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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 mice from the effects of lethal HSV-2 vaginal challenge.BALB/c mice were immunized with HSV529 (106 CCID50) or PBS by the i.m. route on days 0 and 21. On day 48, mice received medroxyprogesterone (2 mg, s.c.) to prevent reproductive cycling. The next day, mice were challenged with an intravaginal inoculation of HSV-2 (strain G; 105 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. *Dead or euthanized animal. Error bars represent the standard error of the mean.
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pone.0121518.g003: HSV529 immunization protects mice from the effects of lethal HSV-2 vaginal challenge.BALB/c mice were immunized with HSV529 (106 CCID50) or PBS by the i.m. route on days 0 and 21. On day 48, mice received medroxyprogesterone (2 mg, s.c.) to prevent reproductive cycling. The next day, mice were challenged with an intravaginal inoculation of HSV-2 (strain G; 105 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. *Dead or euthanized animal. Error bars represent the standard error of the mean.

Mentions: Vaginal HSV-2 infection in mice results in acute disease and a high rate of lethality [13]. Infected animals also lose body weight and shed virus. Following vaginal challenge with a dose of HSV-2 (G strain) equivalent to 50 LD50 (105 CCID50), non-immunized control animals lost significant mean body weight between p.i. days 6 and 27 (p < 0.05, analysis of variance) with a maximum loss of up to 15% on p.i. day 12 (Fig. 3A). They also developed maximum mean lesion scores of nearly 3 between p.i. days 11 and 13 (Fig. 3B), and 90% of them (n = 10) died or were euthanized between p.i. days 11 and 16 (Fig. 3C). In contrast, two immunizations with HSV529 (106 CCID50, i.m.) before HSV-2 vaginal challenge completely protected mice from subsequent weight loss (n = 10) and vaginal lesions (n = 10), and protected 90% of them from lethality (n = 10). The mean titer of shed virus on p.i. day 2 was 4.0 ± 0.7 log10 CCID50/mL in control animals, of which 19 out of 20 (95%) shed virus above the LLOD (Fig. 3D). In HSV529-immunized animals, the mean titer of shed virus remained below the positive threshold value of 2.5 log10 CCID50/mL through p.i. day 10 and was significantly lower than in the control group (p < 0.001, variance analysis). Fewer animals in this group (2 out of 20; 10%) shed virus above the LLOD and only on p.i. day 3.


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 mice from the effects of lethal HSV-2 vaginal challenge.BALB/c mice were immunized with HSV529 (106 CCID50) or PBS by the i.m. route on days 0 and 21. On day 48, mice received medroxyprogesterone (2 mg, s.c.) to prevent reproductive cycling. The next day, mice were challenged with an intravaginal inoculation of HSV-2 (strain G; 105 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. *Dead or euthanized animal. Error bars represent the standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121518.g003: HSV529 immunization protects mice from the effects of lethal HSV-2 vaginal challenge.BALB/c mice were immunized with HSV529 (106 CCID50) or PBS by the i.m. route on days 0 and 21. On day 48, mice received medroxyprogesterone (2 mg, s.c.) to prevent reproductive cycling. The next day, mice were challenged with an intravaginal inoculation of HSV-2 (strain G; 105 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. *Dead or euthanized animal. Error bars represent the standard error of the mean.
Mentions: Vaginal HSV-2 infection in mice results in acute disease and a high rate of lethality [13]. Infected animals also lose body weight and shed virus. Following vaginal challenge with a dose of HSV-2 (G strain) equivalent to 50 LD50 (105 CCID50), non-immunized control animals lost significant mean body weight between p.i. days 6 and 27 (p < 0.05, analysis of variance) with a maximum loss of up to 15% on p.i. day 12 (Fig. 3A). They also developed maximum mean lesion scores of nearly 3 between p.i. days 11 and 13 (Fig. 3B), and 90% of them (n = 10) died or were euthanized between p.i. days 11 and 16 (Fig. 3C). In contrast, two immunizations with HSV529 (106 CCID50, i.m.) before HSV-2 vaginal challenge completely protected mice from subsequent weight loss (n = 10) and vaginal lesions (n = 10), and protected 90% of them from lethality (n = 10). The mean titer of shed virus on p.i. day 2 was 4.0 ± 0.7 log10 CCID50/mL in control animals, of which 19 out of 20 (95%) shed virus above the LLOD (Fig. 3D). In HSV529-immunized animals, the mean titer of shed virus remained below the positive threshold value of 2.5 log10 CCID50/mL through p.i. day 10 and was significantly lower than in the control group (p < 0.001, variance analysis). Fewer animals in this group (2 out of 20; 10%) shed virus above the LLOD and only on p.i. day 3.

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