Rational Design of Live-Attenuated Vaccines against Herpes Simplex Viruses

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.

40 Years after the Registration of Acyclovir: Do We Need New Anti-Herpetic Drugs?

“…The vaccine was previously tested without FDA approval in a small group of HSV-infected patients. The investigators reported a reduction in the recurrence rates in this group [ 198 , 199 ].…”

“…HSV vaccines currently under investigation are shown in Table 5 [ 158 , 190 , 194 , 195 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 ].…”

Herpesvirus-Associated Encephalitis: an Update

“…In addition to antiviral research, there has been a decades-long effort to develop a HSV vaccine without success. However, there are numerous active clinical and preclinical studies for HSV vaccines, including several utilizing the promising new technology of messenger ribonucleic acid (RNA)-based vaccines, which has been highly successful against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [ 34 ].…”

Identifying HSV-1 Inhibitors from Natural Compounds via Virtual Screening Targeting Surface Glycoprotein D

“…Primary infection with HSV-1 occurs by virus penetration at mucosal surfaces or through skin abrasions. From here, HSV-1 infects innervating sensory nerves of the trigeminal or dorsal root ganglia, where it establishes a life-long latent infection with a high rate of periodical reactivation [ 2 , 5 , 6 , 7 ]. The current predominant antiherpetic agents are viral deoxyribonucleic acid (DNA) extension inhibitors, such as acyclovir (ACV), penciclovir, valacyclovir, famciclovir, foscarnet, and cidofovir.…”