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Herpes Simplex Vaccines: Prospects of Live-attenuated HSV Vaccines to Combat Genital and Ocular infections.

ABSTRACT: Herpes simplex virus type-1 (HSV-1) and its closely related type-2 (HSV-2) viruses cause important clinical manifestations in humans including acute ocular disease and genital infections. These viruses establish latency in the trigeminal ganglionic and dorsal root neurons, respectively. Both viruses are widespread among humans and can frequently reactivate from latency causing disease. Currently, there are no vaccines available against herpes simplex viral infections. However, a number of promising vaccine approaches are being explored in pre-clinical investigations with few progressing to early phase clinical trials. Consensus research findings suggest that robust humoral and cellular immune responses may partially control the frequency of reactivation episodes and reduce clinical symptoms. Live-attenuated viral vaccines have long been considered as a viable option for generating robust and protective immune responses against viral pathogens. Varicella zoster virus (VZV) belongs to the same alphaherpesvirus subfamily with herpes simplex viruses. A live-attenuated VZV vaccine has been extensively used in a prophylactic and therapeutic approach to combat primary and recurrent VZV infection indicating that a similar vaccine approach may be feasible for HSVs. In this review, we summarize pre-clinical approaches to HSV vaccine development and current efforts to test certain vaccine approaches in human clinical trials. Also, we discuss the potential advantages of using a safe, live-attenuated HSV-1 vaccine strain to protect against both HSV-1 and HSV-2 infections.

SUBMITTER: Stanfield B

PROVIDER: S-EPMC4840408 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Herpes Simplex Vaccines: Prospects of Live-attenuated HSV Vaccines to Combat Genital and Ocular infections.

Stanfield Brent B Kousoulas Konstantin Gus KG

Current clinical microbiology reports 20150701 3

Herpes simplex virus type-1 (HSV-1) and its closely related type-2 (HSV-2) viruses cause important clinical manifestations in humans including acute ocular disease and genital infections. These viruses establish latency in the trigeminal ganglionic and dorsal root neurons, respectively. Both viruses are widespread among humans and can frequently reactivate from latency causing disease. Currently, there are no vaccines available against herpes simplex viral infections. However, a number of promis ...[more]

PMID: 27114893

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Project description:Diseases caused by human herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) affect millions of people worldwide and range from fatal encephalitis in neonates and herpes keratitis to orofacial and genital herpes, among other manifestations. The viruses can be shed efficiently by asymptomatic carriers, causing increased rates of infection. Viral transmission occurs through direct contact of mucosal surfaces followed by initial replication of the incoming virus in skin tissues. Subsequently, the viruses infect sensory neurons in the trigeminal and lumbosacral dorsal root ganglia, where they are primarily maintained in a transcriptionally repressed state termed "latency", which persists for the lifetime of the host. HSV DNA has also been detected in other sympathetic ganglia. Periodically, latent viruses can reactivate, causing ulcerative and often painful lesions primarily at the site of primary infection and proximal sites. In the United States, recurrent genital herpes alone accounts for more than a billion dollars in direct medical costs per year, while there are much higher costs associated with the socio-economic aspects of diseased patients, such as loss of productivity due to mental anguish. Currently, there are no effective FDA-approved vaccines for either prophylactic or therapeutic treatment of human herpes simplex infections, while several recent clinical trials have failed to achieve their endpoint goals. Historically, live-attenuated vaccines have successfully combated viral diseases, including polio, influenza, measles, and smallpox. Vaccines aimed to protect against the devastation of smallpox led to the most significant achievement in medical history: the eradication of human disease by vaccination. Recently, novel approaches toward developing safe and effective live-attenuated vaccines have demonstrated high efficacy in various preclinical models of herpetic disease. This next generation of live-attenuated vaccines has been tailored to minimize vaccine-associated side effects and promote effective and long-lasting immune responses. The ultimate goal is to prevent or reduce primary infections (prophylactic vaccines) or reduce the frequency and severity of disease associated with reactivation events (therapeutic vaccines). These vaccines' "rational" design is based on our current understanding of the immunopathogenesis of herpesviral infections that guide the development of vaccines that generate robust and protective immune responses. This review covers recent advances in the development of herpes simplex vaccines and the current state of ongoing clinical trials in pursuit of an effective vaccine against herpes simplex virus infections and associated diseases.

Project description:Two herpes zoster (HZ) vaccines licensed in the United States are recommended by the Advisory Committee on Immunization Practices (ACIP): (i) live-attenuated vaccine (ZVL) using vOka strain varicella-zoster virus (VZV) and (ii) recombinant adjuvanted vaccine (RZV) containing recombinant varicella-zoster virus (VZV) glycoprotein E (gE). Two phase 3 clinical trials of RZV led the Advisory Committee on Immunization Practices (ACIP) to recommend it with preferred status. VZV T cell-mediated immunity (CMI), but not humoral immunity, is considered essential for protection against HZ. Published studies of humoral immunity focused on VZV-specific IgG concentration. To complement reports comparing the CMI responses to these vaccines, we compared humoral responses in ZVL and RZV recipients, emphasizing functional qualities (avidity and neutralization). Baseline avidities to a VZV glycoprotein mixture (gp) were near the upper limit of detection, but avidity to gE was much lower. Small increases in gp avidity were observed for both RZV and ZVL vaccination (19 and 12 avidity index units [AIU], respectively). RZV boosted both gE avidity and VZV neutralizing antibody significantly more than ZVL (mean gE avidity boost, 47 AIU versus 22 AIU; mean neutralizing antibody boost, 22-fold versus 8-fold). Increases in neutralizing antibodies strongly correlated with gE avidity increases (r = 0.5) and moderately with gp avidity increases (r = 0.23). After 1 year, 81% of RZV recipients and only 18% of ZVL recipients retained >50% of their peak avidity boosts. These results are consistent with the CMI responses to these vaccines: RZV responses are skewed to long-term memory, whereas ZVL preferentially induces transient effector responses.IMPORTANCE These observations further distinguish the immunogenicity and duration of the immune response of the two vaccines. In addition, measurements of functional humoral immunity (IgG avidity and neutralizing antibody) in response to zoster immunization, alone or combined with other immune markers, might contribute to practical in vitro correlates of protection. Combined with previous observations of the cell-mediated response to these vaccines, this study suggests that vaccine development will benefit from more expansive and granular assessments of acquired immunity during early phase 1 immunogenicity trials.

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Herpes Simplex Vaccines: Prospects of Live-attenuated HSV Vaccines to Combat Genital and Ocular infections.

Publications

Herpes Simplex Vaccines: Prospects of Live-attenuated HSV Vaccines to Combat Genital and Ocular infections.

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