Limits...
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 guinea pigs from the effects of HSV-2 vaginal challenge.Guinea pigs were immunized with HSV529 (106 CCID50; n = 30) or PBS (n = 25) by the i.m. route on days 0 and 21. On day 48, 15 animals in each group were challenged with an intravaginal inoculation of HSV-2 (G strain; 105 CCID50). The remaining animals received a mock challenge of PBS. (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

License
getmorefigures.php?uid=PMC4383384&req=5

pone.0121518.g004: HSV529 immunization protects guinea pigs from the effects of HSV-2 vaginal challenge.Guinea pigs were immunized with HSV529 (106 CCID50; n = 30) or PBS (n = 25) by the i.m. route on days 0 and 21. On day 48, 15 animals in each group were challenged with an intravaginal inoculation of HSV-2 (G strain; 105 CCID50). The remaining animals received a mock challenge of PBS. (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: Vaginal HSV-2 infection in guinea pigs has many of the same features of the human disease including an acute phase, viral shedding, viral latency, and recurrent lesions. In the guinea pig model the HSV-2 challenge dose is intended to infect 100% of the animals but is not necessarily lethal, although some animals may die from the infection or may need to be euthanized due to severe disease. Guinea pigs immunized with HSV529 (106 CCID50, i.m.) 48 and 27 days before HSV-2 vaginal challenge (G strain, 105 CCID50) were protected from subsequent weight loss (n = 14; Fig. 4A) and from developing vaginal lesions (n = 14; Fig. 4B). Control animals (n = 15) attained a peak mean acute lesion score of 3.7 ± 1.4 at p.i. day 8, and 7 of the animals died or were euthanized between p.i. days 8 and 28. In contrast, animals immunized with HSV529 had a maximum mean acute lesion score of only 0.5 ± 0.7 on p.i. day 4 and none of the animals died (Fig. 4C). Overall, lesion scores during all the acute phase were significantly lower in the HSV529-vaccinated group than in the control group (p = 0.0003, analysis of variance). Whereas all 15 control animals shed vaginal virus and had a geometric mean titer of 5.1 ± 0.9 log10 CCID50 on p.i. day 2, only 5 of the 14 immunized animals were shedding virus on p.i. day 2 with a geometric mean titer of 2.5 ± 0.5 log10 CCID50 (Fig. 4D). Overall, viral titers between p.i. days 2 and 4 were significantly lower in the immunized group than in the control group (all p-values < 0.038, Wilcoxon test).


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 guinea pigs from the effects of HSV-2 vaginal challenge.Guinea pigs were immunized with HSV529 (106 CCID50; n = 30) or PBS (n = 25) by the i.m. route on days 0 and 21. On day 48, 15 animals in each group were challenged with an intravaginal inoculation of HSV-2 (G strain; 105 CCID50). The remaining animals received a mock challenge of PBS. (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

License
Show All Figures
getmorefigures.php?uid=PMC4383384&req=5

pone.0121518.g004: HSV529 immunization protects guinea pigs from the effects of HSV-2 vaginal challenge.Guinea pigs were immunized with HSV529 (106 CCID50; n = 30) or PBS (n = 25) by the i.m. route on days 0 and 21. On day 48, 15 animals in each group were challenged with an intravaginal inoculation of HSV-2 (G strain; 105 CCID50). The remaining animals received a mock challenge of PBS. (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: Vaginal HSV-2 infection in guinea pigs has many of the same features of the human disease including an acute phase, viral shedding, viral latency, and recurrent lesions. In the guinea pig model the HSV-2 challenge dose is intended to infect 100% of the animals but is not necessarily lethal, although some animals may die from the infection or may need to be euthanized due to severe disease. Guinea pigs immunized with HSV529 (106 CCID50, i.m.) 48 and 27 days before HSV-2 vaginal challenge (G strain, 105 CCID50) were protected from subsequent weight loss (n = 14; Fig. 4A) and from developing vaginal lesions (n = 14; Fig. 4B). Control animals (n = 15) attained a peak mean acute lesion score of 3.7 ± 1.4 at p.i. day 8, and 7 of the animals died or were euthanized between p.i. days 8 and 28. In contrast, animals immunized with HSV529 had a maximum mean acute lesion score of only 0.5 ± 0.7 on p.i. day 4 and none of the animals died (Fig. 4C). Overall, lesion scores during all the acute phase were significantly lower in the HSV529-vaccinated group than in the control group (p = 0.0003, analysis of variance). Whereas all 15 control animals shed vaginal virus and had a geometric mean titer of 5.1 ± 0.9 log10 CCID50 on p.i. day 2, only 5 of the 14 immunized animals were shedding virus on p.i. day 2 with a geometric mean titer of 2.5 ± 0.5 log10 CCID50 (Fig. 4D). Overall, viral titers between p.i. days 2 and 4 were significantly lower in the immunized group than in the control group (all p-values < 0.038, Wilcoxon test).

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