Initial positive results reported on herpes vaccine — What’s next?
More than 775,000 new herpes infections in U.S. each year, and no cure available
Some 776,000 people in the United States incur new genital herpes infections each year. There is no current cure for such infections. Initial, positive results have just been reported for a therapeutic vaccine candidate for treating patients with genital herpes.1
The seven trial sites are: Birmingham-based University of Alabama Vaccine Research Unit; Cincinnati (OH) Children’s Hospital Medical Center; Houston-based Center for Clinical Studies; Indianapolis-based Indiana University Infectious Disease Research; Portland, OR-based Westover Heights Clinic; Seattle-based University of Washington Virology Research Clinic; and Webster, TX-based Center for Clinical Studies. They are participating in the double-blind, placebo-controlled dose escalation Phase 1/2a clinical trial to evaluate the safety and immunogenicity of GEN-003, a vaccine candidate under development by Genocea Biosciences of Cambridge, MA.
The vaccine candidate is a T cell vaccine designed to reduce the transmission risk and clinical symptoms of herpes simplex virus type 2 (HSV-2). Its chemistry is designed to induce a balanced B cell and T cell immune response. It includes fragments of ICP4 and gD2 antigens, as well as a proprietary adjuvant, Matrix-M, licensed from Novavax of Rockville, MD.
The study enrolled 143 volunteers with a history of moderate-to-severe recurrent HSV-2 infection. Patients were sequentially enrolled into one of three dose cohorts (10, 30, or 100 mcg of each protein) and randomized within cohorts to receive GEN-003, vaccine antigens without adjuvant, or placebo. Patients received three injections of the assigned treatment into an arm muscle at 21-day intervals. Antibody (B cell) and T cell immune responses to the two protein antigens contained in the vaccine were measured. A secondary objective of the study was to compare the quantitative presence of HSV-2, known as shedding, before and after the treatments.
Interim data presented at the 2013 Interscience Conference on Antimicrobial Agents and Chemotherapy indicate that patients who received three doses of GEN-003 had reductions in the frequency of viral shedding of up to 51% (p<0.001). Patients who received a placebo vaccine had no decline in viral shedding. Scientists also looked at T cell immune responses, which are believed to be important for the control of HSV-2 infection; they increased more than twentyfold to the ICP4 vaccine antigen and more than tenfold to the gD2 vaccine antigen. The vaccine candidate also increased neutralizing antibodies to the HSV-2 virus fivefold, on average, compared to baseline values.
The ability to reduce viral shedding is "critical," says Anna Wald, MD, MPH, the study’s principal investigator and professor of medicine, epidemiology, and laboratory medicine at University of Washington. Viral shedding is the main driver of transmission of HSV-2 to sexual partners and infants. "These are the first data that provide compelling evidence that a vaccine administered to people with genital herpes can affect their infection," said Wald in a statement accompanying the presentation. "We are excited that GEN-003 reduced viral shedding, as this finding paves the way for future trials that will measure the impact on clinical outbreaks."
What’s next step?
There are several steps that will need to be taken before scientists will know if the promising early results will hold up, says study co-investigator Kenneth Fife, MD, professor of medicine and of microbiology and immunology at Indiana University. The number of volunteers in the study is small, Fife notes. While researchers do statistical analysis to determine if the results are significant, the real test is whether the positive result can be reproduced in a larger number of research subjects that might be more representative of the overall population of people with genital herpes, he states. There also might be trials of different doses, different numbers of injections, or a different dosing schedule in determining the optimal dose of vaccine, Fife observes.
"One of the big unanswered questions is the durability of the effect. Will this last for six months or a year or five years?" asks Fife. "In other words, will booster immunizations be required and, if so, how often?"
The current study looked at the impact of the vaccine on viral shedding, but scientists also will want to know the impact on clinical recurrences, Fife states. Such a study will require additional subjects.
"The bottom line is that we are years away from having a product that will be available for use in practice, or the vaccine could fail at one of the additional steps and never come to market," says Fife. "Despite all of these caveats, our group is still very excited by the results, and we hope to be involved in additional studies that will be conducted in the future."
Immune cells identified
Earlier in 2013, researchers at the at the Seattle-based Fred Hutchinson Cancer Center and the University of Washington were able to identify a class of immune cells that reside long-term in the genital skin and mucosa and are believed to be responsible for suppressing recurring outbreaks of genital herpes.2
The discovery of this subtype of CD8+ immune cells, called CD8aa+ T-cells, might expand avenues to develop a vaccine to prevent and treat HSV-2. Identifying these T-cells’ specific molecular targets, called epitopes, is the next step in developing a vaccine.
For the first time, researchers know the type of immune cells that the body uses to prevent outbreaks, said Lawrence Corey, MD, virologist and president of the Fred Hutchinson Cancer Center in a statement accompanying the published results of the discovery. Scientists also know these cells are quite effective in containing most reactivations of HSV-2, he stated.
"If we can boost the effectiveness of these immune cells, we are likely to be able to contain this infection at the point of attack and stop the virus from spreading," he said.
Scientists think the presence of CD8aa+ T-cells where initial infection occurs might be a factor in why there are asymptomatic recurrences of genital herpes. The cells constantly recognize and eliminate the virus.
What’s in pipeline?
Vical, a San Diego company, is planning to start an early-stage study of a vaccine against HSV-2 before the end of 2013, enlisting approximately 150 HSV-2 positive adults with a history of symptomatic genital herpes lesions.
The road to an effective vaccine has been a rocky one. GlaxoSmithKline Biological of London ceased investigation of its HSV-2 vaccine candidate after Phase III study, data indicates an investigational vaccine, Simplirix, protected some women against infection from one of the two types of herpes simplex viruses that cause genital herpes. While the vaccine was partially effective at preventing HSV-1, data indicate it did not protect women from HSV-2.3 (To read more about the trial, see "New approaches eyed to herpes simplex virus," STI Quarterly supplement, March 2012, p. 3.)
Until a vaccine is developed, patients can reduce the risk of genital herpes through correct and consistent use of latex condoms. However, outbreaks can occur in areas not covered by a condom. According to the Centers for Disease Control and Prevention, the surest way to avoid transmission of sexually transmitted diseases, including genital herpes, is to abstain from sexual contact, or to be in a long-term mutually monogamous relationship with a partner who has been tested and is known to be uninfected.
For patients with herpes, talk with them about abstaining from sexual activity with partners when sores or other symptoms of herpes are present. Emphasize the fact that even if a person does not have any symptoms, he or she can still infect sex partners. (See resource listing below for a patient handout on genital herpes from the Centers for Disease Control and Prevention.)
- Wald A, Bernstein D, Fife K, et al. Novel therapeutic vaccine for genital herpes reduces genital HSV-2 shedding. Presented at the 53rd Interscience Conference on Antimicrobials Agents and Chemotherapy. Denver; September 2013.
- Schiffer JT, Corey L. Rapid host immune response and viral dynamics in herpes simplex virus-2 infection. Nat Med 2013;19(3):280-290.
- Belshe RB, Leone PA, Bernstein DI, et al. Efficacy results of a trial of a herpes simplex vaccine. NEJM 2012; 366(1):34-43.
- The Centers for Disease Control and Prevention offers a freely reproducible fact sheet on genital herpes. Go to http://1.usa.gov/17GlSlr to download the printable version.