Impact of immunization with glycoprotein D2/AS04 on herpes simplex virus type 2 shedding into the genital tract in guinea pigs that become infected

In recent clinical trials, a vaccine that contained herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) and the adjuvant AS04 afforded HSV-seronegative women significant protection against HSV-2 genital disease and limited protection against infection. Similarly, in guinea pigs, immunization with the vaccine provided significant protection against genital HSV-2 disease but did not prevent mucosal infection. We explored the impact of immunization on the magnitude of latent virus infection and on the frequency and magnitude of virus reactivation as measured by both recurrent disease and viral shedding into the genital tract. Guinea pigs immunized with gD2/AS04 were shown by quantitative polymerase chain reaction (qPCR) analysis to have significantly less latent viral DNA in the ganglia than did naive control guinea pigs and to have a reduced incidence and frequency of recurrent disease. By contrast, all immunized guinea pigs shed virus into the genital tract with a frequency comparable to that seen in control guinea pigs. However, the amount of virus shed was significantly reduced, as measured by qPCR. These data suggest that immunization could affect transmission by altering viral shedding patterns.     

Herpes simplex virus vaccines: perspectives

PURPOSE: Despite effective antiviral therapy, infection with herpes simplex virus (HSV) is a critical public health issue, particularly genital herpes by its social and psychological burden and its contribution to the neonatal herpes and possibly to the HIV/AIDS pandemic. CURRENT KNOWLEDGE: Many prophylactic and therapeutic vaccination approaches have been explored but no effective vaccine is presently available. In fact, as members of the Herpesviridae family, both HSV-1 and 2 types have genes involved in immune evasion. FUTURE PROSPECTS: Further research is needed to define determinants of immunity in order to design more effective vaccines.     

Genital reinfection after recovery from initial genital infection with herpes simplex virus type 2 in guinea pigs

The natural history of genital reinfection with herpes simplex virus type 2 (HSV-2) three weeks to one year after initial infection was explored by using a guinea pig model. Intravaginal reinoculation with HSV-2 of animals that had recovered from initial genital infection produced by wild-type or thymidine kinase-deficient HSV-2 produced asymptomatic genital reinfection characterized by high-titered replication of HSV-2 in the vaginal vault. Reinoculation did not result in acute neural infection, as was seen during initial genital herpes, and no evidence of latent infection by the rechallenge strain could be demonstrated. The frequency of recurrences appeared to be established by the initial infection because reinfection did not alter the pattern of recurrent genital herpes. The present study suggest that asymptomatic reinfection may produce a reservoir of communicable virus and that initial infection with a less virulent mutant of HSV-2 may provide protection against subsequent reexposure to wild-type HSV-2.     

NIH Conference. Herpes simplex virus infection: biology, treatment, and prevention

Herpes simplex viruses cause common mucocutaneous infections, but many aspects of their epidemiology and transmission are incompletely defined. Although the incidence of oral herpes remains relatively unchanged, the incidence of genital herpes is increasing significantly. Definitive diagnosis of herpes remains dependent on virus isolation, but techniques involving direct examination of clinical specimens are increasingly sensitive and may simplify and speed diagnosis. With the advent of acyclovir, effective therapy and suppression of infection are feasible for immunodeficient and selected normal patients. Unanswered questions remain regarding the long-term safety of acyclovir and the potential for emergence of clinically significant drug resistance. No effective vaccines are yet available for herpes virus infections. Promising strategies for vaccine development include preparation of immunogenic proteins, engineering of specially attenuated live virus strains, and incorporation of selected herpes genes into live vaccinia virus vectors.     

Herpes simplex virus infections of women and their offspring: implications for a developed society.

Herpes simplex virus infections of humans have been known since ancient times. Contemporary society has witnessed a series of devastating manifestations of herpes simplex virus infections--namely, genital herpes simplex virus infection and neonatal herpes simplex virus infection. With the evolution of society, particularly advances in birth control and increasing promiscuity, the seroprevalence of herpes simplex virus type 2 infections has increased worldwide, however, more so in developed societies. As a consequence, individuals of child-bearing age are at risk for either reactivation of herpes simplex virus at termination of gestation or acquisition of a new primary infection at that time. The consequences of vertical transmission of herpes simplex virus from mother to child, resulting in neonatal herpes simplex virus infection, can be devastating. Current efforts, which are directed toward the treatment of neonatal herpes, have established the value of drugs such as vidarabine and acyclovir. However, the real emphasis for future programs is the prevention of herpes simplex virus infections to avoid person-to-person transmission either horizontally or vertically. The development of vaccines directed against herpes simplex virus may be of value toward this end.     

Immunization with DNA vaccines encoding glycoprotein D or glycoprotein B, alone or in combination, induces protective immunity in animal models of herpes simplex virus-2 disease.

DNA vaccines expressing herpes simplex virus type 2 (HSV-2) full-length glycoprotein D (gD), or a truncated form of HSV-2 glycoprotein B (gB) were evaluated for protective efficacy in two experimental models of HSV-2 infection. Intramuscular (i.m.) injection of mice showed that each construction induced neutralizing serum antibodies and protected the mice from lethal HSV-2 infection. Dose-titration studies showed that low doses (< or = 1 microgram) of either DNA construction induced protective immunity, and that a single immunization with the gD construction was effective. The two DNAs were then tested in a low-dosage combination in guinea pigs. Immune sera from DNA-injected animals had antibodies to both gD and gB, and virus neutralizing activity. When challenged by vaginal infection with HSV-2, the DNA-immunized animals were significantly protected from primary genital disease.     

Genital shedding of herpes simplex virus among men

Epidemiologic studies suggest that most sexual transmission of genital herpes occurs when persons shed virus but lack lesions. This study assessed 79 men (63 with a history of genital herpes simplex virus [HSV] type 2 infection, 5 with a history of genital HSV-1 infection, and 11 with HSV-2 antibodies but no history of genital herpes) and obtained daily swabs for viral culture. HSV was isolated at least once from 60 (81%) HSV-2-seropositive men. The total viral shedding rate in HSV-2-seropositive men was 5%; the subclinical shedding rate was 2.2%. Of 11 HSV-2-seropositive men without a genital herpes history, 7 recognized typical recurrences and HSV was detected in 10. The shedding rate among men with genital HSV-2 was significantly higher than among men with genital HSV-1 infection (odds ratio, 4.4; 95% confidence interval, 1.2-15.3). The frequency of viral shedding in men with genital herpes appears comparable with that in women.     

疱疹病毒治疗性疫苗研究进展

疱疹病毒感染极为普遍,可表现为原发性、潜伏性或复发性感染,几乎能在所有的动物中建立潜伏感染,且潜伏感染期间病毒保持休眠状态,宿主不表现出任何临床症状,机体在受到一些应激后,潜伏的病毒被重新激活,使机体引起复发性感染.目前预防性疫苗免疫接种仍是预防疱疹病毒感染和控制其相应疾病流行的有效手段,然而免疫接种后机体免疫系统虽能...     

The cycle of human herpes simplex virus infection: virus transport and immune control

After infection of skin or mucosa, herpes simplex virus enters the sensory nerve endings and is conveyed by retrograde axonal transport to the dorsal root ganglion, where the virus develops lifelong latency. Intermittent reactivation, which is spontaneous in humans, leads to anterograde transport of virus particles and proteins to the skin or mucosa, where the virus is shed and/or causes disease. Immune control of viral infection and replication occurs at the level of skin or mucosa during initial or recurrent infection and also within the dorsal root ganglion, where immune mechanisms control latency and reactivation. This article examines current views on the mechanisms of retrograde and anterograde transport of the virus in axons and the mechanisms of innate and adaptive immunity that control infection in the skin or mucosa and in the dorsal root ganglion--in particular, the role of interferons, myeloid and plasmacytoid dendritic cells, CD4(+) and CD8(+) T cells, and interferon- gamma and other cytokines, including their significance in the development of vaccines for genital herpes.     

Genital herpes in guinea pigs: pathogenesis of the primary infection and description of recurrent disease

Guinea pigs inoculated intravaginally with herpes simplex virus type 2 (HSV-2) developed a self-limiting infection characterized by vesiculo-ulcerative lesions on the external genital skin, urinary retention, and hindlimb paralysis. Infection rarely resulted in death. Virologic, histologic, and immunoperoxidase data suggested the following scheme for viral pathogenesis: initial replication in the introitus, vagina, and bladder; spread via sensory nerves to the lumbosacral dorsal root ganglia and spinal cord, and transmission via peripheral nerves to the external genital skin to produce the characteristic lesions. After recovery from primary infection, animals developed recurrent vesicular lesions, shed virus from genital sites in the absence of lesions, and harbored latent HSV-2 in dorsal root ganglia. Genital infection in the guinea pig shares many features with genital herpes in humans and provides a model to explore mechanisms of latency and reactivation and to evaluate several methods for control of recurrent disease.     

Herpes simplex virus (HSV) type 2 glycoprotein D subunit vaccines and protection against genital HSV-1 or HSV-2 disease in guinea pigs

In two recent clinical trials, a vaccine containing herpes simplex virus (HSV) type 2 glycoprotein D (gD2) and a novel adjuvant AS04 comprising alum (Al) and 3-deactylated monophosphoryl lipid A (3-dMPL) afforded HSV-seronegative women significant protection against HSV-2 genital disease (vaccine efficacy, 73% in study 1 and 74% in study 2) and limited protection against infection (46% in study 1 and 39% in study 2). In the present report, studies in the guinea pig model investigated the protection afforded by gD2/AS04 against HSV-1 and HSV-2 genital herpes and investigated whether immunization could prevent or reduce recurrent disease in guinea pigs that developed mucosal infection. Immunization with gD2/AS04 conveyed nearly complete protection against primary disease with either virus but did not prevent mucosal infection. Guinea pigs immunized with gD2/AS04 were significantly better protected against recurrent disease than were guinea pigs immunized with a gD2/Al vaccine, which suggests that inclusion of 3-dMPL improved protection against latent infection.     

Efficacy of SIV/deltaB670 glycoprotein-enriched and glycoprotein-depleted subunit vaccines in protecting against infection and disease in rhesus monkeys

Immunization with an inactivated whole-virus vaccine is highly effective in preventing lentivirus infection. The viral protein(s) essential to the induction of protective responses, however, have not been identified. To define the role of virion components in the induction of protective immunity, we evaluated the efficacy of glycoprotein-enriched and glycoprotein-depleted simian immunodeficiency virus (SIV) subunit vaccines prepared by lentil-lectin affinity chromatography of gradient-purified virions using the immunization and challenge regimen previously found successful with an inactivated whole-virus vaccine. Infection was determined by successful recovery of virus, the induction of SIV-specific antibody responses, and infection of naive recipients by inoculation with lymph-node-derived lymphocytes from the vaccinates. Immunization with the glycoprotein-enriched preparation prevented infection in two out of four monkeys, whereas the glycoprotein-depleted vaccine failed to prevent infection in all four vaccinates tested. However, the glycoprotein-depleted vaccine appeared to moderate the progression of SIV-induced disease compared with non-immunized infected control monkeys inoculated with the same challenge dose. These data suggest that subunit vaccines containing sufficient quantities of viral glycoproteins can protect against SIV infection, whereas subunit vaccines composed predominantly of viral core proteins cannot. The development of effective vaccines against HIV infection should include studies on the optimum presentation of the viral envelope glycoproteins to produce long-term broadly protective immune responses.     

Inability of enzyme immunoassays to discriminate between infections with herpes simplex virus types 1 and 2.

OBJECTIVE: To determine the accuracy of three commercial enzyme immunoassays in detecting and subtyping antibodies to herpes simplex virus type 1 or 2. DESIGN: Cross-sectional. SETTING: Referral medical center. PATIENTS: Ninety patients with culture-positive lesions caused by infection with herpes simplex virus type 1 or 2. The results of Western blot and glycoprotein G immunodot enzyme assays showed that an additional 53 patients had subclinical herpes simplex virus 2 infection, that another 20 patients had subclinical herpes simplex virus type 1 infection, and that 23 patients were seronegative. MEASUREMENTS: Three commercial enzyme immunoassays were used to determine herpes simplex virus antibody subtypes. MAIN RESULTS: All three commercial assays performed poorly in all patient groups (except in patients who were seronegative for herpes simplex virus). Among the 40 patients with a first episode of genital herpes, seroconversion to the appropriate viral type was shown by the three assays in only 33%, 55%, and 75% of cases. Among patients with recurrent genital herpes, the three commercial assays identified more than 90% of patients with only herpes simplex virus type 2 antibodies but failed to identify herpes simplex virus type 2 infections in 58% to 76% of patients with antibodies to both virus subtypes. The three assays correctly identified only 55%, 75%, and 85% of the 53 "silent carriers" of herpes simplex virus type 2. Overall, the three enzyme immunoassays detected herpes simplex virus type 2 antibodies in 60%, 62%, and 93% of patients with subtype 2 infections and falsely detected type 2 antibodies in 8%, 27%, and 49% of patients with type 1 infections. CONCLUSION: Currently licensed enzyme immunoassays give inaccurate or misleading results about the correct herpes simplex virus infecting subtype.     

Consequences of herpes simplex virus in pregnancy and their prevention

PURPOSE OF REVIEW: New findings reveal that first-time infection of the mother is the most important factor for the transmission of genital herpes from mother to fetus/newborn. Interventions based on these findings will lead to new management of the pregnant patient with genital herpes prior to pregnancy and measures to prevent the acquisition of herpes during pregnancy. RECENT FINDINGS: Risk factors for the transmission of herpes from mother to newborn have been detailed. It is the pregnant woman who acquires genital herpes as a primary infection in the latter half of pregnancy, rather than prior to pregnancy, who is at greatest risk of transmitting this virus to her newborn. This is true for both herpes simplex virus type-1 and herpes simplex virus type-2. Additional risk factors for neonatal herpes simplex virus infection include the use of a fetal-scalp electrode and maternal age of less than 21 years. SUMMARY: Risk factors for the transmission of herpes from mother to newborn are detailed. Antiviral suppressive therapy initiated in the late third trimester has been shown to decrease viral shedding and the need for cesarean section.     

Therapeutic options for herpes simplex infections

Herpes simplex viruses are responsible for a number of disease states in infected individuals. Capable of establishing latent infection, herpes simplex can reactivate, causing pain, discomfort, and psychosocial consequences. Because no cure is available, treatment modalities for herpes simplex infection are required, from both personal and public health standpoints. To date, therapy has centered around the use of antiviral drugs to control infection and suppress recurrences. To expand the scope of available treatments, efforts have focused on the development of vaccines against herpes simplex virus and new agents such as immune response modifiers. Recent data suggest that these new agents are promising in their therapeutic potential.     

Efficacy of recombinant glycoprotein D subunit vaccines on the development of primary, recurrent, and latent genital infections with herpes simplex virus type 2 in guinea pigs

Vaccination of guinea pigs with recombinant glycoprotein D (subunit vaccine) from either herpes simplex virus type 1 or type 2 (HSV-1, HSV-2), before intravaginal inoculation with HSV-2, markedly altered viral replication in the vaginal tract and reduced, or completely prevented, the development and spread of external genital lesions. Vaccination with glycoprotein D from HSV-2 prevented the establishment of latent HSV-2 infections in dorsal root ganglia and reduced the frequency of recurrent episodes. For all parameters of efficacy that we tested, vaccination with glycoprotein D from HSV-2 was more effective than was vaccination with protein derived from HSV-1. Vaccination after primary infection had no effect on the frequency or duration of recurrent HSV-2 infections.     

HSV-2 Vaccine: Current Status and Insight into Factors for Developing an Efficient Vaccine

Herpes simplex virus type 2 (HSV-2), a globally sexually transmitted virus, and also one of the main causes of genital ulcer diseases, increases susceptibility to HIV-1. Effective vaccines to prevent HSV-2 infection are not yet available, but are currently being developed. To facilitate this process, the latest progress in development of these vaccines is reviewed in this paper. A summary of the most promising HSV-2 vaccines tested in animals in the last five years is presented, including the main factors, and new ideas for developing an effective vaccine from animal experiments and human clinical trials. Experimental results indicate that future HSV-2 vaccines may depend on a strategy that targets mucosal immunity. Furthermore, estradiol, which increases the effectiveness of vaccines, may be considered as an adjuvant. Therefore, this review is expected to provide possible strategies for development of future HSV-2 vaccines.