Infection of mucosal epithelium by papillomaviruses is responsible for the induction of genital and oral warts and plays a critical role in the development of human cervical and oropharyngeal cancer. We have employed a canine model to develop a systemic vaccine that completely protects against experimentally-induced oral mucosal papillomas. The major capsid protein, Li, of canine oral papillomavirus (COPV) was expressed in Sf9 insect cells in native conformation. LI protein, which self-assembled into virus-like particles, was purified on CsCl gradients and injected intradermally into the foot pad of beagles. Vaccinated animals developed circulating antibodies against COPV and became completely resistant to experimental challenge with COPV. Successful immunization was strictly dependent upon native Li protein conformation and LI type. Partial protection was achieved with as little as 0.125 ng of LI protein, and adjuvants appeared useful for prolonging the host immune response. Serum immunoglobulins passively transferred from COPV LI-immunized beagles to naive beagles conferred protection from experimental infection with COPV. Our results indicate the feasibility of developing a human vaccine to prevent mucosal papillomas, which can progress to malignancy.Papillomaviruses are small (55 nm), nonenveloped DNA viruses that induce epidermal and mucosal papillomas in humans and animals (1, 2). Canine, bovine, rabbit, and some human papillomas can progress to the malignant state (3-7). In humans, the development of cervical carcinoma is closely associated with genital mucosal infection by a small subset of human papillomaviruses (HPVs), including 8). In regions where mass cancer screening is inadequate (e.g., Southeast Asia and South America), cervical cancer represents the leading cause of death by cancer in women. Although the United States has fewer annual deaths (4000-6000) from cervical cancer, the medical health care costs are enormous for screening and treating early HPVrelated lesions. The development of an effective prophylatic HPV vaccine could potentially reduce the occurrence of genital warts, cervical dysplasia, and neoplasia by an estimated 90%.Currently there are no vaccines to prevent disease caused by HPVs. These viruses possess certain properties which make vaccine development difficult. First, HPVs are highly species specific, making it impossible to use animals for the direct evaluation of a vaccines' efficacy. Second, there is no reliable in vivo or in vitro source of intact papillomaviruses. Mucosal lesions caused by and HPV-18 yield small quantities of infectious virus, and papillomaviruses cannot be propagated efficiently in vitro.Infection of animals with species-specific papillomaviruses offers the best opportunity for evaluating vaccines. We recently described the use of canine oral papillomavirus (COPV)The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 sole...

No abstract

The results indicate that the type I IFN pathway is activated in patient subsets of five rheumatic diseases and suggest that these subsets may benefit from anti-IFN therapy.

To identify potential pharmacodynamic biomarkers to guide dose selection in clinical trials using anti-interferon-alpha (IFN-α) monoclonal antibody (mAb) therapy for systemic lupus erythematosus (SLE), we used an Affymetrix human genome array platform and identified 110 IFN-α/β-inducible transcripts significantly upregulated in whole blood (WB) of 41 SLE patients. The overexpression of these genes was confirmed prospectively in 54 additional SLE patients and allowed for the categorization of the SLE patients into groups of high, moderate, and weak overexpressers of IFN-α/β-inducible genes. This approach could potentially allow for an accurate assessment of drug target neutralization in early trials of anti-IFN-α mAb therapy for SLE. Furthermore, ex vivo stimulation of healthy donor peripheral blood mononuclear cells with SLE patient serum and subsequent neutralization with anti-IFN-α mAb or anti-IFN-α receptor mAb showed that anti-IFN-α mAb has comparable effects of neutralizing the overexpression of type I IFN-inducible genes as that of anti-IFNAR mAb. These results suggest that IFN-α, and not other members of type I IFN family in SLE patients, is mainly responsible for the induction of type I IFN-inducible genes in WB of SLE patients. Taken together, these data strengthen the view of IFN-α as a therapeutic target for SLE.

ObjectiveTo evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE).MethodsIn this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed.ResultsOf 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline.ConclusionThe observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.