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.
Highlights
Genital herpes is an important global health problem usually caused by a sexually transmitted infection with herpes simplex virus type 2 (HSV-2), infection by type 1 (HSV-1) is becoming increasingly common [1]
The HSV529 vaccine candidate is being developed for delivery by the i.m. route, which has been effective in mice [11]
We investigated the seroneutralizing immunogenicity of HSV529 (104−106 CCID50) delivered by both routes in guinea pigs (Fig. 1)
Summary
Genital herpes is an important global health problem usually caused by a sexually transmitted infection with herpes simplex virus type 2 (HSV-2), infection by type 1 (HSV-1) is becoming increasingly common [1]. Over 536 million people were estimated to be living with HSV-2 infection in 2003, with over 23 million new infections [2]. HSV-2 infection is a lifelong disease because the latent virus persists in neural ganglia. It frequently manifests as episodic outbreaks of painful genital lesions caused by viral reactivation, which is when individuals are most infectious. Pregnant women with an active HSV-2 infection can transmit the virus during delivery to their neonate which can result in severe neurological disease or neonatal death. Seroprevalence is up to twice as high in women as in men and 2003 regional estimates for HSV-2 infection in women were 17.9% in North America and 13.7% in Western Europe, with highs of 61.8% in East Asia and 78.2% in Sub-Saharan Africa [2]
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