Abstract
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.
Highlights
This article is an open access articleHuman herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are highly infectious and successful human pathogens
Epidemiological models predict that a prophylactic vaccine with a modest 50% efficacy can reduce the number of new infections by 58%, incidence by 60%, and seroprevalence by 21%, reducing the yearly rate of infection by 350,000 new cases per year by 2050 [8]
Bagley et al demonstrated that a DNA vaccine expressing a pool of HSV-2 glycoproteins adjuvanted with IL-12 outperformed the gD2 subunit vaccine but was not as effective in reducing virus shedding compared with the HSV-2
Summary
Human herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are highly infectious and successful human pathogens. HSV-2 is estimated to infect half a billion people globally, and in the United States, these numbers are predicted to grow by >600,000 new infections per year until 2050 [1]. Therapeutic vaccination to reduce or eliminate oral and genital herpes recurrence has long been a highly needed but elusive goal in herpes simplex vaccine development. Several academic laboratories and commercial entities are currently working toward developing a safe and effective herpes simplex vaccine in preclinical animal models (Table 1) and human trials (Table 2). We discuss recent developments in the preclinical pursuit of a safe and effective herpes simplex vaccine and review promising subunit/peptide, vectored/DNA/RNA, and live-attenuated vaccine technologies
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