Large-Animal Model for Establishing E/T Ratio of Adjuvants
To develop novel adjuvants for use in humans, the efficacy/toxicity (E/T) ratio of experimental products in large animal species can be investigated. The test model included two intramuscular immunizations in pigs at 3 weeks interval and analysis of immune responses and local reactions 1 week after the second injection. The antigen used to determine adjuvant activity was a well-defined, purified, viral glycoprotein that without adjuvant induces low immune responses and no detectable local reactions. Efficacy was determined by measuring ELISA and virus-neutralizing antibody titres. Toxicity was determined by necropsy and estimating size and severity of local reactions to each treatment. The persistence of the side effects was deduced from the difference in the local reaction 4 weeks after the first and 1 week after the second injection. For graphic representation of E/T ratios, toxicity was expressed in arbitrary units and plotted against antibody titre. The graphs provided insight into dose– and structure–response relationships and enabled the stepwise optimization of adjuvant candidates.
Key wordsAnimal model pig efficacy local toxicity reactogenicity E/T ratio necropsy risk/benefit ratio
- 2.Hulst, M. M., Westra, D. F., Wensvoort, G., Moormann, R. J. M. (1993) Glycoprotein E1 of hog cholera virus expressed in insect cells protects swine from hog cholera. J Virol 67, 6479–6486.Google Scholar
- 6.Hilgers, L. A. T., Platenburg, P. L. I., Luitjens, A., Groenveld, B., Dazelle, T., Ferrari-Laloux, M., Weststrate, M. W. (1994) A novel non-mineral oil-based adjuvant. I. Efficacy of a synthetic sulfolipopolysaccharide in squalane-in-water emulsion in laboratory animals. Vaccine 12, 653–660.PubMedCrossRefGoogle Scholar
- 10.US Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. (2009). Guidance for Industry: toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials (Draft guidance 2005). Available at http://www.fda.gov/cber/gdlns/toxvac.htm [accessed January 2009].