Herpes simplex research

Herpes simplex research includes all medical research that attempts to prevent, treat, or cure herpes, as well as fundamental research about the nature of herpes. Examples of particular herpes research include drug development, vaccines and genome editing. HSV-1 and HSV-2 are commonly thought of as oral and genital herpes respectively, but other members in the herpes family include chickenpox (varicella/zoster), cytomegalovirus, and Epstein-Barr virus. There are many more virus members that infect animals other than humans, some of which cause disease in companion animals (e.g., cats, dogs, horses) or have economic impacts in the agriculture industry (e.g., pigs, cows, sheep, chicken, oysters).

Various vaccine candidates have been developed, the first ones in the 1920s, but none has been successful to date.

Both herpes simplex virus types (HSV-1 and HSV-2) share a high rate of sequence homology, so the development of a prophylactic-therapeutic vaccine that proves effective against one type of the virus would likely aid in the development of the other. As of 2020^[update], several vaccine candidates are in different stages of clinical trials.

An ideal herpes vaccine should induce immune responses adequate to prevent infection. Short of this ideal, a candidate vaccine might be considered successful if it (a) mitigates primary clinical episodes, (b) prevents colonization of the ganglia, (c) helps reduce the frequency or severity of recurrences, and (d) reduces viral shedding in actively infected or asymptomatic individuals. The fact that a live-attenuated vaccine induced better protection from HSV infection and symptoms is not new, because live-attenuated vaccines account for most of the successful vaccines in use today. However, governmental and corporate bodies seem to support the more recent and safer but possibly less effective approaches such as glycoprotein- and DNA-based vaccines.

Due to the current stigma of the herpes simplex virus, the topic of a cure has always been considered a "taboo" whilst some also consider the symptoms to be mild that a cure or a vaccine is not needed. However, in April 2020, a subreddit group, r/HerpesCureResearch was formed to advocate for cure research and better treatment of HSV. The "Herpes Cure Research" has grown to 20k members and has raised funds for Fred Hutch's genome editing treatment and UPenn's mRNA vaccine research as well as forming a Herpes Cure Advocacy group in which the group is raising awareness on the health complications associated with HSV.

Vaccine-elicited protection against HSV is challenging to achieve due to the ability of herpesviruses to evade many aspects of the mammalian immune response. As a general principle, the effectiveness of a HSV vaccine design is often inversely proportional to its safety. Subunit vaccines, which consist of individual or small groups of viral antigens, remove all risk of complications resulting from the production of vaccine-associated infectious viral particles but are limited in the degree and scope of immunity that can be produced in vaccinated individuals. Inactivated vaccines, which consist of intact viral particles, dramatically increase the repertoire of viral antigens that engender the immune response but like subunit vaccines are generally constrained to producing humoral immunity. Like inactivated vaccines, replication-defective vaccines expose the immune system to a diverse swath of HSV antigens but can produce both cellular and humoral immunity because they retain the ability to enter cells by HSV-induced membrane fusion. However, replication-defective HSV vaccines are challenging to produce at scale and offer limited immunization due to the lack of vaccine amplification. Live-attenuated vaccines are highly efficacious, potentially eliciting both cell-mediated and humoral immunity against structural and non-structural viral proteins, but their ability to replicate can result in vaccine-related illness particularly in immunocompromised individuals. Whereas subunit vaccines have proven effective against some viruses, immunity produced by subunit HSV vaccines have failed to protect humans from acquiring genital herpes in several clinical trials. In contrast, the success of the live-attenuated chickenpox vaccine demonstrates that an appropriately live-attenuated α-herpesvirus may be used to safely control human disease. The challenge of achieving vaccines that are both safe and effective has led to two opposing approaches in HSV vaccine development: increasing the efficacy of subunit vaccines (primarily by improving adjuvant formulations), and increasing the safety of live-attenuated vaccines (including the development of "non-invasive" vaccines).

The chart below is an attempt to list all known proposed HSV and varicella zoster vaccines and their characteristics. Please update with any missing information on vaccines only.

A recent development in live-attenuated HSV vaccine design is the production of replicative vaccines that are ablated for nervous system infection. These vaccines infect the respiratory mucosa where their replication and localized spread provoke a robust immune response. The safety of these vaccines is based on their inability to invade the nervous system and establish life-long latent infections, as opposed to a general attenuation. Unlike other live-attenuated designs, these vaccines are cleared from the body once the immune response from vaccination has matured. In principle, by avoiding attenuation of HSV replication in the mucosa while removing the capacity to infect the nervous system, non-invasive vaccines have the potential to break the safety-efficacy dilemma by producing the strongest possible immune response while maintaining a high degree of safety.