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, VZV), cytomegalovirus (CMV), and Epstein-Barr (EBV). There are many more 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 (pigs, cows, sheep).
- 1 Vaccine research
- 2 Vaccine design
- 3 Vaccine candidates
- 4 Genome editing
- 5 Herpes simplex pharmaceutical drugs
- 6 References
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 2016[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.
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).
The chart below is an attempt to list all known proposed HSV and VZV vaccines and their characteristics. As of 2019, there are no HSV vaccines in production. Please update with any missing information on vaccines only.
|Vaccine||Company & Lead Researcher||Vaccine Type||Status||Trial Results|
|Merck & Co.||Live-attenuated.||In Production||Vaccination showed an immune response of 70% in 50 years old adults. The effectiveness went down to approx 64% in 60 years old, 41% in 70 years old, and 18% in 80 years old individuals.|
|Varivax, Varilrix(Varicella, C.Pox)||Merck & Co. & GlaxoSmithKline||Live-attenuated.||In Production||One dose of vaccine prevents 95% of moderate disease and 100% of severe disease.|
|GlaxoSmithKline||Subunit gE with AS01B/QS-21 adjuvant system. This is primarily a vaccine against Varicella zoster virus, not Herpes simplex virus.||In Production||Strong immune response in adults 65 and older. Final trials results reported an effectiveness of 90% in the first year, which went down slightly to 88% four years after vaccination.|
|Admedus||Admedus||DNA vaccine||Phase II||58% reduction in viral shedding, 81% reduction in outbreaks (post-booster). The booster further reduced outbreaks and shedding. Vaccine is being progressed.|
|dl5-29 / ACAM-529 / HSV-529||Sanofi Pasteur
|HSV-2 replication-defective vaccine with UL5 and UL29 deleted||Phase I||HSV529 was safe, well-tolerated, immunogenic, eliciting significant neutralizing gD and ADCC-mediating antibodies. Modest cellular immune responses were observed only in HSV seronegative individuals.|
|VC2||Louisiana State University
|Live-attenuated HSV vaccine with small deletions in UL20 and UL53||Preclinical||The VC2 vaccine prevents HSV infection of neuronal axons and establishment of latency in animal models such as mice, guinea pig and rhesus monkeys.|
Gregory Smith, Gary Pickard, Ekaterina Heldwein
|Live-attenuated HSV vaccine mutated in R2 coding region of UL37||Preclinical||A single-dose vaccine effective in mice and rats against multiple neuroinvasive herpesviruses including HSV.|
|HSV-2 ΔgD-2||Albert Einstein College of Medicine William Jacobs Jr & Betsy Harold||Live-attenuated HSV-2 vaccine with US6 (gD) deleted||Preclinical||Combats HSV-1 & HSV-2 in mice|
|HSV-2 Trivalent Vaccine||Perelman School of Medicine at the University of Pennsylvania
Harvey Friedman & Sita Awasthi
|HSV-2 subunit trivalent vaccine (containing gC2, gD2, gE2)||Preclinical||Reduced shedding to 0.2% in animals|
|G103||Immune Design||HSV-2 subunit trivalent vaccine (containing gD, pUL19, pUL25)||Preclinical||Prophylactic immunization completely protected against lethal intravaginal HSV-2 infection in mice|
|TBA||Profectus BioSciences||DNA vaccine||Antigen Discovery Stage||N/A|
|HSV-2 ICP0‾ HSV-2 0ΔNLS||Rational Vaccines RVx
|Live-attenuated vaccine||Embroiled in patient consent controversy.||65% of the patients reported being free of symptoms.|
|Vitaherpavac & Herpovax||Russia||?||?||?|
Live-attenuated non-invasive vaccinesEdit
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 LLC 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 vaccineEdit
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 vaccineEdit
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 is now being researched and developed by Sanofi Pasteur.
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 to protect the integrity of the trial.
- Study participants had a marked decrease in viral lesions (outbreaks) with a drop of over 90% in the monthly rate versus baseline.
- The average number of days HSV-2 was detected in patients was reduced versus baseline.
On 19 October 2016, Admedus released interim results from the ongoing HSV-2 Phase IIa study. The unblinded data demonstrated a 58% reduction in viral shedding compared to baseline and a reduction in outbreaks of 52% post vaccination and 81% overall reduction post-booster.
Other vaccine explorationEdit
Vitaherpavac - In patients with monotonously recurrent genital herpes infection and history of failure of standard vaccination, anti-relapse efficacy of Vitaherpavac vaccine was demonstrated after allergometry-based tailored choice of vaccine administration regimen. The used approach was associated with lower antigenic load and sensitization, more than three-fold increase in relapse-free period in 85% of treated patients and improvement of Th1-dependent immunity. The Russian vaccine Vitagerpavak — the only polyvalent vaccine in the world for treatment of the chronic gerpesvirusny infection (CGI) І and ІІ types. It is developed in scientific research institute of virology of D.I. Ivanovsky of the Russian Academy of Medical Science. More than 15 years are applied in the Russian Federation.
A study from the Albert Einstein College of Medicine, where glycoprotein D (gD-2) was deleted from the herpes cell, showed positive results when tested in mice. Researchers deleted gD-2 from the herpes virus, which is responsible for herpes microbes entering in and out of cells. The vaccine is still in early stages of development and more research needs to be conducted before receiving FDA approval for clinical trials.
Research conducted by the NanoBio Corporation indicates that an enhanced protection from HSV-2 is a result of mucosal immunity which can be elicited by their intranasal nanoemulsion vaccine. NanoBio published results showing efficiency in studies conducted in both the prophylactic and the therapeutic guinea pig model. This included preventing infection and viral latency in 92% of animals vaccinated and a reduction in recurrent legions by 64% and viral shedding by 53%. NanoBio hopes to raise funds in 2016 to enter into Phase I clinical testing.
Biomedical Research Models, a Worcester-based biopharmaceutical company has been awarded a fund for the development of a novel vaccine platform to combat mucosally transmitted pathogens such as HSV-2.
The company Tomegavax (recently acquired by Vir Biotechnology) is researching to utilize cytomegalovirus (CMV) vectors in the development of a therapeutic vaccine against herpes simplex virus 2 (HSV-2), the causative agent of genital herpes. It has been awarded a grant by the NIH for this purpose.
Redbiotec, a privately held Swiss biopharmaceutical company, based in Zurich as a spin-off of the ETH Zurich, is focusing on the development of a therapeutic vaccine against HSV-2. Redbiotec's preclinical vaccine shows over 90% of lesion score (vs. approx. 50% for GEN-003 of Genocea) in early findings.
Sanofi Pasteur and the clinical-stage immunotherapy company Immune Design have entered a broad collaboration, which will explore the potential of various combinations of agents against HSV-2, including an adjuvanted trivalent vaccine candidate G103, consisting of recombinantly-expressed viral proteins.
Below is a list of vaccines that are no longer being pursued.
|Vaccine||Organization||Vaccine Type||Reason||Final Results|
|Herpevac, Simplirix||GlaxoSmithKline||Prophylactic, Sub Unit gD2t with alum/MPL adjuvant AS04||Failed in Phase III clinical trial||No statistically significant results found No effect regarding HSV-2 was achieved, partial protection against HSV-1 confirmed|
|Unnamed||PaxVax||Recombinant Vector Vaccine||Discontinued in pre-clinical stage, no longer appears in company's pipeline||N/A|
|ImmunoVEX HSV2 vaccine||Amgen, BioVex||Live, Attenuated, defective in immune evasion||Discontinued in Phase I stage, no longer appears in company's pipeline||N/A|
|Gen-003||Genocea||Sub Unit gD2/ICP4 with Matrix M2 adjuvant||Discontinued after Phase II stage||58% Reduction in Viral Shedding, 69% Reduction in Outbreaks. Spending on vaccine has ceased.|
|AuRx Herpes Vaccine||AuRx||Recombinant Vector Vaccine||Inactive||N/A|
|DISC vaccine||Cantab Pharmaceuticals||Live, Attenuated HSV vaccine with gH deleted||Discontinued in Phase I stage||No clinical or virological benefit was shown|
|Unnamed||Mymetics||?||Discontinued in pre-clinical stage, no longer appears in company's pipeline||N/A|
|HerpV||Agenus||Peptide vaccine/QS-21 adjuvant||Discontinued after Phase II stage||N/A|
|VCL-HB01||Vical||DNA vaccine: gD2+UL46/Vaxfectin adjuvant||Discontinued after Phase II stage||Trial did not show positive outcome.|
Detailed Information on discontinued vaccinesEdit
One vaccine that was under trial was Herpevac, a vaccine against HSV-2. The National Institutes of Health (NIH) in the United States conducted phase III trials of Herpevac. In 2010, it was reported that, after 8 years of study in more than 8,000 women in the United States and Canada, there was no sign of positive results against the sexually transmitted disease caused by HSV-2 (and this despite earlier favorable interim reports).
PaxVax, a specialty vaccine company, partnered with Spector Lab at the UC San Diego Department of Cellular and Molecular Medicine regarding the development of a genital herpes viral vector vaccine. The vaccine was in the pre-clinical stage. The vaccine is no longer listed on their website as a present endeavour and has likely been discontinued.
A private company called BioVex began Phase I clinical trials for ImmunoVEX, another proposed vaccine, in March 2010. The Company had commenced clinical testing in the UK with its vaccine candidate for the prevention and potentially the treatment of genital herpes. The biopharmaceutical company Amgen bought BioVex and their proposed ImmunoVEX vaccine appears to have been discontinued, furthermore it has been removed from the company's research pipeline.
A live, attenuated vaccine (which was proven very effective in clinical trials in Mexico) by the company AuRx has failed to proceed to a Phase III trial in the year 2006, due to financial reasons. The AuRx therapy was shown to be safe and decrease the occurrence of lesions by 86% after one year.
Mymetics is developing a pre-clinical preventative vaccine for HSV 1 and 2 using its virosome technology. There has not been any recent announcement by the company regarding their vaccine, which seems to have been taken off from the company's research product pipeline.
HerpV, a genital herpes vaccine candidate manufactured by the company Agenus, announced Phase II clinical trial results in June 2014. Results showed up to a 75% reduction in viral load and a weak reduction in viral shedding by 14%. These results were achieved after a series of vaccinations and a booster dose after six months, signalling the vaccine may take time to become effective. Further testing results are to show if the vaccine is a viable candidate against genital herpes. There has not been any recent announcement by Agenus regarding the vaccine HerpV, which seems to have been taken off from the company's research product pipeline.
Genocea Biosciences has developed GEN-003, a first-in-class protein subunit T cell-enabled therapeutic vaccine, or immunotherapy, designed to reduce the duration and severity of clinical symptoms associated with moderate-to-severe HSV-2, and to control transmission of the infection. GEN-003 includes the antigens ICP4 and gD2, as well as the proprietary adjuvant Matrix-M. GEN-003 had concluded Phase IIa clinical trials. In December 2015, Genocea announced interim data showing a 58% decrease in viral shedding and a 69% decrease in genital lesions. They also showed one of the doses stopped outbreaks for at least 6 months. GEN-003 was undergoing a Phase IIb clinical trial in the United States. Genocea has announced it would shift their strategic efforts to cancer vaccines while at the same time heavily cutting down on research and development of GEN-003 vaccine against genital herpes. Being unable to secure funding or partnering with another company, Genocea's further vaccine development remains to be determined.
Vical had been awarded grant funding from the National Institute of Allergy and Infectious Diseases division of the NIH to develop a plasmid DNA-based vaccine to inhibit recurring lesions in patients latently infected with herpes simplex virus type 2 (HSV-2). The plasmid DNA encoding the HSV-2 antigens was formulated with Vaxfectin, Vical's proprietary cationic lipid adjuvant. Vical is concluding Phase I clinical trials, while reporting data showing the vaccine candidate failed to meet the primary endpoint. The San Diego-based company was forced to concede that their herpes strategy had misfired, with their vaccine failing to perform as well as a placebo. However, that seemed to may have changed, since 20 June 2016, when Vical released phase I/II results at ASM. Their vaccine (named VCL-HB01) was involved in a Phase II clinical trial. The recent trial, similarly to a past trial again missed the primary endpoint and therefore the company is discontinuing the vaccine and moving to other pipeline products.
Another area of research for HSV treatment or a potential cure is the use of genome editing. It is thought that by cleaving the DNA of HSV that infects neurons, thereby causing destruction or mutational inactivation of the HSV DNA, the virus can be greatly treated or even cured.
The Jerome Lab run by Dr. Keith Jerome at the Fred Hutchinson Cancer Research Center has looked at using zinc finger nuclease as well as endonuclease to prevent HSV from replicating. Most recently Dr. Jerome and his lab were able to demonstrate cleavage of latent HSV in a living organism, which is vital to disabling the virus. The lab is now looking at ways to better optimize the process, including using CRISPR-Cas9, with several years of work expected before clinical trials are considered.
Researchers at Temple University have been researching how to disrupt HSV from replicating that could eventually lead to a cure. Some members of research team at Temple University have also joined forces to create Excision BioTheraputics. The company intends to begin clinical trials in 2019-2020.
Researchers at the University Medical Center Utrecht, using the CRISPR-Cas9 system, have showed promising results in clearing HSV-1 infection by simultaneously targeting multiple essential vital genes in vitro. The researchers are now looking at targeting latent HSV-1 genomes and are investigating in vivo model systems to assess the potential therapeutic application.
Herpes simplex pharmaceutical drugsEdit
A research paper providing an overview of the relatively recent state of research can be found on this page.
Since the introduction of the nucleoside analogs decades ago, treatment of herpes simplex virus (HSV) infections has not seen much innovation, except for the development of their respective prodrugs (Aciclovir, Famciclovir, Valacilovir..). Drawbacks such as poor bioavailability or limited effectiveness of these drugs require further research effort of new pharmaceutical drugs against the herpes simplex disease. The inhibitors of the Helicase-primase complex of HSV represent a very innovative approach to the treatment of herpesvirus disease.
|Pharmaceutical Drug||Company||Lead Researcher||Type||Status|
|Aciclovir||patents expired||Schaeffer & B. Elion||nucleic acid analogue||In Production|
|Valaciclovir||patents expired||?||nucleic acid analogue||In Production|
|Famciclovir||patents expired||?||nucleic acid analogue||In Production|
|Pritelivir||AICuris||?||helicase-primase inhibitor||Phase II|
|Amenamevir||Astellas Pharma Inc||Kiyomitsu Katsumata||helicase-primase inhibitor||In Production|
|BX795||?||Deepak Shukla||kinase inhibitor||Preclinical|
|SADBE||Squarex, LLC||Hugh McTavish, PhD, JD||Topical solution; immunological adjuvant||Phase II|
Researchers have made a Hammerhead ribozyme that targets and cleaves the mRNA of essential genes in HSV-1. The hammerhead, which targets the mRNA of the UL20 gene, greatly reduced the level of HSV-1 ocular infection in rabbits, and reduced the viral yield in vivo. The gene-targeting approach uses a specially designed RNA enzyme to inhibit strains of the herpes simplex virus. The enzyme disables a gene responsible for producing a protein involved in the maturation and release of viral particles in an infected cell. The technique appears to be effective in experiments with mice and rabbits, but further research is required before it can be attempted in people infected with herpes.
In 2016, researchers showed that the genome editing technology known as CRISPR/Cas can be used to limit viral replication in multiple strains of herpesviruses, in some cases even eliminating the infection altogether. The researchers tested three different strains of herpesviruses: Epstein-Barr virus (EBV), the cause of mononucleosis and some cancers; Herpes simplex viruses (HSV-1) and (HSV-2), which cause cold sores and genital herpes respectively; and Human cytomegalovirus (HCMV), which causes congenital herpes.The results indicated that CRISPR can be used to eliminate replication in all three strains of the virus, but that the technology was so far only successful in actually eradicating EBV. The authors think this may be because the EBV genome is located in dividing cells that are easily accessible to CRISPR. Comparatively, the HSV-1 genome targeted by CRISPR is located in closed-off, non-replicating neurons, which makes reaching the genome much more challenging.
Another possibility to eradicate the HSV-1 variant is being pursued by a team at Duke University. By figuring out how to switch all copies of the virus in the host from latency to their active stage at the same time, rather than the way the virus copies normally stagger their activity stage, leaving some dormant somewhere at all times, it is thought that immune system could kill the entire infected cell population, since they can no longer hide in the nerve cells. This is a potentially risky approach especially for patients with widespread infections as there is the possibility of significant tissue damage from the immune response. One class of drugs called antagomir could trigger reactivation. These are chemically engineered oligonucleotides or short segments of RNA, that can be made to mirror their target genetic material, namely herpes microRNAs. They could be engineered to attach and thus 'silence' the microRNA, thus rendering the virus incapable of keeping latent in their host. Professor Cullen believes a drug could be developed to block the microRNA whose job it is to suppress HSV-1 into latency.
Herpes has been used in research with HeLa cells to determine its ability to assist in the treatment of malignant tumors. A study conducted using suicide gene transfer by a cytotoxic approach examined a way to eradicate malignant tumors. Gene therapy is based on the cytotoxic genes that directly or indirectly kill tumor cells regardless of its gene expression. In this case the study uses the transfer of the Herpes simplex virus type I thymidine kinase (HSVtk) as the cytotoxic gene. Hela cells were used in these studies because they have very little ability to communicate through gap junctions. The Hela cells involved were grown in a monolayer culture and then infected with the HSV virus. The HSV mRNA was chosen because it is known to share characteristics with normal eukaryotic mRNA.
The HSVtk expression results in the phosphorylation of drug nucleoside analogues; in this case the drug ganciclovir, an anitiviral medication used to treat and prevent cytomegaloviruses, converts it into the nucleoside analogue triphosphates. Once granciclovir is phosphorylated through HSV-tk it is then incorporating DNA strands when the cancer cells are multiplying. The nucleotide from the ganciclovir is what inhibits the DNA polymerization and the replication process. This causes the cell to die via apoptosis.
Apoptosis is regulated with the help of miRNAs, which are small non-coding RNAs that negatively regulate gene expression. These miRNAs play a critical role in developing the timing, differentiation and cell death. The miRNAs effect on apoptosis has affected cancer development by the regulation of cell proliferation, as well as cell transformation. Avoidance of apoptosis is critical for the success of malignant tumors, and one way for miRNAs to possibly influence cancer development is to regulate apoptosis. In order to support this claim, Hela cells were used for the experiment discussed.
The cytotoxic drug used, ganciclovir, is capable of destroying via apoptosis transduced cells and non-transduced cells from the cellular gap junction. This technique is known as the "bystander effect," which has suggested to scientists that the effect of some therapeutic agents may be enhanced by diffusion through gap junctional intercellular communication (GJIC) or cell coupling. GJIC is an important function in the maintaining of tissue homeostasis and it is a critical factor in balance of cells dying and surviving.
When Hela cells were transfected with the HSV-tk gene, and were then put in a culture with nontransfected cells, only the HSV-tk transfected Hela cells were killed by the granciclovir, leaving the nonviral cells unharmed. The Hela cells were transfected with the encoding for the gap junction protenin connexin 43 (Cx43) to provide a channel that permits ions and other molecules to move between neighboring cells. Both Hela cells with the HSV-tk and without the HSV-tk were destroyed. This result has led to the evidence needed to state that the bystander effect in the HSV-tk gene therapy is possibly due to the Cx-mediated GJIC.
- Chentoufi AA, Kritzer E, Yu DM, Nesburn AB, Benmohamed L (2012). "Towards a rational design of an asymptomatic clinical herpes vaccine: the old, the new, and the unknown". Clinical & Developmental Immunology. 2012: 1–16. doi:10.1155/2012/187585. PMC 3324142. PMID 22548113.
- Whitley RJ, Roizman B (July 2002). "Herpes simplex viruses: is a vaccine tenable?". The Journal of Clinical Investigation. 110 (2): 145–51. doi:10.1172/JCI16126. PMC 151069. PMID 12122103.
- "Efficacy in Adults Aged 50 Years or Older". Retrieved 2018-01-15.
- "VARIVAX® Varicella Virus Vaccine Live" (PDF). Retrieved 30 August 2016.
- "VARILRIX® Live attenuated varicella vaccine" (PDF). Retrieved 23 August 2016.
- "Releve epidemiologique hebdomadaire / Section d'hygiene du Secretariat de la Societe des Nations = Weekly epidemiological record / Health Section of the Secretariat of the League of Nations" (PDF). Retrieved 2018-07-03.
- "Vaccine Detail GSK1437173A". Retrieved 31 August 2016.
- Sandgren KJ, Bertram K, Cunningham AL (July 2016). "Understanding natural herpes simplex virus immunity to inform next-generation vaccine design". Clinical & Translational Immunology. 5 (7): e94. doi:10.1038/cti.2016.44. PMC 4973325. PMID 27525067.
- "Shingrix, herpes zoster vaccine (recombinant, adjuvanted)". Retrieved 2018-07-02.
- Loyd L (2017-06-21). "GlaxoSmithKline reports positive results with its shingles vaccine". Philly.com. Retrieved 2017-09-26.
- "Admedus AU Immunotherapies". www.admedus.com. Retrieved 2017-01-18.
- "Admedus US Research & Development - Admedus US". www.admedus.com. Retrieved 2016-08-02.
- "ADMEDUS ANNOUNCES POSITIVE UNBLINDED HSV-2 PHASE II INTERIM DATA" (PDF). Admedus. 19 October 2016.
- "Knipe Lab | Harvard Medical School". knipelab.med.harvard.edu. Retrieved 2016-08-02.
- Lee YC (December 1967). "Ventricular fusion beats". JAMA. 202 (10): S415–S416. doi:10.1093/ofid/ofx163.1041. PMC 5630753.
- Stanfield BA, Stahl J, Chouljenko VN, Subramanian R, Charles AS, Saied AA, Walker JD, Kousoulas KG (2014). "A single intramuscular vaccination of mice with the HSV-1 VC2 virus with mutations in the glycoprotein K and the membrane protein UL20 confers full protection against lethal intravaginal challenge with virulent HSV-1 and HSV-2 strains". PLOS ONE. 9 (10): e109890. Bibcode:2014PLoSO...9j9890S. doi:10.1371/journal.pone.0109890. PMC 4211657. PMID 25350288.
- Stanfield BA, Pahar B, Chouljenko VN, Veazey R, Kousoulas KG (January 2017). "Vaccination of rhesus macaques with the live-attenuated HSV-1 vaccine VC2 stimulates the proliferation of mucosal T cells and germinal center responses resulting in sustained production of highly neutralizing antibodies". Vaccine. 35 (4): 536–543. doi:10.1016/j.vaccine.2016.12.018. PMID 28017425.
- Stanfield BA, Rider PJ, Caskey J, Del Piero F, Kousoulas KG (May 2018). "Intramuscular vaccination of guinea pigs with the live-attenuated human herpes simplex vaccine VC2 stimulates a transcriptional profile of vaginal Th17 and regulatory Tr1 responses". Vaccine. 36 (20): 2842–2849. doi:10.1016/j.vaccine.2018.03.075. PMID 29655629.
- "Herpes Virus Mutant Points Towards New Vaccine Strategy". news.feinberg.northwestern.edu. Retrieved 2018-08-13.
- Richards AL, Sollars PJ, Pitts JD, Stults AM, Heldwein EE, Pickard GE, Smith GA (December 2017). "The pUL37 tegument protein guides alpha-herpesvirus retrograde axonal transport to promote neuroinvasion". PLoS Pathogens. 13 (12): e1006741. doi:10.1371/journal.ppat.1006741. PMC 5749899. PMID 29216315.
- Petro CD, Weinrick B, Khajoueinejad N, Burn C, Sellers R, Jacobs WR, Herold BC (August 2016). "HSV-2 ΔgD elicits FcγR-effector antibodies that protect against clinical isolates". JCI Insight. 1 (12). doi:10.1172/jci.insight.88529. PMC 4985247. PMID 27536733.
- "New Genital Herpes Vaccine Candidate Provides Powerful Protection in Preclinical Tests". Penn Medicine News. 19 January 2017. Retrieved 28 January 2017.
- "Penn Institute for Immunology - The Friedman laboratory". med.upenn.edu. 2018-09-03. Retrieved 2018-10-01.
- Awasthi S, Hook LM, Shaw CE, Pahar B, Stagray JA, Liu D, Veazey RS, Friedman HM (January 2017). "An HSV-2 Trivalent Vaccine Is Immunogenic in Rhesus Macaques and Highly Efficacious in Guinea Pigs". PLoS Pathogens. 13 (1): e1006141. doi:10.1371/journal.ppat.1006141. PMC 5245903. PMID 28103319.
- "Immune Design Pipeline". Immune Design. Retrieved 22 April 2017.
- Odegard JM, Flynn PA, Campbell DJ, Robbins SH, Dong L, Wang K, Ter Meulen J, Cohen JI, Koelle DM (January 2016). "A novel HSV-2 subunit vaccine induces GLA-dependent CD4 and CD8 T cell responses and protective immunity in mice and guinea pigs". Vaccine. 34 (1): 101–9. doi:10.1016/j.vaccine.2015.10.137. PMC 6322202. PMID 26571309.
- "GV2207 – HSV-2 Immunotherapeutic :: GenVec, Inc. (GNVC)". www.genvec.com. Retrieved 2016-08-16.
- "Nanobio - HSV-2 Vaccine". Retrieved 2 August 2016.
- Corporation, NanoBio. "NanoBio's Genital Herpes Vaccine Demonstrates Efficacy In Guinea Pigs As Both A Prophylactic And A Therapeutic Vaccine". Retrieved 2 August 2016.
- "PBS Vax™ Therapeutic Vaccines". profectusbiosciences.com. Retrieved 15 August 2016.
- "Introducing RVx". 2016-03-12. Retrieved 2016-08-02.
- "Herpes Vaccine Research". Herpes Vaccine Research. Retrieved 2016-08-02.
- "FDA Launches Criminal Investigation Into Unauthorized Herpes Vaccine Research". khn.org. Retrieved 2018-05-21.
- "Rational Vaccines: A case study in pharma deregulation - MedCity News". medcitynews.com. March 2017. Retrieved 26 September 2017.
- "Herpes Virus Mutant Points Towards New Vaccine Strategy".
- Halford WP, Püschel R, Gershburg E, Wilber A, Gershburg S, Rakowski B (March 2011). "A live-attenuated HSV-2 ICP0 virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine". PLOS ONE. 6 (3): e17748. Bibcode:2011PLoSO...617748H. doi:10.1371/journal.pone.0017748. PMC 3055896. PMID 21412438.
- Halford WP, Geltz J, Gershburg E (2013). "Pan-HSV-2 IgG antibody in vaccinated mice and guinea pigs correlates with protection against herpes simplex virus 2". PLOS ONE. 8 (6): e65523. Bibcode:2013PLoSO...865523H. doi:10.1371/journal.pone.0065523. PMC 3675040. PMID 23755244.
- Halford WP, Püschel R, Rakowski B (August 2010). "Herpes simplex virus 2 ICP0 mutant viruses are avirulent and immunogenic: implications for a genital herpes vaccine". PLOS ONE. 5 (8): e12251. Bibcode:2010PLoSO...512251H. doi:10.1371/journal.pone.0012251. PMC 2923193. PMID 20808928.
- Bloom J (2018-02-08). "I Met With A Theravax Herpes Vaccine Patient And Here Is What He Said". acsh.org. Retrieved 2018-08-09.
- Mundle ST, Hernandez H, Hamberger J, Catalan J, Zhou C, Stegalkina S, Tiffany A, Kleanthous H, Delagrave S, Anderson SF (2013). "High-purity preparation of HSV-2 vaccine candidate ACAM529 is immunogenic and efficacious in vivo". PLOS ONE. 8 (2): e57224. Bibcode:2013PLoSO...857224M. doi:10.1371/journal.pone.0057224. PMC 3582571. PMID 23468943.
- "Immunization with a replication-defective herpes simplex virus 2 mutant reduces herpes simplex virus 1 infection and prevents ocular disease" (PDF). ScienceDirect. Retrieved May 20, 2014.
- "NIH Launches Trial of Investigational Genital Herpes Vaccine". NIAID. Retrieved 17 September 2014.
- "Comparative Efficacy and Immunogenicity of Replication-Defective, Recombinant Glycoprotein, and DNA Vaccines for Herpes Simplex Virus 2 Infections in Mice and Guinea Pigs" (PDF). JOURNAL OF VIROLOGY. Retrieved May 20, 2014.
- "FOCUS | March 7, 2008 | LICENSING: Herpes Vaccine Developed at HMS Licensed for Preclinical Trials".
- "Potential Cure For Herpes Simplex Virus". HSV Outbreak. Retrieved 19 August 2014.
- "Gardasil inventor Professor Ian Frazer's new genital herpes vaccine proves safe in passing first human trials". Retrieved 21 February 2014.
- "Admedus vaccine for herpes has success; moves to next clinical trial". Proactive Investors. Retrieved 3 October 2014.
- "Admedus increases interest in Prof Ian Frazer's vaccines". Proactive Investors. 2014-07-24. Retrieved 3 September 2014.
- "Admedus has high hopes for Herpes vaccine as dosing commences - Proactiveinvestors (AU)". 2015-04-10. Retrieved 2 August 2016.
- "ADMEDUS ANNOUNCES POSITIVE UNBLINDED HSV-2 PHASE II INTERIM DATA" (PDF). Admedus.
- "Витагерпавак". vitagerpavak.ru. Retrieved 2018-11-09.
- Petro C, González PA, Cheshenko N, Jandl T, Khajoueinejad N, Bénard A, Sengupta M, Herold BC, Jacobs WR (March 2015). "Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease". eLife. 4. doi:10.7554/eLife.06054. PMC 4352706. PMID 25756612.
- "Radical Vaccine Design Effective Against Herpes Virus". HHMI.org. Retrieved 12 March 2015.
- "NanoBio's Genital Herpes Vaccine Demonstrates Efficacy In Guinea Pigs As Both A Prophylactic And A Therapeutic Vaccine". NanoBio Corporation. Retrieved 2 October 2015.
- "Pipeline for PBS Vax™ Therapeutic Vaccines". Profectus Biosciences. Retrieved 12 December 2015.
- "BioMedical Research Models Inc awarded Grant for Mucosal HSV-2 vaccine". Vaccine Nation (Cameron Bisset). Retrieved 13 June 2014.
- "Project Information - NIH RePORTER - NIH Research Portfolio Online Reporting Tools Expenditures and Results". Retrieved 2 August 2016.
- "HSV2 therapeutic vaccine program".
- "Sanofi Pasteur and Immune Design Enter Broad Collaboration for the Development of a Herpes Simplex Virus Therapy". Retrieved 17 October 2014.
- "Status of Vaccine Research and Development of Vaccines for Herpes Simplex Virus" (PDF). Retrieved 30 August 2016.
- "QUESTIONS AND ANSWERS The Herpevac Trial for Women". Retrieved 30 August 2016.
- Cohen J (October 2010). "Immunology. Painful failure of promising genital herpes vaccine". Science. 330 (6002): 304. Bibcode:2010Sci...330..304C. doi:10.1126/science.330.6002.304. PMID 20947733.
- "Better Neutralization of Herpes Simplex Virus Type 1 (HSV-1) Than HSV-2 by Antibody From Recipients of GlaxoSmithKline HSV-2 Glycoprotein D2 Subunit Vaccine". The Journal of Infectious Diseases. 2014-08-15. Retrieved 10 July 2019.
- "PaxVax Signs R&D Collaboration with UC San Diego to Develop a Vaccine to Prevent Herpes Simplex Virus Infections". paxvax.com. 2014-06-10. Retrieved 15 August 2016.
- "About". Retrieved 4 January 2017.
- "The PaxVax Platform - Product Pipeline". Retrieved 5 September 2016.
- Awasthi S, Zumbrun EE, Si H, Wang F, Shaw CE, Cai M, Lubinski JM, Barrett SM, Balliet JW, Flynn JA, Casimiro DR, Bryan JT, Friedman HM (April 2012). "Live attenuated herpes simplex virus 2 glycoprotein E deletion mutant as a vaccine candidate defective in neuronal spread". Journal of Virology. 86 (8): 4586–98. doi:10.1128/JVI.07203-11. PMC 3318599. PMID 22318147.
- "Amgen Pipeline". Retrieved 2 August 2016.
- "Genocea Announces Strategic Shift to Immuno-oncology and the Development of Neoantigen Cancer Vaccines". Genocea. 25 September 2017. Archived from the original on 2017-09-26.
- "AuRx, Inc". AuRx. Retrieved 4 January 2017.
- "AuRx, Inc". AuRx. Retrieved 4 January 2017.
- McAllister SC, Schleiss MR (November 2014). "Prospects and perspectives for development of a vaccine against herpes simplex virus infections". Expert Review of Vaccines. 13 (11): 1349–60. doi:10.1586/14760584.2014.932694. PMC 4385587. PMID 25077372.
- "Mymetics HSV Vaccine Candidate". Mymetics. Retrieved 22 April 2016.
- "Biological Efficacy Study of HerpV Vaccine With QS-21 to Treat Subjects With Recurrent Genital Herpes". Retrieved 31 August 2016.
- "Vical HSV-2 Therapeutic Vaccine VCL-HB01". Retrieved 18 January 2016.
- "Vical Reports Phase 2 Trial of HSV-2 Therapeutic Vaccine Did Not Meet Primary Endpoint". Vical.com. Retrieved 16 June 2018.
- "Herpevac Trial for Women". Archived from the original on 2007-10-20. Retrieved 2008-03-04.
- "PaxVax Signs R&D Collaboration with UC San Diego to Develop a Vaccine to Prevent Herpes Simplex Virus Infections - PaxVax - Socially Responsible Vaccines". 2014-06-10. Retrieved 2 August 2016.
- "BioVex commences dosing in Phase 1 study of ImmunoVEX live attenuated genital herpes vaccine". 5 March 2010. Retrieved 2 August 2016.
- "Amgen completes acquisition of BioVex Group". Boston.com. 4 March 2011. Retrieved 2 August 2016 – via The Boston Globe.
- "AuRx, Inc". Retrieved 2 August 2016.
- "Agenus Vaccine Shows Significant Reduction in Viral Burden after HerpV Generated Immune Activation". Business Wire. 2014-06-26. Retrieved 10 September 2014.
- "Herpes News: Early 2014 Roundup - Just Herpes". 2014-03-07. Retrieved 2 August 2016.
- "Pipeline - Agenus". agenusbio.com. Retrieved 26 September 2017.
- "Genocea Corporate Overview" (PDF). Genocea. Retrieved 5 March 2016.
- "Genocea Announces Strategic Shift to Immuno-oncology and the Development of Neoantigen Cancer Vaccines". genocea.com. Retrieved 26 September 2017.
- "Vical (VICL) Genital Herpes Vaccine Phase 1/2 Missed Primary Endpoint". StreetInsider.com. Retrieved 22 June 2015.
- "Vical Reports Top-Line Results From Phase 1/2 Trial of Therapeutic Genital Herpes Vaccine". FierceMarkets. 22 June 2015. Retrieved 23 June 2015.
- "Vical's Phase 1/2 Trial Data Presented at ASM 2016 Shows Bivalent Vaccine Imparts Reduction in Genital Herpes Lesions Durable to 9 Months". Globe Newswire. 2018-06-20. Retrieved 29 June 2018.
- Kennedy EM, Cullen BR (January 2017). "Gene Editing: A New Tool for Viral Disease". Annual Review of Medicine. 68 (1): 401–411. doi:10.1146/annurev-med-051215-031129. PMID 27576009.
- Aubert M, Madden EA, Loprieno M, DeSilva Feelixge HS, Stensland L, Huang ML, Greninger AL, Roychoudhury P, Niyonzima N, Nguyen T, Magaret A, Galleto R, Stone D, Jerome KR (September 2016). "In vivo disruption of latent HSV by designer endonuclease therapy". JCI Insight. 1 (14). doi:10.1172/jci.insight.88468. PMC 5026126. PMID 27642635.
- Engel M (8 September 2016). "Can gene editing cure herpes?". Fred Hutch News Service. Retrieved 7 January 2017.
- Kennedy EM, Cullen BR (May 2015). "Bacterial CRISPR/Cas DNA endonucleases: A revolutionary technology that could dramatically impact viral research and treatment". Virology. 479-480: 213–20. doi:10.1016/j.virol.2015.02.024. PMC 4424069. PMID 25759096.
- Roehm PC, Shekarabi M, Wollebo HS, Bellizzi A, He L, Salkind J, Khalili K (April 2016). "Inhibition of HSV-1 Replication by Gene Editing Strategy". Scientific Reports. 6: 23146. Bibcode:2016NatSR...623146R. doi:10.1038/srep23146. PMC 4827394. PMID 27064617.
- Gordon L (2016-01-26). "Researchers aim to find cure for herpes". The Temple News. Retrieved 8 January 2017.
- "Therapeutic and Vaccine Pipeline". Excision BioTherapeutics - Gene Editing Therapeutics. Excision BioTherapeutics. Retrieved 19 January 2017.
- van Diemen FR, Kruse EM, Hooykaas MJ, Bruggeling CE, Schürch AC, van Ham PM, Imhof SM, Nijhuis M, Wiertz EJ, Lebbink RJ (June 2016). "CRISPR/Cas9-Mediated Genome Editing of Herpesviruses Limits Productive and Latent Infections". PLoS Pathogens. 12 (6): e1005701. doi:10.1371/journal.ppat.1005701. PMC 4928872. PMID 27362483.
- Kassabian S (4 August 2016). "CRISPR Puts Up a Fight Against Persistent Herpesviruses: A Short Animation". PLOS BLOGS. Retrieved 8 January 2017.
- Helicase–primase inhibitors as the potential next generation of highly active drugs against herpes simplex viruses
- "AiCuris - R&D Pipeline". www.aicuris.com. Retrieved 2016-09-16.
- Katsumata K, Chono K, Sudo K, Shimizu Y, Kontani T, Suzuki H (August 2011). "Effect of ASP2151, a herpesvirus helicase-primase inhibitor, in a guinea pig model of genital herpes". Molecules. 16 (9): 7210–23. doi:10.3390/molecules16097210. PMC 6264763. PMID 21869749.
- "Products". 2016-11-10.
- "Double-blind, Vehicle-controlled Study of the Efficacy and Safety of SADBE in Subjects With Recurrent Herpes Labialis - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 29 January 2019.
- Molecular Therapy (2006-05-01). "Molecular Therapy – Abstract of article: 801. RNA Gene Therapy Targeting Herpes Simplex Virus". Nature.com. Retrieved 2011-04-12.
- "University of Florida News –Potential new herpes therapy studied". News.ufl.edu. 2009-02-03. Archived from the original on 2010-06-13. Retrieved 2011-04-12.
- Kassabian S (2016-08-04). "CRISPR Puts Up a Fight Against Persistent Herpesviruses: A Short Animation". Speaking of Medicine - PLOS Community Blog. PLOS.org. Retrieved 4 August 2016.
- van Diemen FR. "Using CRISPR to combat viral infections: a new way to treat herpes?". PLOS Media YouTube Channel. PLOS.org. Retrieved 4 August 2016.
- Fox M (2008-07-02). "New approach offers chance to finally kill herpes". Reuters. Retrieved 2011-04-12.
- Kingsbury K (2008-07-02). "A Cure for Cold Sores?". Time. Retrieved 2010-05-04.
- Trepel M, Stoneham CA, Eleftherohorinou H, Mazarakis ND, Pasqualini R, Arap W, Hajitou A (August 2009). "A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage-mediated, vascular-targeted suicide gene transfer". Molecular Cancer Therapeutics. 8 (8): 2383–91. doi:10.1158/1535-7163.MCT-09-0110. PMC 2871293. PMID 19671758.
- Mesnil M, Piccoli C, Tiraby G, Willecke K, Yamasaki H (March 1996). "Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins". Proceedings of the National Academy of Sciences of the United States of America. 93 (5): 1831–5. Bibcode:1996PNAS...93.1831M. doi:10.1073/pnas.93.5.1831. PMC 39867. PMID 8700844.
- Stringer JR, Holland LE, Swanstrom RI, Pivo K, Wagner EK (March 1977). "Quantitation of herpes simplex virus type 1 RNA in infected HeLa cells". Journal of Virology. 21 (3): 889–901. PMC 515626. PMID 191652.
- Jovanovic M, Hengartner MO (October 2006). "miRNAs and apoptosis: RNAs to die for". Oncogene. 25 (46): 6176–87. doi:10.1038/sj.onc.1209912. PMID 17028597.