Custom-engineered chimeric foot-and-mouth disease vaccine elicits protective immune responses in pigs.

Chimeric foot-and-mouth disease viruses (FMDV) of which the antigenic properties can be readily manipulated is a potentially powerful approach in the control of foot-and-mouth disease (FMD) in sub-Saharan Africa. FMD vaccine application is complicated by the extensive variability of the South African Territories (SAT) type viruses, which exist as distinct genetic and antigenic variants in different geographical regions. A cross-serotype chimeric virus, vKNP/SAT2, was engineered by replacing the external capsid-encoding region (1B-1D/2A) of an infectious cDNA clone of the SAT2 vaccine strain, ZIM/7/83, with that of SAT1 virus KNP/196/91. The vKNP/SAT2 virus exhibited comparable infection kinetics, virion stability and antigenic profiles to the KNP/196/91 parental virus, thus indicating that the functions provided by the capsid can be readily exchanged between serotypes. As these qualities are necessary for vaccine manufacturing, high titres of stable chimeric virus were obtained. Chemically inactivated vaccines, formulated as double-oil-in-water emulsions, were produced from intact 146S virion particles of both the chimeric and parental viruses. Inoculation of guinea pigs with the respective vaccines induced similar antibody responses. In order to show compliance with commercial vaccine requirements, the vaccines were evaluated in a full potency test. Pigs vaccinated with the chimeric vaccine produced neutralizing antibodies and showed protection against homologous FMDV challenge, albeit not to the same extent as for the vaccine prepared from the parental virus. These results provide support that chimeric vaccines containing the external capsid of field isolates can be successfully produced and that they induce protective immune responses in FMD host species.

Mapping of amino acid residues responsible for adhesion of cell culture-adapted foot-and-mouth disease SAT type viruses.

Foot-and-mouth disease virus (FMDV) infects host cells by adhering to the alpha(V) subgroup of the integrin family of cellular receptors in a Arg-Gly-Asp (RGD) dependent manner. FMD viruses, propagated in non-host cell cultures are reported to acquire the ability to enter cells via alternative cell surface molecules. Sequencing analysis of SAT1 and SAT2 cell culture-adapted variants showed acquisition of positively charged amino acid residues within surface-exposed loops of the outer capsid structural proteins. The fixation of positively charged residues at position 110-112 in the beta F-beta G loop of VP1 of SAT1 isolates is thought to correlate with the acquisition of the ability to utilise alternative glycosaminoglycan (GAG) molecules for cell entry. Similarly, two SAT2 viruses that adapted readily to BHK-21 cells accumulated positively charged residues at positions 83 and 85 of the beta D-beta E loop of VP1. Both regions surround the fivefold axis of the virion. Recombinant viruses containing positively charged residues at position 110 and 112 of VP1 were able to infect CHO-K1 cells (that expresses GAG) and demonstrated increased infectivity in BHK-21 cells. Therefore, recombinant SAT viruses engineered to express substitutions that induce GAG-binding could be exploited in the rational design of vaccine seed stocks with improved growth properties in cell cultures.

Pharmacokinetic interaction of solifenacin with an oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women: a double-blind, placebo-controlled study.

BACKGROUND: Solifenacin succinate (YM905; Vesicare, Astellas Pharma Inc., Tokyo, Japan) is a new once-daily, orally administered muscarinic receptor antagonist under investigation for the treatment of overactive bladder. OBJECTIVE: The aim of this study was to evaluate the effect of solifenacin on the pharmacokinetic (PK) parameters of an oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LNG). METHODS: In a double-blind, placebo-controlled, 2-period, crossover study, 24 healthy, young, white women received a combined OC (EE 30 microg + LNG 150 microg) daily for two 21-day cycles, separated by a 7-day washout. On day 12 of each cycle, subjects began a 10-day regimen of solifenacin 10 mg QD, which is 2 times the suggested starting dose, or placebo. Subjects crossed over to the other treatment arm for the second cycle. Primary PK end points were C(max) and AUC from time 0 to 24 hours (AUC(0-24 h)) for EE and LNG. Women ranged in age from 20 to 37 years and had a mean body weight of 64 kg, mean height of 167.4 cm, and mean body mass index of 23 kg/m2. Seven women had never smoked, while 5 were former smokers and 12 were regular smokers. Safety assessments included the nature, frequency, and severity of spontaneously reported or observed adverse events, vital signs, electrocardiogram, laboratory values, and physical examination. RESULTS: Statistical analysis of AUC(0-24 h)/product of baseline concentration and total blood sampling time, and C(max)/baseline concentration ratios of solifenacin versus placebo for EE and LNG found the 90% CI to be within the predefined range of 0.8 to 1.25 (EE: 0.854-1.164 and 0.822-1.167; LNG: 0.920-1.125 and 0.910-1.139). The number of samples with non-quantifiable luteinizing hormone (LH) and folliclestimulating hormone (FSH) levels were comparable after administration of the OC with either solifenacin or placebo. The adverse event most frequently reported was dry mouth (solifenacin, n = 25 [9 mild, 13 moderate, and 3 severe] vs placebo, n = 1 [moderate]). There were no clinically relevant effects on vital signs, electrocardiogram, or laboratory parameters. CONCLUSIONS: A PK interaction between solifenacin and the OC containing EE and LNG was not found in this study. Solifenacin was not found to have altered suppression of LH or FSH. The drug was well tolerated in these healthy, young, white, adult female volunteers.

Solifenacin demonstrates high absolute bioavailability in healthy men.

OBJECTIVE: Solifenacin succinate (YM905; Vesicare) is a promising new bladder selective muscarinic receptor antagonist under investigation for the treatment of overactive bladder. This study was designed to assess the absolute bioavailability of a single oral dose of solifenacin 10 mg, which is twice the suggested starting dose. STUDY DESIGN: Single-centre, open-label, randomised, two-period, crossover, single-dose study. METHODS: Solifenacin was administered orally as a 10 mg dose and intravenously as a 5 mg dose. Oral and intravenous (IV) doses were divided by a washout period of > or =14 days. STUDY PARTICIPANTS: The study group consisted of 12 healthy young men, aged 20-45 years, nine of whom completed the study. RESULTS: The pharmacokinetic analysis comprised nine subjects. A single oral dose of solifenacin 10 mg had a high absolute bioavailability of 88.0% (95% confidence interval 75.8, 102.1), low clearance (9.39 L/h [SD 2.68]), and an extensive mean volume of distribution at steady state (599L [SD 86]). Only 7% of solifenacin was excreted intact in the urine. Single oral and IV administration of solifenacin was well tolerated in this study. The most common adverse events related to drug treatment were headache and somnolence. CONCLUSIONS: Pharmacokinetic analyses of single oral and IV doses of solifenacin demonstrated that the drug has a high absolute oral availability of 88%. This finding suggests that solifenacin may have a higher and less variable bioavailability than other antimuscarinic agents.