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 -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 ICP0 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]

Admedus'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 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.[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 passed human safety trials in a trial of 20
Australians.[14] In October 2014, Admedus 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, Admedus 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 ICP4 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 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.
[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 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.[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 helicaseprimase complex of HSV represent a very innovative
approach to the treatment of herpesvirus disease.[43]

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