Herpes simplex virus type 2 (HSV-2) is the cause of genital herpes. The hallmark of herpesvirus infections is the establishment of a lifelong, latent infection that can reactivate to cause one or more rounds of disease. Latent HSV-2 infection occurs primarily in neurons found in the sacral root ganglia. The clinical spectrum of HSV-2 includes primary infection, characterized by the appearance of vesicles on the vulva or the penis that soon break to leave shallow, painful ulcerating lesions. The ulcers heal in 2–3 weeks, although healing may be very slow in immunocompromised patients. Primary infection is then followed by recurrent episodes of clinical disease (4–5 per year). The proportion of symptomatic infections is estimated to be between 13% and 37%, and probably higher in HIV positive individuals. Subclinical infection may be associated with infectious viral shedding. The virus is transmitted in genital secretions. Transmission of HSV-2 to newborns at the time of delivery may lead to devastating systemic infection with encephalitis. The risk of neonatal herpes fortunately is low among HIV-negative pregnant women living in industrialized countries (less than 3%), but few data are available on neonatal herpes in developing countries.
Genital herpes is one of the most common ulcerating diseases of the genital mucosa. It is estimated that in the USA, for example, from 40 to 60 million people are HSV-2-infected, with an incidence of 1–2 million infections and 600 000–800 000 clinical cases per year. Prevalence in the 30–40 year-old population is about 30%. Overall prevalence is higher in women compared with men, especially among the young. The same independent factors of HSV-2 infection were identified in both genders: older age, higher lifetime number of sexual partners, positive HIV serology and positive syphilis serology. Prevalence in developing countries can vary from 2–74% according to the country, age, gender, or urban versus rural areas. Rates up to 40% have been reported among women 15–19 years of age in rural Costa Rica, Kenya (Kisumu) and Mexico (Mexico-City). A study conducted on truck drivers in Bangladesh showed a high prevalence of HSV-2 (25.8%), compared to syphilis (5.7%), gonorrhoea (2.1%), and chlamydia (0.8%).
There is now ample evidence that HSV-2 infection is a major cofactor of HIV infection. In developed countries, where acquisition of HSV-1 in childhood has decreased, HSV-2 seroprevalence has increased, suggesting a possible protective effect of HSV-1 against HSV-2 acquisition. Although HSV-1 does not actually seem to modify the risk of HSV-2 acquisition, it appears to increase the proportion of asymptomatic seroconverters.
VirologyHSV-2, together with HSV-1 and the varicella-zoster virus (chickenpox), belongs to the subfamily Alphaherpesvirinae in the family Herpesviridae. These are large, complex enveloped viruses with an outer lipid envelope studded with at least 10 viral glycoproteins, an intermediate tegument layer comprising at least 15 viral proteins, and an icosahedral nucleocapsid containing the double-stranded DNA genome. The genome is organized into a 126-kb long and a 26-kb short region of double-stranded DNA bracketed by inverted repeat sequences that readily allow isomerization or recombination of the two regions. The genome comprises some 84 open reading frames. These have been divided into immediate-early genes, whose transcription depends on a virally-encoded activating protein, VP16, and which encode the viral α proteins; the early genes, which are turned on by the α proteins and whose products (β proteins) are involved in DNA replication; and the late genes, the products of which (γ proteins) are virion structural proteins and proteins needed for virus particle assembly and egress. Some of the viral envelope glycoproteins (gD) are antigenically related to those of HSV-1, whereas most are type-specific (particularly gG1 and gG2). Numerous viral gene products, which are dispensable for virus growth in vitro, can be considered as virulence genes that are involved in preventing apoptosis in the infected host cell, blocking the induction of interferons, or downregulating the presentation of viral antigens in the context of class I histocompatibility antigens (HLAs).
When the latent state is established in the neural ganglia, transcription is severely restricted such that a single transcript is produced from the latency-associated transcript (LAT) promoter, and only a few viral proteins are made. At intervals, changes in neuronal physiology induced by trauma, hormones, stress or immune suppression, render the neurones permissive to virus replication, resulting in full transcription of the genome and a burst of progeny virions. 5.3.3. Vaccines The prospect for developing a vaccine against HSV-2 that could provide sterilizing immunity is thought to be unrealistic. The goals of the vaccines under development are rather to prevent the establishment of latent infection by blocking access of the virus to sensory ganglia, to reduce the severity of the symptoms, and/or to reduce the frequency of recurrences. The correlates of protective immunity against HSV-2 are not entirely understood. Passive maternal antibody seems important in preventing infection of the newborn and CD4+ Th1 T-cells appear to be crucial to the immune response. IFN-γ secretion and CD8+ CTL may also play a major role, particularly in the prevention of recurrences.
HSV-2 subunit vaccines were developed based on the use of viral envelope glycoproteins.
- A two-component gB2 and gD2 recombinant glycoproteins subunit vaccine formulated in MF59 adjuvant was developed by Chiron. The 2-component vaccine induced high antibody titres and showed 26% efficacy in women for a period of six months but protection did not persist and male volunteers were not protected.
- GSK developed a single component gD2 vaccine formulated in AS04 adjuvant (alum + monophosphoryl lipid A). The gD2 vaccine induced good Th1 immunity in mice, including high IFN-γ secretion, and provided good protection against vaginal HSV-2 challenge in female guinea pigs. The vaccine was tested in two large, double-blind, controlled Phase III trials on volunteers with a partner with genital herpes disease. In the first study, 847 subjects were selected as seronegative for both HSV-1 and HSV-2, whereas in the second study the 2491 selected subjects were selected only on the basis of HSV-2 seronegativity. The vaccine was 73% efficacious against genital herpes disease in doubly seronegative women. Trends towards protection against infection were also observed, but the figures were not statistically significant (less than 48% efficacy). Most unexpectedly, however, the vaccine was not effective in women previously seropositive for HSV-1 and in men, regardless of their HSV seropositivity status. This suggests that HSV-1 immunity is protective against HSV-2, but no satisfactory explanation is available of why subunit vaccines seem to provide only gender-specific protection. Further Phase III efficacy trials of the gD2 vaccine (Herpevac) are in progress in collaboration with the NIH, involving about 7500 persons from 18 to 30 years of age, double HSV-1/HSV-2 seronegative women. A vaccine that protects women could be expected to decrease the rate of neonatal HSV infection and have an impact on the epidemic spread of genital herpes. Lack of efficacy of vaccines in HSV-1 infected individuals would however render the vaccine of little use in developing countries, where HSV-1 infection is ubiquitous.
- A novel, live attenuated HSV-2 candidate vaccine has been developed by Xenova/GSK using a replication-impaired virus mutant that lack the gene of the essential glycoprotein gH (ICP8 gene mutation) as a disabled infectious single cycle (DISC) virus vaccine. The vaccine was tested in Phase II trials in the USA as a therapeutic vaccine in HSV-2 seropositive symptomatic patients. It was well tolerated and induced neutralizing antibodies and CTL in 83% of the vaccinees, but no difference in time to recurrence and no difference in virus shedding were observed as compared with controls. The development of the DISC vaccine has been refocused towards its use as a prophylactic vaccine.
- Another live, replication-impaired vaccine is currently under development by Avant Immunotherapeutics. Other viral mutants that are defective for replication and impaired for establishment of latency, such as mutant dl5–29, are at a preclinical stage of development.
- A live attenuated vaccine based on a replication-competent ICP10 mutant of HSV-2 developed by AuRix is in Phase II clinical study.
DNA vaccine formulations have shown incomplete efficacy in animal models. Similarly, whole inactivated virus vaccines did not show efficacy and their development has been stopped.
