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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

Guinea pigs immunized with HSV529 produce antibodies that neutralize HSV-2 infection in vitro.Guinea pigs were immunized with HSV529 (104 CCID50, 105 CCID50, or 106 CCID50) by the intramuscular (IM; n = 5 each) or subcutaneous (SC; n = 5 each) route or with PBS (n = 3) by the intramuscular route on days 0 (D0) and 21 (D21). Sera were collected from all animals on days 21 and 29 (D29) and measured for HSV-2 neutralizing activity by preincubating dilutions of heat-inactivated sera with 100 CCID50 of live HSV-2 virus for 1 hour prior to infection of Vero cell cultures. Infected cells were detected with anti-HSV glycoprotein D antibodies. The serum dilution that neutralized 50% of the virus (SN50) was determined by plotting the neutralization activity versus the serum dilutions. Error bars represent standard error of the mean.
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pone.0121518.g001: Guinea pigs immunized with HSV529 produce antibodies that neutralize HSV-2 infection in vitro.Guinea pigs were immunized with HSV529 (104 CCID50, 105 CCID50, or 106 CCID50) by the intramuscular (IM; n = 5 each) or subcutaneous (SC; n = 5 each) route or with PBS (n = 3) by the intramuscular route on days 0 (D0) and 21 (D21). Sera were collected from all animals on days 21 and 29 (D29) and measured for HSV-2 neutralizing activity by preincubating dilutions of heat-inactivated sera with 100 CCID50 of live HSV-2 virus for 1 hour prior to infection of Vero cell cultures. Infected cells were detected with anti-HSV glycoprotein D antibodies. The serum dilution that neutralized 50% of the virus (SN50) was determined by plotting the neutralization activity versus the serum dilutions. Error bars represent standard error of the mean.

Mentions: HSV529 is capable of generating strong cellular and humoral immune responses to HSV-2 virus. In all previous studies of dl5-29 immunogenicity in guinea pigs, immunization was performed by the subcutaneous (s.c.) route [8, 12, 13]. However, the HSV529 vaccine candidate is being developed for delivery by the i.m. route, which has been effective in mice [11]. We therefore investigated the seroneutralizing immunogenicity of HSV529 (104−106 CCID50) delivered by both routes in guinea pigs (Fig. 1). Although the 104 CCID50 dose did not induce a seroneutralizing antibody response, 21 days after being immunized once with 105 or 106 CCID50 by either delivery route, guinea pigs produced similar dose-dependent titers of antibodies capable of neutralizing wild-type HSV-2 virus (G) in vitro. Eight days after administration of a second dose, seroneutralization titers increased further but the magnitude of these increases varied according to dose and route of administration. Globally, after the second immunization, seroneutralization responses were significantly greater with the i.m. than with the s.c. route by an overall mean of 4-fold (p = 0.02, analysis of covariance).


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)

Guinea pigs immunized with HSV529 produce antibodies that neutralize HSV-2 infection in vitro.Guinea pigs were immunized with HSV529 (104 CCID50, 105 CCID50, or 106 CCID50) by the intramuscular (IM; n = 5 each) or subcutaneous (SC; n = 5 each) route or with PBS (n = 3) by the intramuscular route on days 0 (D0) and 21 (D21). Sera were collected from all animals on days 21 and 29 (D29) and measured for HSV-2 neutralizing activity by preincubating dilutions of heat-inactivated sera with 100 CCID50 of live HSV-2 virus for 1 hour prior to infection of Vero cell cultures. Infected cells were detected with anti-HSV glycoprotein D antibodies. The serum dilution that neutralized 50% of the virus (SN50) was determined by plotting the neutralization activity versus the serum dilutions. 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.g001: Guinea pigs immunized with HSV529 produce antibodies that neutralize HSV-2 infection in vitro.Guinea pigs were immunized with HSV529 (104 CCID50, 105 CCID50, or 106 CCID50) by the intramuscular (IM; n = 5 each) or subcutaneous (SC; n = 5 each) route or with PBS (n = 3) by the intramuscular route on days 0 (D0) and 21 (D21). Sera were collected from all animals on days 21 and 29 (D29) and measured for HSV-2 neutralizing activity by preincubating dilutions of heat-inactivated sera with 100 CCID50 of live HSV-2 virus for 1 hour prior to infection of Vero cell cultures. Infected cells were detected with anti-HSV glycoprotein D antibodies. The serum dilution that neutralized 50% of the virus (SN50) was determined by plotting the neutralization activity versus the serum dilutions. Error bars represent standard error of the mean.
Mentions: HSV529 is capable of generating strong cellular and humoral immune responses to HSV-2 virus. In all previous studies of dl5-29 immunogenicity in guinea pigs, immunization was performed by the subcutaneous (s.c.) route [8, 12, 13]. However, the HSV529 vaccine candidate is being developed for delivery by the i.m. route, which has been effective in mice [11]. We therefore investigated the seroneutralizing immunogenicity of HSV529 (104−106 CCID50) delivered by both routes in guinea pigs (Fig. 1). Although the 104 CCID50 dose did not induce a seroneutralizing antibody response, 21 days after being immunized once with 105 or 106 CCID50 by either delivery route, guinea pigs produced similar dose-dependent titers of antibodies capable of neutralizing wild-type HSV-2 virus (G) in vitro. Eight days after administration of a second dose, seroneutralization titers increased further but the magnitude of these increases varied according to dose and route of administration. Globally, after the second immunization, seroneutralization responses were significantly greater with the i.m. than with the s.c. route by an overall mean of 4-fold (p = 0.02, analysis of covariance).

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