Regulatory considerations for emergency use of non-USDA licensed vaccines in the United States.

The Virus-Serum-Toxin Act of 1913 (21 US Code 151-159) provides the legal basis for the regulation of veterinary biologicals in the United States; the United States Department of Agriculture's Center for Veterinary Biologicals (CVB) has the regulatory authority for the issue of licences and permits for such products. The law was intended to establish standards and control the importation of products into the United States and the distribution of products interstate assuring the purity, safety, potency, and efficacy of veterinary biological products. Administrative regulations and standards appear in the Title 9, Code of Federal Regulations, Parts 101-118, with additional programme guidance found in CVB Notices, Veterinary Services Memoranda, General Licensing Considerations, and other guidance documents. Pre-licensing data evaluation procedures are designed to assess the purity, safety, potency, and effectiveness of each product and support all product label claims. To fulfil these criteria, data from all phases of product development are evaluated against these key elements. Under the standard licensing process, this spectrum of evaluation includes complete characterization and identification of seed material and ingredients, laboratory and host animal safety and efficacy studies, stability studies, and post-licensing monitoring of field performance. This comprehensive evaluation may not be possible during the emergence of a new animal disease. While there are no specific regulations addressing the licensing standards of products for an emerging animal disease, there are mechanisms that allow for the availability of products in an emergency animal health situation. These mechanisms include autogenous biologicals, conditional licences, experimental and emergency use authorizations, and the importation of products in use elsewhere in the world. Pre-approved vaccine banks provide an additional mechanism.

Distribution of bluetongue virus in tissues of experimentally infected pregnant dogs as determined by in situ hybridization.

Six female dogs (four pregnant and two nonpregnant) were inoculated with bluetongue virus (BTV), serotype 11. Pregnant animals and one nonpregnant dog received 5.5-6.3 log10 of cell culture-adapted virus. The other nonpregnant dog received a modified live vaccine contaminated with bluetongue virus. The non-pregnant animals never became clinically ill and were euthanatized 35 days post-inoculation. Three of the four pregnant dogs aborted, and all four died or were euthanatized 5-10 days post-inoculation. The predominant pathologic feature in the adults was severe pulmonary edema. Various tissues from the bitches and fetuses were examined by in situ hybridization using a digoxigenin-labeled probe corresponding to the nonstructural protein-1 gene of BTV-17. By this technique, viral nucleic acid was detected predominantly in endothelial cells of lung of all four dogs, with lesser amounts in capillaries of uterus, spleen, and kidney in some of the dogs. In two adult dogs, bluetongue viral nucleic acid was detected in mononuclear cells of the periarteriolar lymphoid sheaths of spleen. There was minimal staining of capillaries in placenta in three of the five fetuses examined. There was no viral nucleic acid detected in any of the other fetal tissues.

Statistical methods for analysis of in vitro antigen quantification data for veterinary biologic products.

In vitro assay systems that measure the antigen content of veterinary biologic products use a statistical model for quantification. The most prevalent assay system for measuring veterinary biologics in the United States compares a reference, demonstrated to be protective in the host species, to the serial being tested. An ideal statistical model evaluates the similarity of response and compares the amount of antigen of a serial to the reference. This method is defined as the relative potency approach. Various statistical methods have been proposed for relative potency determinations. The standard curve, slope ratio assay, parallel line assay, four-parameter (logistics) fit, and integration of the area under the curve have been used. Each statistical method has strengths and weaknesses. The parallel line assay accepts data from assays with non-ideal dose response curves, provides a similarity comparison, and evaluates the relative potency in the most linear portion of the curve. The parallel line method is recommended for evaluation of in vitro assays for potency determination of U.S. licensed veterinary biologics.

Use of subcutaneously implanted chambers in calves for in vivo study of isolates of Moraxella bovis.

Selected cultures of Moraxella bovis were studied in calves, using chambers fabricated from a semipermeable membrane supported and protected by perforated plastic golf balls. Plain balls, semipermeable membrane-covered balls, and balls that contained bags fabricated from semipermeable membranes were surgically implanted subcutaneously in calves at a site approximately 25 cm ventral to the paralumbar fossa and cranial to the prefemoral lymph node. After calves recovered from surgery, chambers were inoculated with different cultures of M bovis. Cultural examination of samples taken from inoculated chambers indicated that M bovis cultures were maintained within the chambers for variable times, depending on the characteristics of the culture inoculated. A smooth (piliated) culture dissociated into a rough (nonpiliated) culture after 4 weeks of incubation within a chamber but none of the rough cultures became smooth. The technique offers a method to study the in vivo variations in a series of cultures or strains of microorganisms under the influence of the same host factors. The selective permeability of the chamber may be controlled by using membranes of different porosities to control the flow of entering or exiting dialysate.