBS controls were challenged with an intravaginal inoculation of HSV-2 (G strain, 2 x 106 CCID50). (A) Mean body weight change after HSV-2 challenge. (B) Mean vaginal lesion score after HSV-2 challenge. (C) Percent survival after HSV-2 challenge. (D) HSV-2 viral shedding after challenge. (E) Cumulative number of recurrent lesions per animal. *Dead or euthanized animal. Error bars represent standard error of the mean.

Mentions: HSV529 immunization protected most HSV-1-seropositive animals from most HSV-2 genital disease features (Fig. 5). Immunized animals continued to grow and gain weight following HSV-2 challenge; though over time they tended to gain less weight than unchallenged control animals (Fig. 5A). In contrast, HSV-1-naïve control animals lost >10% of their body weight after challenge (p.i. day 10) and HSV-1-primed animals lost 2%. During the 14-day acute phase, genital disease was far less severe in immunized animals than HSV-1 seronegative or HSV-1 seropositive but PBS immunized animals, and none of the HSV529-immunized animals died (Fig. 5B and 5C). In HSV529-immunized animals, 7 (40%) remained lesion-free, 8 had lesion scores no higher than 2, and the mean lesion score was significantly lower than the mean scores in the two other HSV-2-challenged groups regardless of their HSV-1 serological status (all p-values ≤ 0.0002, analysis of variance). In non-vaccinated animals, lesions developed in all 14 HSV-1-naïve control animals, the maximum mean lesion score was 2.8 on p.i. day 8, and 7 of the animals died or were euthanized. Lesions developed in 13 of the 14 HSV-1-seropositive animals, with a maximum mean lesion score of 1.4 on p.i. day 8 and one death.


Immunogenicity, protective efficacy, and non-replicative status of the HSV-2 vaccine candidate HSV529 in mice and guinea pigs.

Bernard MC, Barban V, Pradezynski F, de Montfort A, Ryall R, Caillet C, Londono-Hayes P - PLoS ONE (2015)

HSV529 immunization protects HSV-1-primed guinea pigs from effects of HSV-2 vaginal challenge.Guinea pigs were inoculated with HSV-1 (KOS strain; 106 CCID50; n = 30) or PBS (n = 18) by the intranasal route on day 0. All animal inoculated with HSV-1 were positive for HSV-1 at week 5. At weeks 7 and 10, animals inoculated with HSV-1 were immunized with HSV529 (106 CCID50; n = 15) or PBS (n = 14) by the i.m. route. At week 14, all animals except 3 PBS controls were challenged with an intravaginal inoculation of HSV-2 (G strain, 2 x 106 CCID50). (A) Mean body weight change after HSV-2 challenge. (B) Mean vaginal lesion score after HSV-2 challenge. (C) Percent survival after HSV-2 challenge. (D) HSV-2 viral shedding after challenge. (E) Cumulative number of recurrent lesions per animal. *Dead or euthanized animal. Error bars represent standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

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pone.0121518.g005: HSV529 immunization protects HSV-1-primed guinea pigs from effects of HSV-2 vaginal challenge.Guinea pigs were inoculated with HSV-1 (KOS strain; 106 CCID50; n = 30) or PBS (n = 18) by the intranasal route on day 0. All animal inoculated with HSV-1 were positive for HSV-1 at week 5. At weeks 7 and 10, animals inoculated with HSV-1 were immunized with HSV529 (106 CCID50; n = 15) or PBS (n = 14) by the i.m. route. At week 14, all animals except 3 PBS controls were challenged with an intravaginal inoculation of HSV-2 (G strain, 2 x 106 CCID50). (A) Mean body weight change after HSV-2 challenge. (B) Mean vaginal lesion score after HSV-2 challenge. (C) Percent survival after HSV-2 challenge. (D) HSV-2 viral shedding after challenge. (E) Cumulative number of recurrent lesions per animal. *Dead or euthanized animal. Error bars represent standard error of the mean.
Mentions: HSV529 immunization protected most HSV-1-seropositive animals from most HSV-2 genital disease features (Fig. 5). Immunized animals continued to grow and gain weight following HSV-2 challenge; though over time they tended to gain less weight than unchallenged control animals (Fig. 5A). In contrast, HSV-1-naïve control animals lost >10% of their body weight after challenge (p.i. day 10) and HSV-1-primed animals lost 2%. During the 14-day acute phase, genital disease was far less severe in immunized animals than HSV-1 seronegative or HSV-1 seropositive but PBS immunized animals, and none of the HSV529-immunized animals died (Fig. 5B and 5C). In HSV529-immunized animals, 7 (40%) remained lesion-free, 8 had lesion scores no higher than 2, and the mean lesion score was significantly lower than the mean scores in the two other HSV-2-challenged groups regardless of their HSV-1 serological status (all p-values ≤ 0.0002, analysis of variance). In non-vaccinated animals, lesions developed in all 14 HSV-1-naïve control animals, the maximum mean lesion score was 2.8 on p.i. day 8, and 7 of the animals died or were euthanized. Lesions developed in 13 of the 14 HSV-1-seropositive animals, with a maximum mean lesion score of 1.4 on p.i. day 8 and one death.

Bottom Line: Immunization effectively prevented HSV-2 infection in all three animal models by reducing mortality, acute genital disease severity and frequency, and viral shedding.It also reduced ganglionic viral latency and recurrent disease in naïve and HSV-1 seropositive guinea pigs.These results further support the clinical investigation of HSV529 in human subjects as a prophylactic vaccine.

View Article: PubMed Central - PubMed

Affiliation: Sanofi Pasteur, Research and Development, Marcy-l'Étoile, France.

ABSTRACT
HSV-2 vaccine is needed to prevent genital disease, latent infection, and virus transmission. A replication-deficient mutant virus (dl5-29) has demonstrated promising efficacy in animal models of genital herpes. However, the immunogenicity, protective efficacy, and non-replicative status of the highly purified clinical vaccine candidate (HSV529) derived from dl5-29 have not been evaluated. Humoral and cellular immune responses were measured in mice and guinea pigs immunized with HSV529. Protection against acute and recurrent genital herpes, mortality, latent infection, and viral shedding after vaginal HSV-2 infection was determined in mice or in naïve and HSV-1 seropositive guinea pigs. HSV529 replication and pathogenicity were investigated in three sensitive models of virus replication: severe combined immunodeficient (SCID/Beige) mice inoculated by the intramuscular route, suckling mice inoculated by the intracranial route, and vaginally-inoculated guinea pigs. HSV529 immunization induced HSV-2-neutralizing antibody production in mice and guinea pigs. In mice, it induced production of specific HSV-2 antibodies and splenocytes secreting IFNγ or IL-5. Immunization effectively prevented HSV-2 infection in all three animal models by reducing mortality, acute genital disease severity and frequency, and viral shedding. It also reduced ganglionic viral latency and recurrent disease in naïve and HSV-1 seropositive guinea pigs. HSV529 replication/propagation was not detected in the muscles of SCID/Beige mice, in the brains of suckling mice, or in vaginal secretions of inoculated guinea pigs. These results confirm the non-replicative status, as well as its immunogenicity and efficacy in mice and guinea pigs, including HSV-1 seropositive guinea pigs. In mice, HSV529 produced Th1/Th2 characteristic immune response thought to be necessary for an effective vaccine. These results further support the clinical investigation of HSV529 in human subjects as a prophylactic vaccine.

No MeSH data available.


Related in: MedlinePlus