Search

VGX-1027, a novel oral immune modulator, is under development for the treatment of rheumatoid arthritis. The safety, tolerability, and pharmacokinetics of single (1-800 mg) and multiple (40-400 mg) oral doses were evaluated in 2 clinical studies. The doses were well tolerated up to 800 mg in a single dose and 200 mg twice daily in multiple doses. Adverse events were mild to moderate in severity with no identifiable dose-related pattern. There were no clinically significant physical or laboratory findings. The pharmacokinetic data indicated that increases in Cmax and AUC0-inf were dose-proportional, and AUC0- τ was approximately dose-proportional. For the single-dose study, median Tmax ranged from 0.5 to 2 hours and mean t1/2 ranged from 4.9 to 8.7 hours. For the multiple-dose study, median Tmax ranged from 0.5 to 2.0 hours and mean t1/2 ranged from 7.05 to 10.05 hours. No accumulation of the drug was observed after day 1, indicating that steady-state concentrations were attained with single and multiple dosing for 5 days. Approximately 90% of the administered dose was excreted in urine as unchanged drug.

Control of seasonal and pandemic influenza represents a global public health challenge due to the virus's ability to circumvent protective immune responses through frequent mutation and subunit recombination. These characteristics, coupled with influenza's ability to spread rapidly during outbreaks, require continuous global surveillance, frequent vaccine reformulation, and tightly scheduled manufacturing. Egg- and cell-culture–based vaccine production methods are resource- and time-intensive, leaving little room for error in selection of vaccine components or timing of production. For example, in 2014–2015, long manufacturing lead times prevented the industry from addressing a discrepancy between the H3 virus predominantly circulating in the northern hemisphere and the H3 included in the licensed vaccine [1]. Furthermore, low vaccine effectiveness in the 2012–2013 season was attributed to mutations introduced as part of egg-based manufacturing [2]. Rapid response, high-yield methods that remain faithful to the circulating virus sequences are therefore needed to address the shortcomings of current approaches. Recombinant technologies have the potential to address such current shortcomings and include production of recombinant HA [3], virus-like particles consisting of hemagglutinin (HA), neuraminidase (NA), and matrix (M1) proteins [4, 5], vaccinia virus-based expression of HA and NA [6], the HA1 fragment of HA [7], or the HA2 stalk of HA [8], as well as DNA vector-based expression of multiple antigens [9]. To date, none has achieved a combination of rapid, high-yield production, potency, and ability to remain faithful to the circulating sequence that is sufficient to address the deficiencies associated with egg- and cell-based approaches. We have developed a recombinant influenza vaccine platform whereby the globular head domain of the major protective antigen, HA, is fused to the Toll-like receptor (TLR)5 agonist, flagellin (Salmonella typhimurium flagellin type 2 [STF2]) [10–12]. The binding of STF2 to TLR5 on the surface of sentinel immune cells activates the innate immune system and, in turn, enhances the adaptive immune response [10]. The flagellin moiety of the vaccine therefore serves as a built-in adjuvant. These relatively simple recombinant fusion proteins can be rapidly and inexpensively produced in standard Escherichia coli production systems at high yield. Specifically, current production yields range from 0.3 to 1 mg of purified bulk drug substance per liter of fermentation, with a cycle time of under 2 weeks (unpublished observations). In animal models and in humans, the individual HA-STF2 fusion proteins elicit HA-specific neutralizing antibodies at low microgram doses of vaccine [13]. We have reproduced these results using HA from a variety of influenza type A and B strains, and we have also determined the optimal, subtype or type-specific placement of each HA subunit within the STF2 protein sequence [12–17]. The low dose of antigen required, coupled with the rapidity and efficiency of production, further demonstrate that the platform has the capacity to address the shortcomings associated with current licensed vaccines. Extending on this work, we are developing a prototypic quadrivalent seasonal flu vaccine, VAX2012Q. We report results from a Phase I dose-ranging study designed to identify the total antigen dose and component ratio that provides optimal tolerability and immunogenicity profiles.

Subjectsor = 55 years of age were immunized with attenuated varicella zoster virus (VZV) vaccine (live) or with the same vaccine, which had been heated to 56 degrees C for 7 days (killed). The ability of subjects' blood lymphocytes to lyse target cells infected with VZV was determined before and 3 months after immunization using autologous Epstein-Barr virus (EBV) lymphoblasts as targets for human leukocyte antigen (HLA) class I restricted cytotoxicity and human fibroblasts as targets for unrestricted (natural killer [NK]) cytotoxicity. The live vaccine recipients showed an increase in their class I-restricted lysis of targets compared with the recipients of the killed vaccine. The two populations showed equivalent increase in their NK-dependent lysis of fibroblast targets. The results support the view that both the live and killed vaccines stimulate cytotoxicity by VZV-specific lymphocytes but that the live vaccine stimulates relatively more class I-restricted killing.

The investigational vaccine, NDV-3, contains the N-terminal portion of the Candida albicans agglutinin-like sequence 3 protein (Als3p) formulated with an aluminum hydroxide adjuvant in phosphate-buffered saline. Preclinical studies demonstrated that the Als3p vaccine antigen protects mice from oropharyngeal, vaginal and intravenous challenge with C. albicans and other selected species of Candida as well as both intravenous challenge and skin and soft tissue infection with Staphylococcus aureus. The objectives of this first-in-human Phase I clinical trial were to evaluate the safety, tolerability and immunogenicity of NDV-3 at two different antigen levels compared to a saline placebo. Forty healthy, adult subjects were randomized to receive one dose of NDV-3 containing either 30 or 300 μg of Als3p, or placebo. NDV-3 at both dose levels was safe and generally well-tolerated. Anti-Als3p total IgG and IgA1 levels for both doses reached peak levels by day 14 post vaccination, with 100% seroconversion of all vaccinated subjects. On average, NDV-3 stimulated peripheral blood mononuclear cell (PBMC) production of both IFN-γ and IL-17A, which peaked at day 7 for subjects receiving the 300 μg dose and at day 28 for those receiving the 30 μg dose. Six months after receiving the first dose of NDV-3, nineteen subjects received a second dose of NDV-3 identical to their first dose to evaluate memory B- and T-cell immune responses. The second dose resulted in a significant boost of IgG and IgA1 titers in >70% of subjects, with the biggest impact in those receiving the 30 μg dose. A memory T-cell response was also noted for IFN-γ in almost all subjects and for IL-17A in the majority of subjects. These data support the continued investigation of NDV-3 as a vaccine candidate against Candida and S. aureus infections.

Despite the development of highly effective prophylactic vaccines against human papillomavirus (HPV) serotypes 16 and 18, prevention of cervical dysplasia and cancer in women infected with high-risk HPV serotypes remains an unmet medical need. We report encouraging phase 1 safety, tolerability, and immunogenicity results for a therapeutic HPV16/18 candidate vaccine, VGX-3100, delivered by in vivo electroporation (EP). Eighteen women previously treated for cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) received a three-dose (intramuscular) regimen of highly engineered plasmid DNA encoding HPV16 and HPV18 E6/E7 antigens followed by EP in a dose escalation study (0.3, 1, and 3 mg per plasmid). Immunization was well tolerated with reports of mild injection site reactions and no study-related serious or grade 3 and 4 adverse events. No dose-limiting toxicity was noted, and pain was assessed by visual analog scale, with average scores decreasing from 6.2/10 to 1.4 within 10 min. Average peak interferon-γ enzyme-linked immunospot magnitudes were highest in the 3 mg cohort in comparison to the 0.3 and 1 mg cohorts, suggesting a trend toward a dose effect. Flow cytometric analysis revealed the induction of HPV-specific CD8(+) T cells that efficiently loaded granzyme B and perforin and exhibited full cytolytic functionality in all cohorts. These data indicate that VGX-3100 is capable of driving robust immune responses to antigens from high-risk HPV serotypes and could contribute to elimination of HPV-infected cells and subsequent regression of the dysplastic process.

Mifepristone is a glucocorticoid receptor inhibitor shown in vitro to have anti-HIV activity and anti-simian immunodeficiency virus activity in a macaque model. A phase I/II trial was performed to assess the drug's safety and anti-HIV activity.A 28-day double-blind, placebo-controlled trial of mifepristone at doses of 75 mg, 150 mg, and 225 mg given daily was conducted in HIV+ persons with CD4+ lymphocyte countsor=350 cells per cubic millimeter who had no recent antiretroviral therapy.Fifty-six male and 1 female subjects with a median entry CD4+ lymphocyte count of 555 cells per cubic millimeter and plasma HIV-1 RNA of 15,623 copies per milliliter were accrued. Forty-five subjects (78.9%) were available for endpoint analysis. In each arm, changes from baseline to day 28 in plasma HIV-1 RNA and CD4+ lymphocyte count were not significantly different from zero (no change). There was no relationship between mifepristone trough concentrations and plasma HIV-1 RNA. Day 28 morning plasma cortisol levels were significantly higher in the 150 mg and 225 mg arms compared with placebo, confirming biologic activity, and returned to baseline by day 56. Serum lipids did not change during the trial. Fasting blood sugar was 2.5 mg/dL higher on day 28 in the mifepristone arms, but the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) did not change. Three subjects (7.3%) receiving mifepristone developed a grade 2 rash.Mifepristone at doses of 75-225 mg daily was safe and well-tolerated, but did not show significant anti-HIV activity.

Four hundred nineteen children and adolescents immunized with live varicella vaccine 4-6 years earlier were enrolled in a study to evaluate the safety and immune response to a booster dose containing approximately 3300 pfu of virus. Of the subjects, 99% (414/419) maintained antibody to varicella zoster virus (VZV) with a geometric mean titer of 25.7 and mean stimulation index (SI) for VZV-specific lymphoproliferation response of 40.3 +/- 5.3 (SE). Some 7-10 days after the booster immunization, seropositivity rates increased to 100% (302/302), and GMT was 143.6 (anamnestic response). At 6 weeks after the booster inoculation, a subset of subjects had 100% seropositivity (74/74) with a GMT of 218.8 and an SI of 58.6. After 3 months, seropositivity was 100% (358/358), GMT was 119.0, and SI was 61.4.

The Oka varicella vaccine has been tested in clinical trials worldwide in thousands of children. Following licensure in Japan, Korea, Germany, and the United States, the vaccine has been used in several millions of children. The vaccine has been generally well-tolerated with the most common complaints being pain and redness at the injection site and a mild rash following vaccination. The incidence of herpes zoster has not increased in vaccinees and may have decreased. Efficacy rates vary between 65% and 100% depending on the intensity of exposure to natural varicella and the potency of the vaccine. In those few vaccinees who develop MVLS, the rash is generally milder than seen following natural infection (median < 50 versus 300 lesions, respectively, as well as a lower incidence of fever). There has been no evidence to date to indicate waning immunity postvaccination. Studies are in progress in the United States to evaluate whether this will occur and the effect of booster doses of vaccine. It is expected that in countries where there is widespread use of the vaccine in healthy children, disease rates will fall dramatically as will the morbidity and mortality associated with natural varicella in this population.

Background HIV-infected persons have less robust antibody responses to influenza vaccines. Objective To compare the immunogenicity of high-dose influenza vaccine with that of standard dosing in HIV-positive participants. Design Randomized, double-blind, controlled trial. (ClinicalTrials.gov: NCT01262846) Setting The MacGregor Clinic of the Hospital of the University of Pennsylvania, Philadelphia, from 27 October 2010 to 27 March 2011. Participants HIV-infected persons older than 18 years. Intervention Participants were randomly assigned to receive either a standard dose (15 mcg of antigen per strain) or a high dose (60 mcg/strain) of the influenza trivalent vaccine. Measurements The primary end point was the rate of seroprotection, defined as antibody titers of 1:40 or greater on the hemagglutination inhibition assay 21 to 28 days after vaccination. The primary safety end point was frequency and intensity of adverse events. Secondary end points were seroconversion rate (defined as a greater than 4-fold increase in antibody titers) and the geometric mean antibody titer. Results 195 participants enrolled, and 190 completed the study (93 in the standard-dose group and 97 in the high-dose group). The seroprotection rates after vaccination were higher in the high-dose group for the H1N1 (96% vs. 87%; treatment difference, 9 percentage points [95% CI, 1 to 17 percentage points]; P = 0.029), H3N2 (96% vs. 92%; treatment difference, 3 percentage points [CI, -3 to 10 percentage points]; P = 0.32), and influenza B (91% vs. 80%; treatment difference, 11 percentage points [CI, 1 to 21 percentage points]; P = 0.030) strains. Both vaccines were well-tolerated, with myalgia (19%), malaise (14%), and local pain (10%) the most frequent adverse events. Limitations The effectiveness of the vaccine in preventing clinical influenza was not evaluated. The number of participants with CD4 counts less than 0.200 × 109 cells/L was limited. Conclusion HIV-infected persons reach higher levels of influenza seroprotection if vaccinated with the high-dose trivalent vaccine than with the standard-dose. Primary funding source National Institute of Allergy and Infectious Diseases and Center for AIDS Research of the University of Pennsylvania.