Herpes Infection, Disease, Vaccine & Immunotherapy

“Testing Tomorrow’s Vaccines Today”

Herpes infects more than half of Americans. In fact over 90% of adults have antibodies against Herpes showing that they have been during their lifetime in contact with herpes simplex virus type 1 and/or type 2. Studies of asymptomatic individuals (people that are seropositive but never develop any kind of herpes disease) and symptomatic individuals (people that are seropositive and often develop some type herpes disease) reveal silent shedding of virus in saliva, tears and genital secretions. Even those taking anti-herpes medication orally continue to shed virus. Herpes of the eye is a recurrent viral infection that is mainly caused by HSV-1 and is the most common infectious cause of corneal blindness in the United States. Over 400,000 Americans have had some form of recurrent ocular herpes disease. Each year, nearly 50,000 new and recurring cases are diagnosed in the U.S. with the most serious, stromal keratitis, accounting for about 25 percent. Hundreds of patients that come to the clinic end up taking some form of antiviral like oral acyclovir, which “makes a difference” for them, by improving their symptoms. However, these drug therapies do not guarantee that a recurrence will not occur again. Oro-facial herpes (cold sores) is also caused by HSV-1 and is also treated by oral acyclovir. About 1 billion people – one-sixth of the world’s population – are infected with herpes simplex virus type 2 (HSV-2), the most common cause of genital herpes. In the U.S. an estimated 50 million people carry the virus, and up to 3 million of those people suffer recurrent outbreaks of genital herpes as often as four times a year. Both oro-facial and genital herpes are also treated by acyclovir medication and derivatives.

 

WHY DO WE NEED A VACCINE AGAINST HERPES?

While the antiviral drug therapies with Acyclovir (and derivatives) have been helpful they also have several other disadvantages: (1) Antiviral drugs decrease the disease but never eliminate the virus itself. Current drug therapies, often used to suppress ocular, oro-facial and genital herpes, can treat the disease but do not prevent future outbreaks (2) Acyclovir has limited activity and prevents only 40 – 50% of recurrences, and no topical agent prevents recurrences. (3) To be effective, these antiviral drugs must be taken daily for life. (4) Many herpes isolates are now relatively resistant to these medications. The original and all derivative drugs share cross-resistance. (5) Antiviral drugs are hundreds of times more expensive than vaccines. 
A vaccine that could attack the virus at the root of the disease is currently unavailable on the market. More than half Americans, who are currently infected with herpes, might benefit from a therapeutic herpes vaccine. In addition this will help over 1 billion people – one-sixth of the world’s population – that are currently infected with herpes. A prophylactic vaccine that could protect the uninfected individuals would also attract many users.
With a mucosal vaccine people will be able to safely, painlessly, and effectively vaccinate themselves against herpes. The mucosal vaccine can be conveniently applied either as eye or intranasal drops or intravaginal drops or suppositories, by the patients themselves. With a doctor’s prescription but without using syringes and needles, without having to visit a clinic and in the privacy of their own home they will be able to protect themselves and their family from herpes.

The Laboratory of Cellular and Molecular Immunology is engaged in vaccine development by pursuing a variety of vaccine strategies for stimulating the body’s immune system to fight herpes. New approaches in vaccine discovery and development involve stimulation of all arms of the immune system using novel immunogenic peptide and lipopeptide antigens to stimulate B-cell and T-cells and dendritic cells. A great deal of attention is being focused on the discovering and evaluation of mucosal sub-unit vaccines because of their well-positioned efficacy, safety (no significant side effects) and cost-effective delivery. New and proprietary technologies developed by the Laboratory of Cellular and Molecular Immunology allows mucosal (i.e. topical ocular, intranasal, intravaginal or intrarectal) delivery of self-adjuvanting lipid-tailed peptide epitopes (designated as lipopeptide vaccines). This process provides the tools to better deliver peptide vaccine without the use of potentially toxic external immuno-adjuvant. Similar vaccine technology to protect against HIV-1 is currently in clinical trial in Europe. The Laboratory of Cellular and Molecular Immunology is the only research lab in the US and the world that is applying such technology to vaccinate against herpes.

The Laboratory of Cellular and Molecular Immunology is currently carrying out rounds of animal protective studies. The animal studies use human leukocyte antigen (HLA) transgenic mice and HLA transgenic rabbits. Our novel “humanized” HLA-A*0201 transgenic (HLA Tg) rabbit model of ocular HSV-1 that develops spontaneous reactivation, recurrent corneal disease and mounts specific CD8+ T-cell responses to human HSV epitopes. Although HLA Tg mice can also mount humanized CD8+ T-cell responses, they do not develop recurrent corneal disease. We have already shown that immunization of naïve HLA Tg rabbits with a lipopeptide vaccine comprised of asymptomatic human CD8+ T-cell epitopes from HSV-1 gD, induces strong human epitope-specific CD8+ T cell responses in draining lymph nodes, corneas and TGs and reduces HSV-1 shedding in tears and corneal disease following primary ocular virus challenge. This HLA Tg rabbit model will allow us for the first time to test the hypothesis that spontaneous HSV-1 shedding and recurrent eye disease can be reduced by “protective” CD8+ T-cell responses through therapeutic immunization with asymptomatic human CD8+ T-cell epitopes. Conversely, recurrent eye disease (and possibly spontaneous shedding) may be exacerbated by “pathogenic” CD8+ T-cells induced by therapeutic immunization with symptomatic human CD8+ T-cell epitopes. Validation of this hypothesis would have important implications for prevention of recurrent ocular disease.

 

OUR T CELL EPITOPES DISCOVERY TECHNOLOGY

The Laboratory of Cellular and Molecular Immunology herpes vaccine development programs are built around a transformational platform divided in 2 major in vivo and in vitro steps (illustrated below) for the rapid discovery of “protective” “asymptomatic” herpes simplex type 1 and type 2 (HSV-1 and HSV-2) T cell epitopes. T cell epitopes that stimulate ab CD4+ and CD8+ T cells, are critical to generating either pathogenic or protective-specific cellular immune responses and long-term T cell memory.

To date, protective T cell epitope discovery has proven a significant barrier to herpes vaccine development. While several advances have been made in epitope delivery methods, relatively few have been made in developing strategies to identify protective T cell epitopes that can be incorporated into herpes vaccine formulations. The Laboratory of Cellular and Molecular Immunology approach addresses several key challenges to protective epitope discovery, including: identification of promising protective epitopes from among the hundreds of possible candidate epitopes derived for each of the 84+ herpes protein antigens and selection of protective asymptomatic human epitopes with potential to provide protection across diverse populations.

In the last 3 years, The Laboratory of Cellular and Molecular Immunology has taken programs in three herpes diseases (ocular, genital and oro-facial) from project initiation to human leukocyte antigen (HLA) transgenic rabbits, mice and guinea pig models proof-of-concept, with its first herpes program on a track for clinical trials in early 2016. The technology is based on pioneering research from The Laboratory of Cellular and Molecular Immunology. 

 

AN ORIGINAL VACCINE APPROACH THAT MIMICS NATURAL IMMUNE RESPONSE 

At the core of The Laboratory of Cellular and Molecular Immunology epitope discovery technology (illustrated above) is a high throughput screening process that mimics the natural mammalian immune response to peptide epitopes, including antigen processing and presentation by antigen presenting cells (APCs); CD4+ and CD8+ T cell recognition of APC-displayed peptides; and immune activation. Critically, the Laboratory of Cellular and Molecular Immunology screens all of a herpes proteins against T cells obtained from human donors with diverse HLA types as well as HLA transgenic animals who have either generated a potentially “protective” (asymptomatic) or “pathogenic” (symptomatic) immune responses after exposure to a herpes epitopes. As part of its discovery approach the company creates a library of symptomatic and asymptomatic epitopes.

As a result, through The Laboratory of Cellular and Molecular Immunology discovery process the 84+ herpes proteins produced by HSV-1 and HSV-2 are rapidly reduced down to a set of 5-10 epitopes that correlate with protective natural immunity. A subset of best “protective” asymptomatic” epitopes from that group is selected for in vivo testing, based on recognition across multiple HLA supertypes and other criteria, with the goal of identifying five best “protective” asymptomatic” epitopes for formulation and development into a herpes vaccine candidate that will be protective across diverse ethnic populations.

Project-2 | Project-3 | Project-4