Vaccine Research 1p2p3h

Vaccine Research[edit] Various vaccine candidates have been developed, the first ones in the 1920s, but none has been successful to date.[1] Due to the genetic similarity of both herpes simplex virus types (HSV-1 and HSV-2), the development of a prophylactic-therapeutic vaccine which is proven effective against one type of the virus would provide fundamentals for vaccine-development for the other virus type. As of 2015, several vaccine candidates are in different stages of clinical trials as they are being tested for safety and efficacy, including at least three vaccine candidates in the US and one in Australia. 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.[2]

Attenuated Vaccines[edit] Live, Attenuated Variant of the HSV-2 Vaccine[edit] While until the present day, 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 a human disease. This principle may be expanded to include HSV-1 or HSV-2 as portrayed in a new approach of the HSV-2 I0 live-attenuated HSV-2 vaccine investigated by Professor William Halford at the Southern Illinois University (SIU) School of Medicine.[3][4] Although already proven as very safe and effective in studies on animals, Halford's vaccine is currently not involved in any clinical trials, mainly due to lack of funding.[5][6] Replication-defective HSV-2 Vaccine[edit]

Principle of HSV529

Professor David Knipe, in his laboratory at Harvard Medical School has developed dl5-29. The dl529 vaccine is also known under the name ACAM-529[7] 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.[8] 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).[9] 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; greatly reduces the severity of recurrent disease; provides crossprotection against HSV-1; and renders the virus unable to revert to a virulent state or to become latent.[10] The vaccine is now being researched and developed by Sanofi Pasteur.[11] 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.[12]

The NIH in collaboration with Sanofi Pasteur is testing the drug in Phase I clinical trial of HSV-529. The trial is expected to be completed in October 2016.

Glycoprotein gD- and DNA-based vaccines[edit] edus's Vaccine[edit] 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 edus 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.[13] 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 ed human safety trials in a trial of 20 Australians.[14] In October 2014, edus announced success in creating a positive T-cell response in 95% of participants.[15] Further research is required to determine if the vaccine can prevent transmission. In July 2014, edus increased its stake in Professor Frazer's vaccines by 16.2%. In addition, $18.4 million was posted as funds raised towards Phase II vaccine testing and research. [16] The Phase II trial began in April 2015 with results expected by the end of the year.[17] Genocea's Vaccine[edit] 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 I4 and gD2, as well as the proprietary adjuvant Matrix-M. Results from the 1/2a study showed a strong reduction of genital lesions by 65% and reduction in viral shedding by 52%.[18] GEN-003 is undergoing Phase II clinical trials. In May 2015, Genocea announced top line data showing better than expected results from the Phase 1/2a trial - including a 55% decrease in viral shedding. The study continues into first quarter of 2016. [19] More information on Phase II top line results can be found here.

Other Vaccines[edit] 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.[20] 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.[21] 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%.[22] 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.[23]

PaxVax, a specialty vaccine company has started a cooperation with the Spector Lab at the UC San Diego Department of Cellular and Molecular Medicine, regarding the development of a genital herpes viral vectorvaccine, which is currently in the preclinical stage. [24] 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. [25] 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.[26]

Discontinued Vaccines[edit] 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.[27] 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 [28] (and this despite earlier favorable interim reports[27]). 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.[29] 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. [30] A private company called BioVex began Phase I clinical trials for ImmunoVEX, another proposed vaccine, in March 2010.[31] 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[32] and their proposed Immunovex vaccine appears to have been discontinued, furthermore it has been removed from the company's research pipeline. [33] 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.[34] The fact that a live, attenuated vaccine induced better protection from HSV infection and symptoms is not new, because live-attenuated vaccines for the most of the successful vaccines in the use until today. However, governmental and corporate bodies seem to the more recent but possibly less effective approaches such as Glycoprotein and DNA based vaccines. [citation needed]

Herpes Simplex Virus Research[edit] Researchers at the University of Florida 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.[35] 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.[36] 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. [37] Professor Cullen believes a drug could be developed to block the microRNA whose job it is to suppress HSV-1 into latency.[38] 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.[39] 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.[40] 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.[41] 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.[40] The nucleotide from the ganciclovir is what inhibits the DNA polymerization and the replication process. This causes the cell to die via apoptosis.[39] Apoptosis is regulated with the help of miRNAs, which are small non-coding RNAs that negatively regulate gene expression.[42] 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 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.[40] 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. 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. The inhibitors of the helicase–primase complex of HSV represent a very innovative approach to the treatment of herpesvirus disease.[43]

References[edit] 1.

Jump up^ 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". Clin. Dev. Immunol. 2012: 187585. doi:10.1155/2012/187585. PMC 3324142.PMID 22548113.

2.

Jump up^ Whitley, Richard J. and Roizman, Bernard (15 July 2002). "Herpes simplex viruses: is a vaccine tenable?". J Clin Invest. 110 (2): 145– 151. doi:10.1172/JCI16126. PMC 151069. PMID 12122103.

3.

Jump up^ Halford WP, Püschel R, Gershburg E, Wilber A, Gershburg S, Rakowski B (2011). "A live-attenuated HSV-2 I0 virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine". PLoS ONE 6 (3): e17748.doi:10.1371/journal.pone.0017748. PMC 3055896.PMID 21412438.

4.

Jump up^ Halford WP, Geltz J, Gershburg E. "Pan-HSV-2 IgG Antibody in Vaccinated Mice and Guinea Pigs Correlates with Protection against Herpes Simplex Virus 2". PLoS ONE 8 (6): e65523.doi:10.1371/journal.pone.0065523. Retrieved 9 March 2014.

5.

Jump up^ William, Halford. "Herpes Vaccine Research".

6.

Jump up^ Halford WP. "Funding". Retrieved 21 July 2015.

7.

Jump up^ "High-purity preparation of HSV-2 vaccine candidate ACAM529 is immunogenic and efficacious in vivo". PLoS One. Retrieved May 20,2014.

8.

Jump up^ "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.

9.

Jump up^ "NIH Launches Trial of Investigational Genital Herpes Vaccine".NIAID. Retrieved 17 September 2014.

10.

Jump up^ "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.

11.

Jump up^ "FOCUS | March 7, 2008 | LICENSING: Herpes Vaccine Developed at HMS Licensed for Preclinical Trials".

12.

Jump up^ "Sanofi Pasteur and Immune Design Enter Broad Collaboration for the Development of a Herpes Simplex Virus Therapy". Retrieved17 October 2014.

13.

Jump up^ "Potential Cure For Herpes Simplex Virus". HSV Outbreak. Retrieved 19 August 2014.

14.

Jump up^ "Gardasil inventor Professor Ian Frazer's new genital herpes vaccine proves safe in ing first human trials". Retrieved 21 February2014.

15.

Jump up^ "edus vaccine for herpes has success; moves to next clinical trial". Proactive Investors. Retrieved 3 October 2014.

16.

Jump up^ "edus increases interest in Prof Ian Frazer’s vaccines". Proactive Investors. Retrieved 3 September 2014.

17.

Jump up^http://www.proactiveinvestors.com.au/companies/news/61686/edus-has-highhopes-for-herpes-vaccine-as-dosing-commences-61686.html

18.

Jump up^ "Genocea HSV-2 Immunotherapeutic GEN-003 Elicits Significant, Durable T Cell Responses in Vaccinated Subjects". Market Watch. Retrieved 10 September 2014.

19.

Jump up^ "Genocea Announces Positive Top-Line Phase 2 Data for Genital Herpes Immunotherapy GEN-003". Genocea. Retrieved 7 June 2015.

20.

Jump up^ "Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease". eLife Science. Retrieved12 March 2015.

21.

Jump up^ "Radical Vaccine Design Effective Against Herpes Virus". HHMI.org. Retrieved 12 March 2015.

22.

Jump up^ "Agenus Vaccine Shows Significant Reduction in Viral Burden after HerpV Generated Immune Activation". Business Wire. Retrieved10 September 2014.

23.

Jump up^ Herpes News: Early 2014 Roundup

24.

Jump up^ PaxVax Signs R&D Collaboration with UC San Diego to Develop a Vaccine to Prevent Herpes Simplex Virus Infections

25.

Jump up^ "NanoBio's Genital Herpes Vaccine Demonstrates Efficacy In Guinea Pigs As Both A Prophylactic And A Therapeutic Vaccine". NanoBio Corporation. Retrieved 2 October 2015.

26.

Jump up^ "BioMedical Research Models Inc awarded Grant for Mucosal HSV-2 vaccine". Vaccine Nation (Cameron Bisset). Retrieved 13 June 2014.

27.

^ Jump up to:a b "Herpevac Trial for Women". Archived from the original on 2007-10-20. Retrieved 2008-03-04.

28.

Jump up^ Jon Cohen (15 October 2010). "aPainful Failure of Promising Genital Herpes Vaccine". Science 330 (6002): 304.doi:10.1126/science.330.6002.304. PMID 20947733.

29.

Jump up^ "Vical (VICL) Genital Herpes Vaccine Phase 1/2 Missed Primary Endpoint". StreetInsider.com. Retrieved 22 June 2015.

30.

Jump up^ "Vical Reports Top-Line Results From Phase 1/2 Trial of Therapeutic Genital Herpes Vaccine". FierceMarkets. 22 June 2015. Retrieved23 June 2015.

31.

Jump up^ BioVex commences dosing in Phase 1 study of ImmunoVEX live attenuated genital herpes vaccine

32.

Jump up^ Amgen completes acquisition of BioVex Group

33.

Jump up^ Amgen research pipeline

34.

Jump up^ AuRx Press Release Baltimore, September 11, 2006

35.

Jump up^ Molecular Therapy (2006-05-01). "Molecular Therapy – Abstract of article: 801. RNA Gene Therapy Targeting Herpes Simplex Virus". Nature.com. Retrieved 2011-04-12.

36.

Jump up^ "University of Florida News –Potential new herpes therapy studied". News.ufl.edu. 2009-02-03. Retrieved 2011-04-12.

37.

Jump up^ Fox, Maggie (2008-07-02). "New approach offers chance to finally kill herpes". Reuters. Retrieved 2011-04-12.

38.

Jump up^ Kingsbury, Kathleen (2008-07-02). "A Cure for Cold Sores?". Time. Retrieved 2010-05-04.

39.

^ Jump up to:a b Martin, Trepel; Charlotte A. Stoneham2,5, Hariklia Eleftherohorinou3, Nicholas D. Mazarakis2, Renata Pasqualini4, Wadih Arap4, and Amin Hajitou2 (August 2009). "A Heterotypic Bystander Effect for Tumor Cell Killing after AAVPmediated Vascular-targeted Suicide Gene Transfer". Mol Cancer Ther. 8 (8): 2383–2391.doi:10.1158/1535-7163.MCT-090110. PMC 2871293.PMID 19671758. Retrieved 6 April 2012.

40.

^ Jump up to:a b c Mesnil, M.; Piccoli, C.Tiraby, G.,Willencke K., Yamasaki,H. (March 1996). "Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins". Medical Sciences93 (5): 1831– 1835. doi:10.1073/pnas.93.5.1831. PMC 39867.PMID 8700844. Retrieved 6 April 2012.

41.

Jump up^ Stringer, J.R; LOUIS E. HOLLAND; RONALD I. SWANSTROM; 1 KENNETH PIVO; AND EDWARD K. WAGNER (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. Retrieved 6 April 2012.

42.

Jump up^ Jovanovic, M; MO Hengartner (2006). "miRNAs and apoptosis: RNAs to die for". Nature 25 (46): 6176–6187. doi:10.1038/sj.onc.1209912. Retrieved 6 April 2012.

43.

Jump up^ Helicase–primase inhibitors as the potential next generation of highly active drugs against herpes simplex viruses