Application of risk assessment to veterinary biologicals: the perspective of the animal health industry.

The authors review the perspective of the animal health industry on the changing regulatory climate for the registration and free circulation of veterinary vaccines. The industry supports the increased mutual acceptance of technical standards, the harmonization of these standards and the use of proper risk analysis for regulating the free movement of veterinary vaccines. The veterinary vaccine industry is relatively small, but a large number of products are manufactured and the regulation of these products is highly complex. This complexity results in divergent policies on the importation of vaccines, thus limiting the flexibility of the industry in deciding where to develop and manufacture products. The industry welcomes moves by governments to dispense with "zero risk' policies and to adopt consistent scientific risk analysis approaches, in line with the World Trade Organisation agreement on the application of sanitary and phytosanitary measures. The risks involved in the handling, development and manufacture of veterinary biological products are reviewed, and the factors to be taken into account in the assessment and in the management or control of these risks are presented. Dissection of the production process into its various phases enables identification of the critical points and application of specific risk control measures. An important aspect of the risk assessment is the evaluation of the existing testing methods. A specific programme intended to establish the equivalence or harmonization of various test methods is being proposed. In conclusion, the industry is willing to be actively involved in the harmonization process and expects an equally clear political and technical commitment from the governments of the major trading countries.

Flurazepam and temazepam in the treatment of insomnia in a general hospital population.

This study is a double-blind comparative trial of flurazepam and temazepam in the treatment of insomnia, using subjective assessments with an analogue scale technique and questionnaire. The main dependent variable in this experiment is vigilance. The two drugs differ essentially in their half life value. (Flurazepam +/- 72 h; temazepam +/- 8 h). It can be predicted that temazepam causes less impairment of vigilance than flurazepam, and that the difference between the two drugs is more pronounced when the number of days the drugs are taken consecutively, increases. In statistical terms an interaction effect between drugs and days should be expected. The results show no effect at all, neither the predicted interaction effect, nor any main effect. If there is a difference in efficiency reduction between patients, the assessment methods used were unable to measure it. These findings warn against a possible overestimation of clinical relevance of the plasma elimination half-life of benzodiazepines.

Protection against experimental infection with influenza virus A/equine/Miami/63 (H3N8) provided by inactivated whole virus vaccines containing homologous virus.

Thirty-one ponies immunized with inactivated virus vaccine containing A/equine/Miami/63 (H3N8) virus and six seronegative ponies were experimentally challenged with the homologous virus strain. All 6 unvaccinated ponies and 11 out of 31 vaccinated ponies became infected. A clear relationship between pre-challenge antibody, measured by single radial haemolysis (SRH), and protection was demonstrated as judged by virus excretion, febrile responses and antibody responses. Those ponies with SRH antibody levels greater than 74 mm2 were completely protected against challenge infection by the intranasal route.

Vaccination against avian encephalomyelitis with special reference to the spray method.

Three vaccination methods against avian encephalomyelitis have been tested in different types of housing. The product used was a vaccine improved by Philips-Duphar, having an optimal disseminative and immunogenic capacity, and a high virus titer per bird dose. We have tested: 1) administration per os in 2-5% of the flock, 2) administration via drinking water in the whole flock and 3) spray vaccination. Observations by Schneider (1967), that administration in the beak in part of the animals may only be satisfactory under optimal conditions, have herewith been confirmed. With the actual rearing on batteries, the chance of horizontal spreading of the vaccine virus is minimal. The two other methods of administration eliminate this problem. Already 3 weeks after vaccination more than 50% of the animals show a positive serological reaction. Later this level increases quickly to more than 80%, even in batteries. Under widely varying circumstances (concentaration of animals, ventilation, length of water tubes, etc) a dosage response effect becomes apparent. The practical results obtainable will be dependent on the titer of the vaccine, care while vaccinating and conditions of housing.

Studies with inactivated equine influenza vaccine. 1. Serological responses of ponies to graded doses of vaccine.

Serological responses to three bivalent aqueous equine influenza vaccines of different potency and an adjuvanted bivalent vaccine containing inactivated A/equine/Prague/56 (H7N7) and A/equine/Miami/63 (H3N8) viruses, were examined in seronegative ponies. Potencies of the vaccines, measured by single-radial-diffusion tests, ranged from 4 to 56 micrograms of haemagglutinin (HA) antigen activity/virus strain per dose. Serological responses to vaccination were examined by haemagglutination-inhibition (HI) and single-radial-haemolysis (SRH) tests. Four weeks after a primary dose, HI responses to both vaccine viruses were barely detectable; after a second dose the HI responses to A/Miami/63 virus were low or undetectable but HI responses to A/Prague/56 virus were higher (17/20 ponies with titres greater than or equal to 1:16). In contrast SRH tests revealed dose-related antibody responses to both virus strains after one and two vaccine doses; levels after the second dose were 2- to 5-fold higher than after the primary dose. Highest post-vaccination antibody titres were obtained with the adjuvanted vaccine which contained 2- to 4-fold less antigen (13-23 micrograms HA) than the most potent aqueous vaccine. Post-vaccination antibody reacted well in SRH tests with recent antigenic variants of equine influenza virus. A remarkable finding was the high rate of decline in antibody, detected by HI or SRH tests, following one or two doses of vaccine. Even in animals with the highest post-vaccine antibody levels 2-4 weeks after a booster dose, antibody levels had declined to low or indetectable levels 14 weeks later. The low antibody titres detected at 14-32 weeks after vaccination were nevertheless vaccine dose-related.

Studies with inactivated equine influenza vaccine. 2. Protection against experimental infection with influenza virus A/equine/Newmarket/79 (H3N8).

Forty ponies immunized with inactivated virus vaccine containing A/equine/Miami/63 (H3N8) virus and six unvaccinated, seronegative ponies were experimentally challenged with a representative of recent equine H3N8 virus isolates, A/equine/Newmarket/79. All unvaccinated ponies became infected as judged by virus excretion, febrile responses and antibody responses, but only two of the vaccinated ponies were fully protected. Pre-challenge antibody levels to A/Newmarket/79 virus detected by single radial haemolysis (SRH) correlated well with the degree of clinical protection but the levels required for complete protection (SRH zones greater than 65 mm2) were high. The importance of these results in relation to conventional vaccination procedures against equine influenza is discussed.

The standardization of inactivated equine influenza vaccines by single-radial immunodiffusion.

Single-radial-immunodiffusion (SRD) assays were used for measuring the haemagglutinin (HA) antigen content of equine influenza vaccines containing the virus strains A/equine/Prague/56 (H7N7) and A/equine/Miami/63 (H3N8). Three bivalent aqueous vaccines and one bivalent adjuvanted vaccine were standardized by SRD to contain graded amounts of HA antigen activity. The SRD reaction was influenza subtype specific and was not influenced by the presence of adjuvant in vaccine.