DEF-funded prototype vaccine shows promise in preventing eye and other diseases.

A priority of The Discovery Eye Foundation (DEF) is the research of ocular herpes (OH) and infectious blindness. In addition to causing swelling, redness, watery eye discharge, sensitivity to light, or even blisters on the eyelids, OH – or herpes of the eye – can cause severe scarring of the cornea, the transparent dome-shaped membrane that covers the center eye. This scarring can lead to vision loss or legal blindness. In fact, in the United States, OH is a leading cause of corneal blindness, with more than 500,000 people having a medical history of recurrent OH.

DEF-funded research works toward understanding the molecular mechanisms of OH, and developing new medical approaches and therapies to eradicate it. One of the most promising advancements has been made in developing a new vaccine that would eventually prevent the spread of the Herpes Simplex Virus (HSV), the main cause of ocular herpes.

“DEF has approached the study of ocular herpes in several different ways,” said Dr. Anthony Nesburn, medical director of DEF and vice chair for research in the Ophthalmology Department of UC Irvine. “The herpes simplex virus is quite complex, and we are examining how the virus gains access to the nerve cells, how it becomes and remains latent – or dormant – in the body for a lifetime, and why it flares up again.”

About 80-90 percent of people are infected with HSV-1 in the early part of their lives. In most cases, the virus remains dormant in the brain. However, in certain cases, psychological, chemical or environmental stress may activate the virus, which can travel through the optical nerve to infect the eye’s corneal region and lead to a severe blinding disease known as HSK (Herpetic Stroma Keratitis). Antiviral drugs can reduce ocular herpetic disease symptoms, but they do not prevent the virus reactivation or kill the virus (the cause of the disease).

Research and models

Dr. Nesburn and Dr. Lbachir BenMohamed, an associate professor of immunology and the founder and head of the Laboratory of Cellular and Molecular Immunology in the Department of Ophthalmology at UC Irvine, whose research is being funded by DEF and the NIH, are working on a way to stop the virus?before?it is activated from the brain.

During the past eight years, they developed a novel approach using a model system. They identified several immune white-cell parts from the two most responsive glycoproteins (gB and gD) expressed by the herpes virus, allowing researchers, for the first time, to develop a candidate vaccine to target them.

Their long-term goal is to work on a “humanized” or “transgenic” laboratory animal, whose eyes are not only physiologically similar to human eyes, but who have a major immune regulatory gene replaced by the identical counterpart from a human gene. As a result, the humanized model can develop immune responses that are virtually identical to human immune responses upon vaccination.

In preclinical studies, two test groups were infected with the herpes virus until they developed latency in their brain cells. One group was immunized with the therapeutic vaccine, while the other group remained a non-immunized control group.

The results were just as the researchers had hoped: The group that was immunized with the vaccine candidate did not develop ocular disease.

Why is this vaccine different?

In order to work, the “sensitive peptides” (those protein sequences that will be well-recognized by antibodies and white T-cells) in most vaccines must be mixed with an immuno-adjuvant, which enhances the immune response. Unfortunately, while most immuno-adjuvants are efficient, they are also toxic.

Nesburn and BenMohamed are making a “lipopeptide” vaccine, which is composed of small parts selected from the most responsive glycoproteins and chemically linked to a lipid molecule (a fatty acid molecule normally present in the body), which replaces the toxic external adjuvant. The new lipopeptide vaccine is extremely safe and can boost the immune response significantly.

What’s more, BenMohamed said, the lipopeptide vaccines are formulated in saline solution and can be applied as topical eye drops. The vaccine can be entirely self-delivered: Application does not require any needles, does not need the help of a physician and does not require hospitalization. According to BenMohamed, injectable vaccines can cost up to six times the expense of the vaccine itself and can raise other complications such as contamination and access issues. The self-delivered topical vaccines are user-friendly, safe, cost-effective and powerful for global use.

The lipopeptide vaccine is already used in Europe in humans with HIV, but Nesburn and BenMohamed’s group is the first in the world using the lipopeptide vaccine against ocular herpes – thanks, in large part, to the Discovery Eye Foundation.

“Developing a vaccine is time-consuming and money-consuming, compared to drug development,” BenMohamed said. “That’s why there are not a lot of companies interested in developing a vaccine – they want the money fast, so they are more interested in drug therapies. Because of DEF, we were able to spend more than six years working on this vaccine development. We think we are going to do Phase 1 FDA clinical trials in the next two to three years.”

Other applications

In addition to working against OH, lipopeptide vaccines show promise in combating genital herpes, breast and prostate cancers, and HIV. BenMohamed said the herpes vaccine may be especially powerful and indirectly prevent co-infection with HIV-1.

The highest prevalence of HIV in the world is in Sub-Saharan Africa, which also boasts the highest prevalence of ocular and genital herpes. Herpes is know to down-regulate the immune system, so people who have herpes in their bodies have a lower immune response. When you link this fact to the high rate of HIV, BenMohamed said, it may be that having herpes predisposes you to HIV. In fact, chances of contracting HIV rise 5-6 times in people who have herpes.

Enter the OH vaccine: While an AIDS vaccine has been elusive for nearly two decades, BenMohamed believes it may be better to first use the lipopeptide vaccine against ocular and genital herpes, so the compromised immune system can be boosted, which could consequently reduce HIV and AIDS.

The main goal of the Discovery Eye Foundation is to eradicate diseases of the eye. The truly groundbreaking research funded by DEF is making unprecedented strides not only toward preventing and treating OH and other eye conditions, but some of the other great diseases facing the human race, as well.

by Lauren Hauptman

Posted November 2008