Establishing the Pharmacokinetics of Genetic Vaccines is Essential for Maximising their Safety and Efficacy.

In a typical course of drug development, thorough pharmacokinetic (PK) studies are essential for the determination of drug biodistribution, dosage and efficacy without toxicity. For vaccines, however, unless a new formulation component is used, most regulatory agencies rule out the need for studying the biodistribution of the vaccine antigenic material per se, and only dose-immunogenicity studies are performed. This is because traditional vaccines are meant to directly induce immunogenicity by locally recruiting immunocytes that will carry on with the pursuing immunogenic processes. Thus, the clinical outcome from traditional vaccines is determined mainly by an immunological response phase. Yet, the case is significantly different for the emergent genetic vaccines (vectorised DNA or mRNA vaccines), where the clinical outcome is dependent on a combination of two major response phases: a pharmacological phase that involves biodistribution, assimilation, gene translation and epitope(s) presentation, followed by an immunological phase, which is similar to that of traditional vaccines. From a mathematical perspective, processes involved in drug administration are typically subject to inter- and intra-patient statistical distributions like most physiological processes. Therefore, the clinical outcome after administering genetic vaccines obeys a statistical probability distribution combined of the sum of two major response probability distributions, pharmacological and immunological. This implies that the variance coefficient of the summed response probability distributions has a larger value than the variance of each underlying distribution. In other words, due to the multi-phased mode of action of genetic vaccines, their clinical outcome has more variability than that of traditional vaccines. This observation points toward the necessity for regulating genetic vaccines in a similar manner to bio-therapeutics to ensure better efficacy and safety. A structural PK model is provided to predict the sources of variability, biodistribution and dose optimisation.