Non-clinical toxicology of therapeutic vaccines: Regulatory considerations and species selection: A comprehensive review.

Vaccines, a proven medical innovation, have reduced mortality from infectious diseases for billions worldwide, when used prophylactically. Vaccine technology is also used to treat disease, including cancer and autoimmune disease, offering effective therapies with limited side effects. Vaccines have a good safety record and most adverse events are transient and minor. Severe adverse events occur but are extremely rare. Safety testing of vaccines is essential and require a toxicology assessment. However, therapeutic vaccines lack specific regulatory guideline and definitions vary globally, which results in confusion, suboptimal study designs and inappropriate species selection. The paper looks at how to design a toxicology program for therapeutic vaccines and considers the 3Rs (Replacement, Reduction, Refinement) by applying the principles of prophylactic vaccine testing. The focus is on species selection and considers the target antigen, mode of action and comparative immunology across mammalian species. The paper highlights that for certain therapeutic vaccines, there may be no relevant species that models the human adaptive immune response, which means the safety assessment is about investigating potential risks related to innate immunity and/or off-target toxicity and as such, considers the future of vaccine toxicology testing in relation to ethics and science.