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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 does not propagate in the brains of 4−6-day-old suckling mice.Four- to 6-day-old sucking mice received an intracranial injection of vaccine buffer (gray squares), HSV529 (gray triangles, 5 x 105 CCID50), or wild-type (wt) HSV-2 186 syn+-1 (black circles, 10 CCID50). Brains were collected on p.i. days 0 (4 hours p.i.), 2, 4, 6, and 14, and from animals that died during the experiment. The titer of each animal is represented by an individual symbol and the mean titer is represented by a horizontal bar. Virus titers were determined on AV529-19 cells.
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pone.0121518.g006: HSV529 does not propagate in the brains of 4−6-day-old suckling mice.Four- to 6-day-old sucking mice received an intracranial injection of vaccine buffer (gray squares), HSV529 (gray triangles, 5 x 105 CCID50), or wild-type (wt) HSV-2 186 syn+-1 (black circles, 10 CCID50). Brains were collected on p.i. days 0 (4 hours p.i.), 2, 4, 6, and 14, and from animals that died during the experiment. The titer of each animal is represented by an individual symbol and the mean titer is represented by a horizontal bar. Virus titers were determined on AV529-19 cells.

Mentions: To verify that the HSV529 vaccine candidate is unable to replicate or produce progeny virus and cause disease in vivo, we evaluated it in three sensitive models of HSV-2 infection and pathogenicity. Four- to six-day-old suckling mice received an intracranial inoculation of buffer, HSV529 (5 x 105 CCID50), or HSV-2 186 syn+-1 (10 CCID50) (Fig. 6). All mice inoculated with wild-type HSV-2 died by p.i. day 3 and had high intracranial titers (> 6 log10 CCID50/brain) of virus as soon as D2 after inoculation. In contrast, none of the mice inoculated with HSV529 developed disease or died during the 14 days after injection, despite having received a dose of virus 50,000 times higher than the dose of wild-type HSV-2. No virus was detected (titers under the limit of titration of 3.4 log10 CCID50/brain) in the brains of these animals collected between p.i. days 0 and 6 (n = 4 per time point) or on p.i. day 14 (n = 1). Residual HSV529 genomic DNA was detected by qPCR in the brains of animals collected 4 hours after injection on day 0 (not shown).


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 does not propagate in the brains of 4−6-day-old suckling mice.Four- to 6-day-old sucking mice received an intracranial injection of vaccine buffer (gray squares), HSV529 (gray triangles, 5 x 105 CCID50), or wild-type (wt) HSV-2 186 syn+-1 (black circles, 10 CCID50). Brains were collected on p.i. days 0 (4 hours p.i.), 2, 4, 6, and 14, and from animals that died during the experiment. The titer of each animal is represented by an individual symbol and the mean titer is represented by a horizontal bar. Virus titers were determined on AV529-19 cells.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121518.g006: HSV529 does not propagate in the brains of 4−6-day-old suckling mice.Four- to 6-day-old sucking mice received an intracranial injection of vaccine buffer (gray squares), HSV529 (gray triangles, 5 x 105 CCID50), or wild-type (wt) HSV-2 186 syn+-1 (black circles, 10 CCID50). Brains were collected on p.i. days 0 (4 hours p.i.), 2, 4, 6, and 14, and from animals that died during the experiment. The titer of each animal is represented by an individual symbol and the mean titer is represented by a horizontal bar. Virus titers were determined on AV529-19 cells.
Mentions: To verify that the HSV529 vaccine candidate is unable to replicate or produce progeny virus and cause disease in vivo, we evaluated it in three sensitive models of HSV-2 infection and pathogenicity. Four- to six-day-old suckling mice received an intracranial inoculation of buffer, HSV529 (5 x 105 CCID50), or HSV-2 186 syn+-1 (10 CCID50) (Fig. 6). All mice inoculated with wild-type HSV-2 died by p.i. day 3 and had high intracranial titers (> 6 log10 CCID50/brain) of virus as soon as D2 after inoculation. In contrast, none of the mice inoculated with HSV529 developed disease or died during the 14 days after injection, despite having received a dose of virus 50,000 times higher than the dose of wild-type HSV-2. No virus was detected (titers under the limit of titration of 3.4 log10 CCID50/brain) in the brains of these animals collected between p.i. days 0 and 6 (n = 4 per time point) or on p.i. day 14 (n = 1). Residual HSV529 genomic DNA was detected by qPCR in the brains of animals collected 4 hours after injection on day 0 (not shown).

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