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HSV-2 Vaccine

Summary

  • HSV-2 is a herpes virus that is the leading cause of genital herpes worldwide
  • Approximately one in six individuals in the U.S. is infected by HSV-2 before age 50
  • There is no approved vaccine or cure for HSV-2 or genital herpes
  • Vical is developing a therapeutic HSV-2 vaccine intended to prevent or reduce genital lesion recurrences and prevent transmission of this herpes virus to uninfected individuals
  • Vical initiated a Phase 1/2 clinical study in December 2013, and results are expected in 2015

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Disease Overview

Herpes simplex virus type 2 (HSV-2) is a sexually transmitted virus that is the main cause of recurrent genital herpes, accounting for the majority of genital ulcerative lesions worldwide.1,2 HSV-2 is transmitted following intimate contact of infected mucocutaneous tissues or secretions and establishes a persistent, lifelong infection characterized by alternating periods of latency in sensory neurons and active viral replication at mucocutaneous surfaces where virus may be shed subclinically or manifest as recurrent genital herpes lesions.1,2 Genital herpes is not only physically taxing (pain, itching and other morbidities) but can also be psychologically-debilitating, especially given the fear of transmission.2 Transmission is a major concern among discordant couples (i.e., where only one partner is infected).

The CDC estimated the U.S. prevalence of HSV-2 in 2005-2008 as 16.2% of 14- to 49-year-olds3 and the WHO estimated the global prevalence in 2003 as roughly 16%, or 536 million, people aged 15 to 49 years.4 Importantly, only 10% to 25% of HSV-2-seropositive individuals are symptomatic and recognize their genital herpes infection.2,3

Most people “shed” virus asymptomatically, which actually accounts for the majority (~70%) of transmission events.5 HSV-2 shedding can be readily monitored by measuring the amount of viral DNA from genital swabs using a validated PCR assay, such as the widely-used assay developed at the University of Washington. Recent studies indicate that HSV-2 shedding occurs on 20% of days in symptomatic people and 10% of days in those who are asymptomatic.6 Similarly, people with herpes lesions typically have higher viral shedding rates for longer periods of time as compared to those who are asymptomatic.6 This relationship suggests that measuring HSV shedding rates as a virologic endpoint in clinical trials may provide proof-of-concept for a treatment that reduces a clinical endpoint, i.e., genital herpes lesions.

Unmet Medical Need

A high unmet medical need exists for treatments that reduce HSV-2 genital herpes recurrences and viral transmission, because no licensed therapeutic vaccine exists for this indication. Acyclovir-based drugs such as valacyclovir when taken daily have been demonstrated to be safe and effective in decreasing, but not eliminating, genital herpes lesions, viral shedding, and transmission.7 However, after over 30 years of usage, these drugs have not appreciably impacted HSV-2 seroprevalence rates; an important limitation is that the drugs do not cure subjects of HSV-2, thereby allowing the virus to rebound upon drug cessation. Therefore, an unmet need remains for additional treatment options such as a therapeutic HSV-2 vaccine.

Opportunity for a Therapeutic HSV-2 Vaccine

Therapeutic vaccines represent a new treatment modality against herpes viruses, especially HSV-2. The fundamental approach is to harness the body’s immune response to control HSV-2 replication (i.e., to decrease genital herpes lesions, viral shedding, and transmission) instead of using an antiviral drug. T cells induced to recognize important herpes antigens following therapeutic vaccination are likely to be key participants as antiviral mediators. Recent modeling simulations suggest that increases in frequency/density, function, and/or specificity of T cells targeting genital mucosal tissue may exert sufficient control over HSV-2 replication.8

The plasmid DNA vaccine technology developed at Vical is an attractive vaccine strategy against HSV-2 because induction of robust T-cell responses is a hallmark of this platform.9 Furthermore, plasmid DNA vaccines are noninfectious and can be repeatedly used for vaccine boosting without generating antivector responses (as frequently occur with adenovirus, poxvirus, and other vaccine vectors). DNA vaccines offer the potential benefits of live-attenuated virus vaccines in stimulating T-cell responses but do not inherently possess the attendant safety concerns of live virus vaccines. Vical has already established the precedent of a therapeutic DNA vaccine against a related herpes virus, cytomegalovirus (CMV). This bivalent plasmid DNA vaccine, known as ASP0113, is being developed by Vical in partnership with Astellas Pharma and has demonstrated proof-of-concept by significantly reducing CMV replication (plasma viral loads) as well as inducing higher CMV phosphoprotein 65-specific, interferon-γ-producing T-cell responses in hematopoietic stem cell recipients after transplantation.9

Vical’s Therapeutic HSV-2 Vaccine: Background

Several considerations were of importance in the design and testing of Vical's HSV-2 therapeutic vaccine candidate. From the program’s inception, key collaborations were established with the laboratories of leading HSV experts Dr. David Koelle and Dr. Larry Corey at the University of Washington to leverage their experience in selecting key HSV-2 antigens and in conducting numerous murine studies under a multi-year NIH grant. These studies became the foundation for demonstrating the preclinical immunogenicity and efficacy of a plasmid DNA approach; importantly, these studies demonstrated both an adjuvant effect for Vical’s proprietary cationic lipid-based formulation, Vaxfectin®, as well as the superiority of using a full-length glycoprotein D (gD) antigen compared to a truncated gD protein.10,11

The use of Vaxfectin® as an adjuvant to potentiate the performance of the HSV-2-encoding plasmids is a critical component of Vical’s vaccine. To date, Vaxfectin®-adjuvanted DNA vaccines have advanced into several clinical trials and have shown promising safety and immunogenicity profiles in healthy volunteers.12,13 In collaboration with researchers at the University of Texas Medical Branch, a Vaxfectin®-formulated DNA vaccine expressing HSV-2 gD as well as tegument proteins (encoded by HSV-2 genes UL-46, UL-47) were tested for therapeutic efficacy in a stringent guinea pig HSV-2 challenge model, demonstrating the therapeutic proof-of-concept efficacy of a DNA vaccine expressing full-length gD in reducing genital lesion recurrences in this animal model.14

Finally, extensive planning for Vical’s Phase 1/2 trial ensued in conjunction with researchers at the University of Washington. This trial is designed to be a proof-of-concept study that would capitalize on their lab’s expertise in conducting viral shedding studies that have contributed towards understanding the natural course of HSV-2 infection in humans.

Vical’s Therapeutic HSV-2 Vaccine: Current Status

The current Phase 1/2 trial is a double-blind, placebo controlled study at seven investigational sites in the U.S. All enrolled subjects must be HSV-2 seropositive, as established using the University of Washington’s Western blot assay. In addition, these subjects are required to have a history of symptomatic genital herpes with 2 to 9 lesion recurrences per year; higher herpes shedding rates are observed in symptomatic compared to asymptomatic subjects6 and also permit the opportunity to explore potential reductions in lesions after vaccination.

The trial consists of a dose escalation component to assess the safety of ¼ dose, ½ dose, and a full dose of vaccines in a small number of subjects prior to dosing additional subjects at the full dose. Regardless of dose, all subjects will receive the vaccine or a placebo on days 0, 28, and 56. The trial is currently enrolling subjects who will be receiving the full doses of vaccine or placebo to assess the effectiveness of the vaccines for the primary endpoint of the change in HSV-2 shedding rate from baseline. In addition the safety of the vaccines in all subjects will be assessed.

Each subject in the efficacy cohort will perform daily swabbing to measure HSV shedding rates both before vaccination and again after vaccination. Importantly, sampling periods of 60 days for swab collections were designed for this study to generate robust shedding data to compare the pre-vaccination to the post-vaccination periods. Essentially the amount of viral shedding will be measured for each subject at baseline (pre-vaccination) and then again after the intervention (completion of 3 vaccination series, the post-vaccination period).

With approximately 60 subjects per each vaccine group, the study is powered to show at least a 30% decrease in the shedding rate. Approximately 156 total subjects are planned for enrollment in this trial. Vical expects the trial to be fully enrolled in the fourth quarter of 2014, and topline data are projected to be available in mid-2015.

For more information, please go to the NCT02030301 trial listing at ClinicalTrials.gov.

References

1 Schiffer J, Corey T. Herpes Simplex Virus. In: Mandell G, Bennett J, Dolin R, eds. Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill Livingstone Elsevier; 2010: 1943-62.

2 Gupta R, Warren T, Wald A. Genital herpes. Lancet. 2007; 370(9605):2127-37.

3 Xu F, Sternberg MR, Gottleib SL, et al. Seroprevalence of Herpes Simplex Virus Type 2 Among Persons Aged 14–49 Years — United States, 2005–2008. Morbidity and Mortality Weekly Report. 2010; 59 (15):456-9.

4 Looker KJ, Garnett GP, Schmid GP.An estimate of the global prevalence and incidence of herpes simplex virus type 2 infection. Bull World Health Organ. 2008; 86(10):805-12, A.

5 Mertz GJ, Benedetti J, Ashley R, Selke SA, Corey L. Risk factors for the sexual transmission of genital herpes. Ann Intern Med. 1992; 116(3):197-202.

6 Tronstein E, Johnston C, Huang ML, et al. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA. 2011; 305(14):1441-9.

7 Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004; 350(1):11-20.

8 Schiffer JT, Abu-Raddad L, Mark KE, et al. Mucosal host immune response predicts the severity and duration of herpes simplex virus-2 genital tract shedding episodes. Proc Natl Acad Sci USA. 2010; 107(44):18973-8.

9 Kharfan-Dabaja MA, Boeckh M, Wilck MB, et al. A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis. 2012; 12(4):290-9.

10 Muller, W, Dong, L, Vilalta et al. Herpes simplex virus type 2 tegument proteins contain subdominant T-cell epitopes detectable in BALB/c mice after DNA immunization and Infection. J. Gen. Virol. 2009; 90:1153-63.

11 Shlapobersky M, Marshak, JO, Dong, L, et al. Vaxfectin-adjuvanted plasmid DNA vaccine improves protection in a murine model of genital herpes infection. J. Gen. Virol. 2012; 93:1305-15.

12 Smith LR, Wloch MK, Ye M, et al. Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin. Vaccine. 2010; 28(13):2565-72.

13 Sullivan SM, Doukas J, Hartikka J, Smith L, Rolland A. Vaxfectin: a versatile adjuvant for plasmid DNA- and protein-based vaccines. Expert Opin Drug Deliv. 2010; 7(12):1433-46.

14 Veselenak, RL, Shlapobersky M, Pyles RB, et al. A Vaxfectin-adjuvanted HSV-2 plasmid DNA vaccine is effective for prophylactic and therapeutic use in the guinea pig model of genital herpes. Vaccine 2012; 30:7046-51.

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