herpes simplex research 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 (cats, dogs, horses) or have economic impacts in the agriculture industry (e.g., pigs, cows, sheep, chicken, oysters). vaccine research various vaccine candidates have been developed, the first ones in the 1920s, but none has been successful to date. due to the genetic similarity of both herpes simplex virus types (hsv-1 and hsv-2), the development of a prophylactic-therapeutic vaccine that proves effective against one type of the virus would likely prove effective for the other virus type, or at least provide most of the necessary fundamentals. as of 2020, several vaccine candidates are in different stages of clinical trials, see list below. 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. advocacy 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 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 design 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 (e.g. herpevac) 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). vaccine candidates 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. vaccine company & lead researcher vaccine type trial status and results anteris hsv-2 therapeutic vaccine / cor-1 anteris technologies (formerly admedus) ian frazer dna vaccine phase iia , likely discontinued monoclonal antibody therapy / hdit101 heidelberg immunotheraputics gmbh claudia kunz, phd monoclonal antibodies phase iistudy of hdit101 versus valaciclovir.nov 2019 – sep 2021 ub-621 united biopharma (taiwanese company with a branch in the us.) n/a anti-hsv antibody phase iireceives us fda approval for ub-621 phase 2 trial in recurrent genital herpes patients (2019-06/11).jun 2020 – jun 2021 gsk3943104a gsk phase i-ii bnt163 biontech mrna phase istarted phase 1 clinical trial dl5-29 / acam-529 / hsv-529 sanofi pasteur david knipe hsv-2 replication-defective vaccine with ul5 and ul29 deleted phase i–iihsv529 vaccine was safe and elicited neutralizing antibody and modest cd4+ t-cell responses in hsv-seronegative vaccinees.dec 2019 – may 2023 vc2 louisiana state university gus kousoulas live-attenuated hsv vaccine with small deletions in ul20 and ul53 preclinicalthe vc2 vaccine prevents hsv infection of neuronal axons and establishment of latency in animal models such as mice, guinea pig and rhesus monkeys. r2 thyreos inc gregory smith, gary pickard, ekaterina heldwein live-attenuated hsv vaccine mutated in r2 coding region of ul37 preclinicala single-dose vaccine effective in mice and rats against multiple neuroinvasive herpesviruses including hsv. hsv-2 δgd-2 albert einstein college of medicine / x-vax technology (pre-clinical) william jacobs jr & betsy harold live-attenuated hsv-2 vaccine with us6 (gd) deleted preclinicalcombats hsv-1 & hsv-2 in mice. mice who were hsv-1 positive showed strong protection from hsv-2. hsv-2 mrna trivalent vaccine perelman school of medicine at the university of pennsylvania kevin p. egan, harvey friedman, sita awasthi hsv-2 mrna trivalent vaccine (containing gc2, gd2, ge2) preclinicalthe mrna vaccine prevented death and genital disease in 54/54 (100%) mice infected with hsv-1 and 20/20 (100%) with hsv-2, and prevented infection of the dorsal root ganglia in 29/30 (97%) mice infected with hsv-1 and 10/10 (100%) with hsv-2 (update 27 july 2020) m-rna-1608 moderna mrna preclinical g103 sanofi pasteur, immune design hsv-2 subunit trivalent vaccine (containing gd, pul19, pul25) phase i–iiprophylactic immunization completely protected against lethal intravaginal hsv-2 infection in mice. gv2207 genvec ? preclinical ne-hsv2 bluewillow ? preclinical tba profectus biosciences dna vaccine discoveryimmunogenicity in small animals. hsv-2 icp0‾ hsv-2 0δnls / theravax rational vaccines rvx william halford live-attenuated vaccine terminatedcompany under criminal investigation by the fda and being sued by trial participants. effective for most patients in a small clinical trial (17/20) but with severe side-effects for some (3/20). vitaherpavac & herpovax vitafarma, russia inactivated hsv-1 and hsv-2 vaccine phase ivappears to be for treatment of existing patients. live-attenuated non-invasive vaccines 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. the vc2 non-invasive vaccine was developed by dr. gus kousoulas at louisiana state university. vc2 encodes two attenuating mutations that together reduce hsv entry into neurons. the establishment of latency is prevented in animal models such as mice, guinea pig, and rhesus monkeys. the r2 non-invasive vaccine was developed by drs. gregory smith (northwestern university feinberg school of medicine), patricia sollars & gary pickard (university of nebraska-lincoln), and ekaterina heldwein (tufts university school of medicine). r2 vaccines retain native replication in epithelial cells but are incapable of retrograde axonal transport and invasion of the nervous system. a single dose of the r2 vaccine passively introduced on mucosal tissues protects the nervous system from future infections and affords protection against lethal encephalitic infections in mice and rats. this vaccine strategy is noted for its effectiveness against both veterinary and clinical neuroinvasive herpesviruses. thyreos inc was founded to develop a herpesvirus vaccine platform based on the r2 design with targeted applications in human health, companion animal health, and livestock productivity. live-attenuated hsv-2 vaccine dr. william halford at the southern illinois university (siu) school of medicine tested a live-attenuated hsv-2 icp0∆nls vaccine in 2016, before his death in june, 2017. vaccine attenuation is achieved by a mutation in icp0 (icp0∆nls) that increases the vaccine strain's sensitivity to interferon responses and limits its replication. already proven as safe and effective in rodents and eliciting 10 to 100 times greater protection against genital herpes than a glycoprotein d subunit vaccine, halford's vaccine was tested outside of the united states, in st. kitts in 20 human volunteers. all 20 of the participants self-reported an improvement in symptoms, but only 17 received and completed all three dosages. blot tests showed a clear antibody response, which cannot be instigated by a placebo effect. however, the human trial was conducted without approval from the fda or from the siu institutional review board. replication-defective hsv-2 vaccine principle of hsv529 david m. knipe, a professor at harvard medical school has developed dl5-29. the dl5-29 vaccine is also known under the name acam-529 or hsv-529, a replication-defective vaccine that has proved successful in preventing both hsv-2 and hsv-1 infections and in combating the virus in already-infected hosts, in animal models. the hsv-529 is a leading vaccine candidate which has been investigated in numerous research publications, and is endorsed by many researchers in the field (i.a. lynda a. morrison and jeffrey cohen). the vaccine induces strong hsv-2-specific antibody and t-cell responses, protects against challenge with a wild-type hsv-2 virus, reduces the severity of recurrent disease, and provides cross-protection against hsv-1. the ongoing trials would prove if a durable immune response in humans is to be successfully achieved or if the vaccine is too over attenuated to do the same. the vaccine was being researched and developed by sanofi pasteur. on 28 april 2022, sanofi announced it had discontinued a trial evaluating four hsv-2 vaccines. the pipeline section of the sanofi website no longer lists any hsv vaccine candidate in active development. dna-based vaccine professor ian frazer developed an experimental vaccine with his team at coridon, a biotechnology company he founded in 2000. the company, now known under the name admedus vaccines, is researching dna technology for vaccines with prophylactic and therapeutic potential. what's different about this vaccine is the way that response is being created. instead of introducing a weakened version of the herpes virus or protein subunit, this vaccine uses a small section of dna to produce t-cells and stimulate the immune response. the new vaccine candidate is designed to prevent new infections, and to treat those who already have the infection. in february 2014, it was announced that frazer's vaccine against genital herpes passed human safety trials in a trial of 20 australians. in october 2014, admedus announced success in creating a positive t-cell response in 95% of participants. further research is required to determine if the vaccine can prevent transmission. in july 2014, admedus increased its stake in frazer's vaccines by 16.2%. in addition, $18.4 million was posted as funds raised towards phase ii vaccine testing and research. the hsv-2 phase ii trial began in april 2015. interim results were published on march 4, 2016, and based on the results of a scheduled, blinded, pooled analysis of data from the first 20 patients to receive at least three vaccinations in the randomised, placebo controlled phase ii study with the following results: no safety issues have been noted in this cohort of patients. the data remains blinded