Non-clinical evaluation of vaccines
Vaccines are administered to healthy humans, often in the first year of life. The demands for safety and efficacy are therefore very high. Non-clinical testing is a prerequisite to moving a candidate vaccine from the laboratory to the clinic and includes all aspects of testing, product characterization, proof of concept/ immunogenicity studies and safety testing in animals conducted prior to clinical testing of the product in humans.
The non-clinical evaluation of vaccines includes the initial testing of candidate formulations in animal models. In vivo and in vitro toxicity studies conducted before the start of clinical trials (preclinical) identify potential safety concerns and serve to avoid possible harm to human subjects. Potential concerns include toxicity due to the active ingredients or excipients, reactions to trace impurities such as production substrates, and interactions between components of other vaccines administered simultaneously.
Studies designed to determine the right dose to induce an immune response in appropriate animal models can provide valuable information on the immune response that can be expected in humans, and guide the determination whether the candidate vaccine will be beneficial to both the human study participant and the wider population once marketed. But it must be recognized that there are limitations in animal testing; susceptibility to infection by viruses, bacteria, and other microorganisms are often highly specific, and the immune responses in an animal model, particularly at the elevated doses used for nonclinical testing, may not be predictive of what will ultimately occur in humans. Nevertheless, few people would accept the administration of a candidate medicinal product without some level of assurance of its acceptability in a living animal. Therefore, non-clinical testing continues to be a balance between the desire to reduce the use of animals for testing purposes against the rights of humans to be administered safe and effective vaccines. International harmonization of testing requirements is therefore an essential tool needed to establish uniform approaches to the determination of the safety and efficacy of medicinal products, as well as to restrict animal testing to those critical areas where it cannot be replaced by alternative means.
Non-clinical evaluation of vaccines
Written Standards
WHO guidance on the nonclinical evaluation of vaccines was adopted by the Expert Committee for Biological Standardization (ECBS) in 2003. This document provides recommendations to manufacturers and national regulatory authorities within the context of this document, refers to all in vivo and in vitro testing performed before and during the clinical development of vaccines.
WHO guidelines on non-clinical evaluation of vaccines, WHO Technical Report Series No. 927, Annex 1
Non-clinical evaluation of vaccine adjuvants and adjuvanted vaccines
Over the past decades, strategies and approaches for the development and delivery of vaccine antigens have been expanded. Some of these antigens are weakly immunogenic and require the presence of adjuvants for the induction or enhancement of an adequate immune response. Vaccines with aluminium-based adjuvants have been used extensively in immunization programmes worldwide and a significant body of safety information has accumulated for them. As the knowledge of immunology and the mechanisms of vaccine adjuvant action have developed, the number of vaccines containing novel adjuvants being evaluated in clinical trials has increased. Vaccines containing adjuvants other than aluminium-containing compounds have been authorized for use in many countries (e.g., human papillomavirus and hepatitis B vaccines), and a number of vaccines with novel adjuvants are currently under development, including, but not limited to, vaccines against human immunodeficiency virus (HIV), malaria and tuberculosis, as well as new-generation vaccines against influenza and other diseases.
However, the development and evaluation of adjuvanted vaccines present regulatory challenges. Vaccine manufacturers and regulators have questions about the type of information and extent of data that would be required to support proceeding to clinical trials with adjuvanted vaccines and to eventual authorization. Existing WHO guidelines on nonclinical evaluation of vaccines provide valuable general guidance; however, they provide limited information specifically related to new adjuvants and adjuvanted vaccines.
As a result of international collaborative effort, WHO developed Guidelines on the nonclinical evaluation of vaccine adjuvants and adjuvanted vaccines, which were adopted by the Expert Committee for Biological Standardization (ECBS) in 2013. Given the importance and the complexity of the issues, this updated and more extensive guidance on the nonclinical and preclinical testing of adjuvants and adjuvanted vaccines should allow manufacturers and regulators to proceed in an efficient manner on the critical path towards development and licensure of adjuvanted vaccines indicated for the control of diseases with important global public health impact.