Added: Anne Zambrana - Date: 07.01.2022 19:10 - Views: 25634 - Clicks: 8766
Review Series Free access Phone: Find articles by Johnston, C. Find articles by Koelle, D. Find articles by Wald, A. Published December 1, - More info. Herpes simplex virus type 2 HSV-2 is one of the most prevalent sexually transmitted infections worldwide. In addition to recurrent genital ulcers, HSV-2 causes neonatal herpes, and it is associated with a 3-fold increased risk for HIV acquisition.
Although many HSV-2 vaccines have been studied in animal models, few have reached clinical trials, and those that have been tested in humans were not Seeking a woman hsv2 24 35 effective. Here, we review HSV-2 pathogenesis, with a focus on novel understanding of mucosal immunobiology of HSV-2, and vaccine efforts to date, in an attempt to stimulate thinking about future directions for development of effective prophylactic and therapeutic HSV-2 vaccines. Herpes simplex virus type 2 HSV-2 is a sexually transmitted pathogen that infects more than million people worldwide and causes an estimated 23 million new infections each year 1.
Although HSV-2 is the leading cause of genital ulcer disease worldwide 56most people are not aware of the infection 7and may transmit the virus during periods of subclinical shedding 89. For instance, As HSV-1 and HSV-2 have similar pathogenesis and host interactions, many of the concepts for development of an effective vaccine are likely relevant to both viruses. In addition, infection with HSV-2 provides partial protection against HSV-1 12although the reverse does not appear to be true 13and thus there is potential for generation of cross-reactive immunity The possibility that an HSV-2 vaccine may provide protection against HSV-1 increases its potential value and may shift the optimal time for immunization to early childhood, instead of the more problematic adolescent vaccination series Transmission of HSV from mother to infant during birth is the most serious complication of genital herpes, and women who acquire HSV during pregnancy are at the highest risk of transmitting the infection Neonatal herpes often in long-term neurologic sequelae or mortality The estimated incidence of neonatal herpes varies widely, from 4 to 31 inlive births 12 Although neonatal herpes is too rare to be used as an endpoint in a clinical vaccine trial, prevention of HSV acquisition during pregnancy is an important goal of developing an effective HSV vaccine.
Thus, decreasing either HSV-2 susceptibility or reactivation through prophylactic vaccination could Seeking a woman hsv2 24 35 to a marked decrease in HIV incidence in sub-Saharan Africa Prevention strategies for sexual transmission of HSV-2 include condom use 23disclosure of serostatus 24and suppressive antiviral therapy Moreover, antiviral therapy does not abrogate the increased risk of HIV acquisition 2728 or transmission 29 in HSV-2—seropositive persons.
The currently available strategies are useful for individual patients, but they are unlikely to be of public health benefit. A prophylactic vaccine would be valuable from both the patient and public health standpoint, if it were able to meet or exceed the efficacy of currently available preventive therapies. HSV infects epithelial cells at skin and mucosal surfaces during primary infection, then travels via retrograde transport along nerve axons to the dorsal root ganglia DRGwhere latency is established While epithelial cells are destroyed during lytic HSV replication, neuronal cells are not destroyed and provide a reservoir for latent virus.
During reactivation, the virus travels from the DRG back to the skin and causes detection of virus from epithelial surfaces known as viral shedding. Viral reactivation may be asymptomatic or may be associated with prodrome tingling or burningnonspecific symptoms or lesions, or a classic genital ulcer.
Studies that measure the frequency of viral shedding and the quantity of virus detected from the genital tract have provided insight into the natural history and pathogenesis of HSV-2 infection. HSV was ly thought to be in the latent state most of the time during chronic infection, with rare clinically evident reactivation episodes, conceptually similar to varicella zoster virus VZV.
However, shedding studies using anogenital swabs collected by HSV-2—seropositive persons once or multiple times daily for viral culture or for quantitative real-time PCR have revealed that HSV and the host are in constant conflict, with frequent HSV reactivation and rapid clearance This implies host responses that likely involve cell-intrinsic and -extrinsic mechanisms of innate as well as acquired immunity.
Many of these shedding episodes occur in the absence of lesions or symptoms known as subclinical shedding; ref. Mathematical models suggest that multiple, short, overlapping shedding episodes best simulate the observed shedding patterns 35 and that a nearly constant low quantity of HSV is likely to be released from sensory DRG into the genital tract Recent studies using intensive sampling every 6 hours of the genital and oral mucosa have produced consistent with these models, demonstrating that most HSV detection episodes are short median 13 hourssubclinical, and rapidly cleared In addition, studies using detailed genital mapping to isolate shedding episodes have demonstrated that simultaneous, bilateral widespread genital shedding is detected frequently Thus, even persons with established infection and a functional immune system can experience both subclinical genital HSV shedding and lesional recurrences, which suggests that the virus can evade even mature host immune responses.
These findings indicate that chronic HSV infection involves a dynamic equilibrium between ganglionic and mucosal compartments. Studies in HSV-2—discordant couples have shown that most HSV-2 transmissions occur during periods of subclinical shedding in the source partner 8. The relationship between the inoculum dose, the presence of local abrasions or other epithelial variables, and the likelihood of successful transmission has not been established in humans.
An increase in the inoculum dose required to produce disease or establish ganglionic latency might result from a vaccine, as has been shown with a live attenuated candidate vaccine in guinea pigs 41providing partial protection from infection or disease. HSV-2 is transmitted between sexual partners fairly quickly in a new sexual relationship. In a cohort of patients with laboratory-documented primary HSV-2 infection and a clearly defined transmitting partner, the median of sexual acts between the couple at the time of HSV-2 acquisition was 40 Obversely, our group has identified some HSV-2—seronegative persons in long-term HSV-2—discordant sexual relationships who have T cell responses to HSV-2 42which suggests that not all exposures result in infection.
Preliminary data suggest that these T cell responses may be weighted toward certain HSV-2 proteins If confirmed and extended using the whole HSV-2 proteome, this finding could indicate preferred compositions for future subunit vaccines. Experts have long considered infection by multiple HSV-2 strains in a given individual a rare phenomenon 4344raising the potential for Seeking a woman hsv2 24 35 sterilizing immunity. A more detailed analysis of the prevalence of multistrain HSV-2 infection is now possible because of increased knowledge of viral SNPs 4849 and can be used to establish how well naturally occurring HSV-2 infection protects against infection with a second strain in humans.
These data will discern whether immunity better than, or perhaps fundamentally different from, that provoked by wild-type infection will be a necessary component of a successful vaccine. The importance of the host immune response is demonstrated by the severe, prolonged ulcerations that can occur in patients with AIDS 51 or after solid organ 52 or stem cell transplantation The host and viral determinants of the heterogeneous clinical and virological manifestations of genital HSV-2 are poorly understood.
In our opinion, identification of those components of the host immune system that result in containment of viral reactivation from neurons, and viral clearance from the mucosa, will be essential for development of a successful HSV-2 vaccine. This is most likely to be gained by detailed immunologic and genetic studies of persons with well-defined HSV-2 severity. Interestingly, most host mutations associated with fatal HSV in childhood occur at loci classically associated with innate immunity, such as TLR3 57 and UNC93B1 59although some mutations associated with severe HSV are in genes involved in both innate and acquired immune responses e.
Although innate immune system agonists can lead to profound, local HSV resistance 6162these interventions are outside the realm of classic vaccinology. Single nucleotide polymorphisms in TLR2 are associated with more frequent HSV shedding and genital lesions 63which suggests that there may be a host genetic contribution to the wide heterogeneity of clinical HSV presentation. No acquired cellular immunity correlates of control of HSV reactivation or shedding have been elucidated in humans.
Neutralizing antibodies to viral envelope glycoproteins, which are required for viral entry into cells, develop in response to HSV infection 76 and may provide some type-common protection against HSV acquisition 77 or reduce the severity of HSV infection 78 As a result, glycoprotein B gB and gD subunit vaccines have been pursued in human clinical trials. Physiologically relevant host receptors have been defined 80and crystallographic structures of HSV proteins with their ligands and dynamic Seeking a woman hsv2 24 35 changes during viral entry are newly available 81 — These data may inform the de of a newer generation of glycoprotein-based vaccines deed to elicit optimal neutralizing antibodies, inspired by the success of HPV vaccines, which appear to work at least in part by eliciting higher titers of neutralizing antibodies than those induced by natural infection.
Alphaherpesviruses, such as HSV-2, have coevolved with primate hosts for millions of years and have developed many strategies to evade the host immune response. The latency associated transcript blocks apoptosis and may allow for survival of neurons during latent infection 84whereas other viral genes block apoptosis induced by cytolytic immune effector cells With the knowledge of specific HSV immune evasion mechanisms, it is possible to create replication-competent or -incompetent virus-based vaccines modified to disable inhibitors of innate and acquired immunity.
Examples include deletion of UL41 which encodes a protein with complex properties, including DC downregulation; ref.
Thus, although the components of protective immunity remain unknown, the tools to perform studies to correlate immunity with phenotype are now largely in place: immunocompetent subjects can be phenotyped for shedding frequency, the viral proteome is manageably sized for comprehensive immune studies, and specimens can include infected tissues as well as blood. The mouse and guinea pig models of HSV-2 infection have provided important insight into the immunobiology of genital herpes. The mouse model is limited because HSV does not spontaneously reactivate from mice DRG and therefore does not simulate infection in the human host.
Some viral immune evasion mechanisms are also less active in mice. Although pathogenesis insights into tissue-resident HSV-specific T cells made in mice appear applicable to human infection 9192most vaccine studies in mice use lethality as an endpoint and, due to space constraints, will not be reviewed here. The guinea pig does reactivate HSV spontaneously for a limited period of time after vaginal infection 93but few reagents are available to parse out the components of an effective immune response in this model.
As an alternative, the cotton rat model, in which HSV reactivation does occur, should be further exploited Many prophylactic vaccines have been tested in the guinea pig model, and most have been successful in preventing clinically apparent infection Supplemental Table 1; supplemental material available online with this article; doi: In addition, several therapeutic vaccines prevent recurrences in this model.
Approaches have included recombinant glycoprotein subunit vaccines, DNA-based vaccines using plasmids encoding glycoproteins, live virus vector vaccines with glycoprotein inserts, live-attenuated HSV-2, and replication-incompetent virus. These vaccines resulted in decreased severity of primary disease, rate of recurrent infection, and quantity of virus shed during primary infection and recurrent activation.
Studies in the guinea pig have shown the quantity of HSV that establishes latency in the DRG correlates with frequency of clinical recurrence 95which suggests that partial protection could be a valuable endpoint goal in vaccine de. However, once DRG are infected, shedding still occurs at a rate similar to that of nonimmunized animals 96 These data suggest that once neuronal infection in the DRG is established, the pathobiology of frequent reactivation may not be affected by a therapeutic vaccine, although clinical recurrences and quantity of virus shed may be diminished.
In parallel, long-term studies of HSV-2—infected persons show that most, if not all, reactivate HSV-2, albeit with variable frequency In the HIV vaccine field, a new pipeline for preclinical testing of T cell—based vaccines in nonhuman primates has been proposed 99which requires efficacy for a clinically relevant, predefined virologic endpoint, followed by examination of immunogenicity prior to use in human volunteers. HSV vaccine researchers should also consider virologic efficacy criteria when evaluating prophylactic and therapeutic vaccines, such as reduction or elimination of mucosal shedding or reduction of the establishment of sacral DRG latency, in addition to immunogenicity, in animal models prior to initiating human trials.
Prophylactic vaccines. Testing prophylactic HSV vaccines for efficacy requires prospective follow-up of persons at risk for HSV-2 acquisition. Substantial efforts have been invested into glycoprotein subunits as vaccine targets, with more than 20, human volunteers studied in clinical trials Table 1. Randomized, double-blind, placebo-controlled trials of prophylactic HSV-2 vaccines tested in humans. The first trials randomized HSV-2—seronegative persons in a stable HSV-2—discordant sexual relationship, in which the source partner had clinically evident genital herpes, to receive vaccine or placebo.
Preliminary of the Herpevac trial showed no efficacy against HSV-2 disease or infection These negative trials, while disappointing, have provided insights into the optimal study population, de, and endpoints for future investigations. Future trials should enroll members of both discordant monogamous couples as well as individuals with multiple partners to further evaluate this. Endpoints of interest in a prophylactic vaccine study include both acquisition of HSV-2 infection, to measure the ability of the vaccine to induce sterilizing immunity, and frequency of viral shedding.
Assessment of viral shedding is more precise than identification and attribution of genital s and symptoms, and lack of viral shedding will undoubtedly lead to lack of clinical manifestations of genital herpes. In addition, viral shedding frequency in those who are infected is also of interest to evaluate a potential effect on dynamics of transmission Seeking a woman hsv2 24 35 1 and ref. Therapeutic vaccines. Therapeutic HSV-2 vaccines have been pursued both to improve the clinical course in individual patients and to potentially decrease HSV shedding, and hence transmission, for a public health benefit Table 2.
Most have been safe and have induced a Seeking a woman hsv2 24 35 immune response. Although the first study of a recombinant gD2 vaccine adjuvanted with alum reduced the rate of virologically confirmed recurrenceslater studies of glycoprotein vaccines failed to replicate that effect Unlike the prophylactic vaccine studies, shedding data from our group indicate that the pivotal therapeutic vaccine studies can be performed efficiently with fewer than individuals if viral shedding is used as an endpoint 33whereas prophylactic vaccination studies require a much larger sample size.
Viral shedding rate and quantity of virus shed could serve as useful surrogate endpoints for recurrence rate and transmission likelihood in studies of therapeutic vaccines as well. Randomized, double-blind, placebo-controlled trials of therapeutic HSV-2 vaccines tested in humans.Seeking a woman hsv2 24 35
email: [email protected] - phone:(348) 431-8695 x 9867
Herpes Genitalis: Diagnosis, Treatment and Prevention