"The best vaccines are live, attenuated vaccines." – Nancy Khardori, M.D.
Like a mighty warrior, the strong herpes virus easily combats and defeats the body’s immune system, which can lead to a lifetime of recurring physical infections and emotional trauma. William Halford, Ph.D., associate pro fessor of medical microbiology, immunology and cell biology, is developing a vaccine that effectively strips the herpes virus of its strength, letting the immune system prevail.
Dr. Halford is the principal investigator on a project to de velop a live, attenuated herpes vaccine. He has studied herpes simplex virus for nearly 20 years, formerly as faculty at Mon tana State University and the Tulane University School of Medicine. He joined SIU School of Medicine in 2007, and he credits state-of-the-art research facilities at SIU and recent funding from the National Institutes of Health as key factors that have accelerated his research to develop a vaccine for genital herpes.
His collaborator, David Davido, Ph.D., of the University of Kansas, is working toward a vaccine for oral and ocular herpes. These scientists are challenging not just public misconcep tions of herpes, but also reticence within the scientific commu nity to consider new vaccines that contain live viruses.
“Without an effective vaccine, one in ten of our children will be infected with genital herpes by the time they are married,” Dr. Halford says.
A Public Health Epidemic
There are two types of herpes simplex virus: HSV-1 and HSV-2. Type 1, known as oral herpes infects about two-thirds of the world’s population, an estimated 4 billion people. Dr. Halford says most people acquire HSV-1 before their sixth birthday. Most HSV-1 infections produce no symptoms, and so most people don t know they carry it; only 2-5 percent of those infected with oral herpes experience recurrent cold sores on their lips. Rare, but unfortunate, complications of HSV-1 infection do occur HSV-1 is the leading cause of fatal encephalitis and infectious blindness in the United States and other first world countries.
But HSV-1’s tougher cousin, HSV-2, is more aggressive and causes genital herpes, the infamous sexually-transmitted disease. This lifelong infection can cause recurrent outbreaks of embar rassing and painful genital sores. An estimated 1 billion people worldwide carry HSV-2, and 5 percent (50 million) live with re current genital herpes disease. The Centers for Disease Control reports that genital herpes doubles a person s risk for acquiring HIV, the virus that causes AIDS.
In the United States, genital herpes is one of the most com mon sexually transmitted diseases. According to the Illinois Department of Public Health, genital herpes infections have reached “epidemic levels.”
“Herpes is a public health issue,” says Nancy Khardori, M.D., chair of the infectious diseases division at SIU School of Medi cine. “Herpes is as important a public health issue as HPV, the virus that can lead to cervical cancer. Most people don t know they have herpes or that they can transmit the virus even if no lesions are present. So the cycle keeps going. If a vaccine was available, the chain of transmission would stop.”
Along with the physical symptoms, those suffering from genital herpes often face emotional distress and fear of intimacy. Online postings include the following: “I feel like my life just went to nothing,” writes one. “I don t make new friends. I can never really tell people who I am,” writes another. “I have given up on life.”
Scientists on the Case
Dr. Halford and Dr. Davido are among the scientists hard at work on a vaccine to stop genital herpes. Others include Glaxo Smith Kline, which has invested more than $1 billion testing their Herpevac vaccine. This vaccine contains a single protein, or subunit, of HSV-2 called glycoprotein D. “The attraction of the subunit vaccine approach is its extraordinary safety,” Dr. Halford says. “Unfortunately, over 10 years of clinical trials sug gest that the Herpevac vaccine does not consistently protect people against genital herpes.”
The ACAM-529 vaccine, sponsored by the pharmaceutical company Sanofi Pasteur, has entered clinical trials. This HSV-2 virus vaccine, created in the late 1990s by Dr. David Knipe’s group at Harvard Medical School, infects cells in the body but cannot duplicate and spread. Dr. Halford believes that a low level of virus replication is critical to realize the full immuno genic potential of a vaccine.
The ‘Immunovex’ vaccine, now in clinical trials, was devel oped in the mid-2000s by a group of scientists in the United Kingdom led by Dr. Robert Coffin and Dr. David Latchman. This HSV-2 virus vaccine has a greater potential to duplicate it self and spread in the body, but still the virus carries defects in five different genes. Dr. Halford believes that the Immunovex vaccine strain may be too attenuated to succeed as a human vaccine.
“I hope that these vaccine candidates succeed in preventing genital herpes,” Dr. Halford says. “However, I suspect that more potent HSV-2 vaccines are possible, and I believe that we need to keep refining second generation HSV-2 viral vaccines until it is clear that we have obtained a herpes vaccine that yields un equivocal protection in 100 percent of vaccine recipients.”
An Innovative Strategy
Working toward a more potent vaccine, Dr. Halford is investigating the mechanisms by which the HSV-2 warrior penetrates the body’s defenses.
One of the virus’s critical weapons is a single protein called Infected Cell Protein 0 (ICP0). With this protein, HSV is able to neutralize and penetrate the body’s interferon response, a first line of defense against viral illness. The aggressive HSV-2 virus then can spread to the nervous system. There, in the nerve cells, the virus establishes a permanent home, lurks for decades, and periodically reawakens to cause subsequent outbreaks of genital herpes.
For his vaccine, Dr. Halford has altered ICP0, which attenu ates HSV-2 because it cannot penetrate the body’s interferon defenses. “This attenuated ICP0-mutant virus cannot cause disease in a healthy person but can teach the body’s immune sys tem how to quickly recognize a real HSV-2 infection.”
He believes this HSV-2 ICP0-mutant virus vaccine strikes an ideal balance between attenuation (safety) and immunogenicity (effectiveness) — an innovative approach. “Without the ICP0 to jump start each infection, our HSV-2 vaccine strain can only establish inapparent infections in vaccinated mice. The results are clear-cut, and there is every reason to believe that these HSV-2 ICP0-mutant viruses would be equally safe in people.”
Dr. Halford says that most scientists will not be surprised to learn that HSV-2 ICP0-mutant viruses cannot cause disease in animals; HSV-1 ICP0-mutant viruses display the same properties. “What is surprising is that such an innocuous virus can elicit such a robust immune response,” Dr. Halford explains. “I have seen this time and time again in experiments over the past year, and it still surprises me.” His studies have shown that genetically-altered HSV-2 strains have proven safe and 100 times more effective than an HSV-2 glycoprotein D subunit, such as that found in the Herpevac vaccine.
“The Herpevac vaccine contains 1 of 80 proteins encoded by HSV-2. I don’t think it is realistic to expect that a vaccine containing 1 percent of the virus will leave the body 100 percent prepared to combat an HSV-2 infection. In contrast, a live HSV-2 virus vaccine should expose the body’s immune system to nearly 100 percent of the proteins made by HSV-2. In our experiments, we have observed that this works much better.”
NIH reviewers of Dr. Halford’s project call his concept “innovative” and indicate its potential to have “great clinical significance.” His two-year award from the National Institute of Allergy and Infectious Diseases is his second federal grant.
“This is a very important project with great potential. We need a vaccine for herpes,” notes Morris Cooper, Ph.D., chairman of the Department of Microbiology, Immunology, and Cell Biology. “Dr. Halford is taking an entirely different approach to try to get a vaccine. His genetic approach has a lot of novel aspects to it.” Dr. Cooper has extensively studied sexually transmitted diseases, including gonorrhea and Chlamydia. “The ability to prevent a disease that has such enormous social and physiological recurring consequences would be a huge advance.”
A Controversial Approach
While Dr. Halford’s approach is novel, it’s also controversial. Live HSV-2 viruses in vaccines may establish a latent infection in vaccine recipients, and local replication of the virus will likely occur after vaccination and perhaps periodically over the lifetime of vaccine recipients.
“The concern by scientists and the FDA is that a live, attenuated virus will trigger or mix with the resident dormant virus or cause problems on its own,” Dr. Davido says. “But the advantage is that a live, attenuated vaccine stimulates a stronger immune response that can immediately fight the virus.”
One of HSV-2’s closest cousins is varicella-zoster virus, which causes chickenpox and shingles. Dr. Halford indicates that more than 50 million children have been vaccinated with a live, attenuated varicella-zoster virus called the Oka strain to prevent chickenpox. It is widely used, approved by the Food and Drug Administration, and is now being recommended as a therapeutic vaccine for older adults to prevent shingles.
Dr. Halford points to other viral vaccines that have been given to millions of children for decades — most contain live viruses. “Live, attenuated viruses are how we cured smallpox. A live virus cured polio, mumps, measles, and rubella. These vaccines work well, but are just useful accidents of nature. The reasons behind their safety have never been clear,” Dr. Halford says. “In contrast, Dr. Davido and I are using genetic engineering to disable a specific gene, and we can explain precisely why these HSV-2 ICP0-mutant viruses are safe: because the body’s interferon response prevents their spread from the site of injection; no spread equals no disease. This is a simple approach, and it works remarkably well.”
Dr. Khardori notes that infectious disease specialists are in favor of any vaccine proven safe. “Vaccines are prevention. In the last century, the biggest contributions to medicine were vaccines,” she says. “And the best vaccines are live, attenuated vaccines. Depending on what the clinical trials show, with Dr. Halford’s use of technology and the genetic modifications, his vaccine is likely to give a good immune effective response and not the disease.”
Dr. Cooper notes that this novel project does present greater risk and needs to be carefully considered among the population. “People with immune-compromised systems wouldn’t want to use these kinds of vaccines. But for those with a healthy immune system, live vaccines have a great deal of potential and are generally safe when used with proper controls.”
The scientists assure that the vaccine will not progress without ensuring its safety. “Safety takes precedence over everything,” Dr. Davido stresses. He is continuing initial characterization studies in animal models to confirm the vaccine’s safety and applicability. He has filed a patent for a live, attenuated HSV-1 vaccine.
Hope for the Future
SIU School of Medicine Office of Technology Transfer has filed a patent to license Dr. Halford’s method as a novel vaccine to prevent diseases related to the HSV virus. Testing of the two vaccine strains continues, and the inventors and their universities are planning clinical trials and seeking a commercial partner. “Once we publish our findings, the scientific community can consider the evidence that will ultimately define the pros and cons of our live HSV-2 vaccine approach,” says Dr. Halford.
He envisions the vaccine as a preventative measure. “I’m positive that we can develop an HSV-2 vaccine that protects children against the risk of acquiring genital herpes later in life — that’s what we’ve been doing with vaccines for 200 years.”
Dr. Davido foresees the vaccine benefiting those already infected with the virus, similar to the use of the chickenpox vaccine to prevent shingles. “This vaccine could prevent or minimize sores, and shorten their duration,” he says. “It may make their immune system better.” He also theorizes that their approach could apply to other viruses. The collaborators credit their mentor, the late Dr. Priscilla Schaffer, a leader in the study of herpes viruses, as a pioneer whose work has led the way for the development of their vaccines. Dr. Halford publicly presented his findings for the first time in July at the International Herpesvirus Workshop.
The scientists agree that the benefits of an effective herpes vaccine will far outweigh the risks. In the United State alone, it is estimated that an effective vaccine would prevent 3 million new HSV-1 infections per year and 1 million new HSV-2 infections per year.
For those suffering the stigma of herpes, the vaccine would be life-changing: mothers carrying the virus could kiss their babies without worrying about giving them oral herpes; spouses and sexual partners could get the vaccine, giving new hope for relationships; and for millions, the physical and emotional distress of herpes could be alleviated.