Dr. William Halford and collaborator are close to unveiling an innovative

Written by Karen Carlson l Photography by James Hawker

the strong herpes pes. These scientists are challenging not just public misconcep- Like a mighty warrior, tions of herpes, but also reticence within the scientific commu- easily combats and defeats the body’s immune system, nity to consider new that contain live . which can lead to a lifetime of recurring physical infections “Without an effective vaccine, one in ten of our children and emotional trauma. William Halford, Ph.D., associate pro- will be infected with genital herpes by the time they are mar- fessor of medical microbiology, immunology and cell biology, ried,” Dr. Halford says. 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- A Public Health Epidemic velop a live, attenuated herpes vaccine. He has studied herpes There are two types of virus: HSV-1 and simplex virus for nearly 20 years, formerly as faculty at Mon- HSV-2. Type 1, known as oral herpes infects about two-thirds tana State University and the Tulane University School of of the world’s population, an estimated 4 billion people. Dr. Medicine. He joined SIU School of Medicine in 2007, and he Halford says most people acquire HSV-1 before their sixth credits state-of-the-art research facilities at SIU and recent birthday. Most HSV-1 infections produce no symptoms, and so funding from the National Institutes of Health as key factors most people don’t know they carry it; only 2-5 percent of that have accelerated his research to develop a vaccine for gen- those infected with oral herpes experience recurrent cold sores ital herpes. on their lips. Rare, but unfortunate, complications of HSV-1 His collaborator, David Davido, Ph.D., of the University of infection do occur — HSV-1 is the leading cause of fatal en- Kansas, is working toward a vaccine for oral and ocular her- “The best vaccines are live, attenuated vaccines.”

— Nancy Khardori, M.D.

cephalitis and infectious blindness in the United States and company Sanofi Pasteur, has entered clinical trials. This HSV-2 other first world countries. virus vaccine, created in the late 1990s by Dr. David Knipe’s But HSV-1’s tougher cousin, HSV-2, is more aggressive and group at Harvard Medical School, infects cells in the body but causes genital herpes, the infamous sexually-transmitted disease. cannot duplicate and spread. Dr. Halford believes that a low This lifelong infection can cause recurrent outbreaks of embar- level of virus replication is critical to realize the full immuno- rassing and painful genital sores. An estimated 1 billion people genic potential of a vaccine. worldwide carry HSV-2, and 5 percent (50 million) live with re- The ‘Immunovex’ vaccine, now in clinical trials, was devel- current genital herpes disease. The Centers for Disease Control oped in the mid-2000s by a group of scientists in the United reports that genital herpes doubles a person’s risk for acquiring Kingdom led by Dr. Robert Coffin and Dr. David Latchman. HIV, the virus that causes AIDS. This HSV-2 virus vaccine has a greater potential to duplicate it- In the United States, genital herpes is one of the most com- self and spread in the body, but still the virus carries defects in mon sexually transmitted diseases. According to the Illinois De- five different genes. Dr. Halford believes that the Immunovex partment of Public Health, genital herpes infections have vaccine strain may be too attenuated to succeed as a human reached “epidemic levels.” vaccine. “Herpes is a public health issue,” says Nancy Khardori, M.D., “I hope that these vaccine candidates succeed in preventing chair of the infectious diseases division at SIU School of Medi- genital herpes,” Dr. Halford says. “However, I suspect that more cine. “Herpes is as important a public health issue as HPV, the potent HSV-2 vaccines are possible, and I believe that we need virus that can lead to . Most people don’t know to keep refining second generation HSV-2 viral vaccines until it they have herpes or that they can transmit the virus even if no is clear that we have obtained a herpes vaccine that yields un- lesions are present. So the cycle keeps going. If a vaccine was equivocal protection in 100 percent of vaccine recipients.” available, the chain of transmission would stop.” Along with the physical symptoms, those suffering from geni- An Innovative Strategy tal herpes often face emotional distress and fear of intimacy. Online postings include the following: “I feel like my life just Working toward a more potent vaccine, Dr. Halford is investi- went to nothing,” writes one. “I don’t make new friends. I can gating the mechanisms by which the HSV-2 warrior penetrates never really tell people who I am,” writes another. “I have given the body’s defenses. up on life.” One of the virus’s critical weapons is a single protein called Infected Cell Protein 0 (ICP0). With this protein, HSV is able to Scientists on the Case neutralize and penetrate the body’s interferon response, a first line of defense against viral illness. The aggressive HSV-2 virus Dr. Halford and Dr. Davido are among the scientists hard at then can spread to the nervous system. There, in the nerve cells, work on a vaccine to stop genital herpes. Others include Glaxo the virus establishes a permanent home, lurks for decades, and Smith Kline, which has invested more than $1 billion testing periodically reawakens to cause subsequent outbreaks of genital their Herpevac vaccine. This vaccine contains a single protein, herpes. or subunit, of HSV-2 called glycoprotein D. “The attraction of For his vaccine, Dr. Halford has altered ICP0, which attenu- the subunit vaccine approach is its extraordinary safety,” Dr. ates HSV-2 because it cannot penetrate the body’s interferon Halford says. “Unfortunately, over 10 years of clinical trials sug- defenses. “This attenuated ICP0-mutant virus cannot cause dis- gest that the Herpevac vaccine does not consistently protect ease in a healthy person but can teach the body’s immune sys- people against genital herpes.” tem how to quickly recognize a real HSV-2 infection.” The ACAM-529 vaccine, sponsored by the pharmaceutical He believes this HSV-2 ICP0-mutant virus vaccine strikes an An immunoflourescent stain of human cells under attack by the herpes virus.

Images courtesy Dr. Mingyu Liu

ideal balance between attenuation (safety) and immunogenicity mune response that can immediately fight the virus.” (effectiveness) — an innovative approach. “Without the ICP0 to One of HSV-2’s closest cousins is varicella-zoster virus, which jump start each infection, our HSV-2 vaccine strain can only es- causes and . Dr. Halford indicates that more tablish inapparent infections in vaccinated mice. The results are than 50 million children have been vaccinated with a live, atten- clear-cut, and there is every reason to believe that these HSV-2 uated varicella-zoster virus called the Oka strain to prevent ICP0-mutant viruses would be equally safe in people.” chickenpox. It is widely used, approved by the Food and Drug Dr. Halford says that most scientists will not be surprised to Administration, and is now being recommended as a therapeu- learn that HSV-2 ICP0-mutant viruses cannot cause disease in tic vaccine for older adults to prevent shingles. animals; HSV-1 ICP0-mutant viruses display the same properties. Dr. Halford points to other viral vaccines that have been “What is surprising is that such an innocuous virus can elicit such given to millions of children for decades — most contain live a robust immune response,” Dr. Halford explains. “I have seen viruses. “Live, attenuated viruses are how we cured . A this time and time again in experiments over the past year, and it live virus cured polio, mumps, , and . These vac- still surprises me.” His studies have shown that genetically-altered cines work well, but are just useful accidents of nature. The rea- HSV-2 strains have proven safe and 100 times more effective than sons behind their safety have never been clear,” Dr. Halford an HSV-2 glycoprotein D subunit, such as that found in the Her- says. “In contrast, Dr. Davido and I are using genetic engineer- pevac vaccine. ing to disable a specific gene, and we can explain precisely why “The Herpevac vaccine contains 1 of 80 proteins encoded by these HSV-2 ICP0-mutant viruses are safe: because the body’s HSV-2. I don’t think it is realistic to expect that a vaccine con- interferon response prevents their spread from the site of injec- taining 1 percent of the virus will leave the body 100 percent tion; no spread equals no disease. This is a simple approach, prepared to combat an HSV-2 infection. In contrast, a live and it works remarkably well.” HSV-2 virus vaccine should expose the body’s immune system Dr. Khardori notes that infectious disease specialists are in to nearly 100 percent of the proteins made by HSV-2. In our favor of any vaccine proven safe. “Vaccines are prevention. In experiments, we have observed that this works much better.” the last century, the biggest contributions to medicine were vac- NIH reviewers of Dr. Halford’s project call his concept “inno- cines,” she says. “And the best vaccines are live, attenuated vac- vative” and indicate its potential to have “great clinical signifi- cines. Depending on what the clinical trials show, with Dr. cance.” His two-year award from the National Institute of Halford’s use of technology and the genetic modifications, his Allergy and Infectious Diseases is his second federal grant. vaccine is likely to give a good immune effective response and “This is a very important project with great potential. We not the disease.” need a vaccine for herpes,” notes Morris Cooper, Ph.D., chair- Dr. Cooper notes that this novel project does present greater man of the Department of Microbiology, Immunology, and risk and needs to be carefully considered among the population. Cell Biology. “Dr. Halford is taking an entirely different ap- “People with immune-compromised systems wouldn’t want to proach to try to get a vaccine. His genetic approach has a lot of use these kinds of vaccines. But for those with a healthy immune novel aspects to it.” Dr. Cooper has extensively studied sexually system, live vaccines have a great deal of potential and are gen- transmitted diseases, including and . “The erally safe when used with proper controls.” ability to prevent a disease that has such enormous social and The scientists assure that the vaccine will not progress without physiological recurring consequences would be a huge ad- ensuring its safety. “Safety takes precedence over everything,” Dr. vance.” Davido stresses. He is continuing initial characterization studies in animal models to confirm the vaccine’s safety and applicabil- A Controversial Approach ity. He has filed a patent for a live, attenuated HSV-1 vaccine. While Dr. Halford’s approach is novel, it’s also controversial. Hope for the Future Live HSV-2 viruses in vaccines may establish a latent infection in vaccine recipients, and local replication of the virus will likely SIU School of Medicine Office of Technology Transfer has occur after vaccination and perhaps periodically over the life- filed a patent to license Dr. Halford’s method as a novel vaccine time of vaccine recipients. to prevent diseases related to the HSV virus. Testing of the two “The concern by scientists and the FDA is that a live, attenu- vaccine strains continues, and the inventors and their universities ated virus will trigger or mix with the resident dormant virus or are planning clinical trials and seeking a commercial partner. cause problems on its own,” Dr. Davido says. “But the advan- “Once we publish our findings, the scientific community can tage is that a live, attenuated vaccine stimulates a stronger im- consider the evidence that will ultimately define the pros and

22 aspects | summer 2010 “We need to keep refining second generation HSV-2 viral vaccines until it is clear that we have obtained a herpes vaccine that yields unequivocal protec- tion in 100 percent of vaccine recipients.”

— William Halford, Ph.D.

cons of our live HSV-2 vaccine approach,” says Dr. Halford. sented his findings for the first time in July at the International He envisions the vaccine as a preventative measure. “I’m pos- Herpesvirus Workshop. itive that we can develop an HSV-2 vaccine that protects chil- The scientists agree that the benefits of an effective herpes dren against the risk of acquiring genital herpes later in life — vaccine will far outweigh the risks. In the United State alone, it that’s what we’ve been doing with vaccines for 200 years.” is estimated that an effective vaccine would prevent 3 million Dr. Davido foresees the vaccine benefiting those already in- new HSV-1 infections per year and 1 million new HSV-2 infec- fected with the virus, similar to the use of the chickenpox vac- tions per year. cine to prevent shingles. “This vaccine could prevent or For those suffering the stigma of herpes, the vaccine would be minimize sores, and shorten their duration,” he says. “It may life-changing: mothers carrying the virus could kiss their babies make their immune system better.” He also theorizes that their without worrying about giving them oral herpes; spouses and approach could apply to other viruses. The collaborators credit sexual partners could get the vaccine, giving new hope for rela- their mentor, the late Dr. Priscilla Schaffer, a leader in the study tionships; and for millions, the physical and emotional distress of herpes viruses, as a pioneer whose work has led the way for of herpes could be alleviated. lll the development of their vaccines. Dr. Halford publicly pre-

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