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 (CMV), and Epstein-Barr (EBV).
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 2016, 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.
Vaccine candidate
The chart below is an attempt to list all known proposed vaccines and their characteristics. Please update with any missing information on vaccines only.
Attenuated vaccines
Live, attenuated variant of the HSV-2 vaccine
Diverse subunit HSV vaccines (e.g. Herpevac) have failed to protect humans from acquiring genital herpes in several clinical trials. The success of the chickenpox vaccine demonstrates that a live and appropriately attenuated α-herpesvirus may be used to safely control human disease. A vaccine of this type would present a slow replication process of HSV, thereby also damping down the immune evasion strategies of the virus while simultaneously exposing the host to the full complement of HSV's majority of viral proteins. As a consequence, it is the intent of the vaccine to expose the individual's immune response to the HSV proteins it may have been missing from a wild type virus in order to effectively control the disease. From a historical retrospective, such live attenuated vaccines have had the most success in preventing diseases until today. Dr. William Halford at the Southern Illinois University (SIU) School of Medicine is presently testing a live-attenuated HSV-2 ICP0‾ vaccine. Already proven as safe and effective in studies on animals, eliciting 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine, Halford's vaccine is now currently involved in clinical trials.
In 2016, Rational Vaccines, the company which was founded by Halford, had promising results injecting his vaccine in 20 human subjects, 17 of which got all 3 shots, (the other 3, only 2 shots). 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 can not be instigated by a placebo effect.
Replication-defective HSV-2 vaccine
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). It has also been shown that 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, 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. Both 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.
HSV-529 has concluded phase I clinical trials in March 2017.
Glycoprotein gD- and DNA-based vaccines
Admedus's 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, 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 new vaccine against genital herpes has 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.
Genocea's vaccine
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 is concluding 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 is undergoing a Phase IIb clinical trial in the United States.
Recently, 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.
Other vaccines
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.
Profectus BioSciences intends to use its PBS Vax therapeutic vaccine technology to engineer a vaccine for HSV-2. The vaccine is in early development and much is unknown about its viability.
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 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.
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.
Mymetics is developing a pre-clinical preventative vaccine for HSV 1 and 2 using its virosome technology. Not much is known about this vaccine or its viability.
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 may have changed, since 20 June 2016, when Vical released phase I/II results at ASM.
Discontinued vaccines
Below is a list of vaccines that are no longer being pursued.
Detailed Information
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. The fact that a live, attenuated vaccine induced better protection from HSV infection and symptoms is not new, because live-attenuated vaccines account for the most of the successful vaccines in the use until today. However, governmental and corporate bodies seem to support the more recent but possibly less effective approaches such as Glycoprotein and DNA based vaccines.
Genome editing
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.
Notable research
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.
The Cullen Lab run by Dr. Bryan Cullen at the Duke University School of Medicine is researching a cure for HSV using the CRISPR-Cas9 system. The Cullen lab is presently researching its use for Herpes simplex keratitis and has partnered with Editas Medicine to advance the technology.
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 2018.
Researchers at the University Medical Center Utrecht using the CRISPR-Cas9 system have showed promising results in clearing HSV-1 infection by using simultaneous targeting of 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 virus
A research paper providing an overview of the relatively recent state of research can be found on this page.
Pharmaceutical drugs
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. Even though new categories of drugs may seem promising, these would still be only more effective therapeutic drugs, because the permanent removal of herpes simplex symptoms in patients is highly unlikely, due to the fact that HSV is neurotropic and the virus reservoirs lie within neural tissue.
Notable progress
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.
References
