MSD KK

In an attempt to understand the unique toxicity of adjuvanted vaccines, we studied how toxicity develops over time following vaccine administration. In addition to on- and off-target toxicity typically observed with general pharmaceuticals, we observed toxicity associated with both the generation and the broad action of effectors (antibodies and/or cytotoxic T lymphocytes, CTLs). The impact on effector generation appears to be related to local tolerance specific to the adjuvant. The vaccine immune response by effectors serves to demonstrate species relevance as outlined in the recent WHO guideline on the nonclinical evaluation of adjuvanted vaccines. When regarded as pharmaceuticals that function at sites of local administration, adjuvants have inherent on- and off-target toxicity. On-target toxicity of the adjuvant is typically associated with effector generation, and could vary depending on animal species. Therefore, the use of species with sensitivity to adjuvants described in the WHO guidelines is required to evaluate the toxicity of the vaccine associated with effector generation. Changes in safety pharmacology endpoints would be considered off-target and further studies are conducted only if changes in these endpoints are observed in nonclinical or clinical studies. Thus our decision tree does not recommend the routine conduct of stand-alone safety pharmacology studies.

An autobiog. is presented, focusing on the author's career and research in microbiol.

Microorganisms are capable of producing natural products with widely divergent chemical structures. Greatest attention in the past has been paid to natural products that have antibiotic properties. Natural products accumulate in fermentation broths during secondary metabolism, a characteristic of the incomplete metabolic control operative in growth-inhibited microorganisms. With this general mechanism of biosynthesis, the natural products synthesized by microorganisms would be expected to have a broad range of pharmacological activities. The directed screening for nonantibiotic natural products has been of limited scope. The expectation that new compounds of interest would be found has been validated. The pharmacologically active natural products provide previously unrecognized structures as tools for fundamental research programs, as well as offering the possibility of direct use in medicine or in industrial processes.