Safety of adjuvants1
This section of the meeting involved scientists from academia and industry and experts in vaccine regulation. The Committee heard presentations on the current status of the scientific development of a number of novel adjuvants and considered the potential constraints to their review by national regulatory authorities. Current WHO requirements for production, quality control, preclinical and clinical evaluation of vaccines with respect to adjuvants, as published in the WHO Technical Report Series, were presented to the Committee. Regulatory guidelines relevant to adjuvants in vaccines were discussed, including those of the European Agency for the Evaluation of Medicinal Products the Committee for Proprietary Medicinal Products, and Vaccine Expert Group, draft guidelines on adjuvants in vaccines, and WHO guidelines on preclinical and clinical evaluation of vaccines.
During the past decade, a large number of novel adjuvants have been developed and evaluated clinically. Those considered by the Committee at its meeting included oil-based emulsions such as MF59 and Montanide ISA 720, immunostimulators such as monophosphoryl lipid A, CpG oligonucleotides, saponins such as QS21, and mucosal adjuvants based on bacterial exotoxins that have been developed for nasal and oral delivery. Several adjuvants are already contained in licensed vaccines, and others are likely to be available in coming years. A number will have a bearing on the scientific development, efficacy, safety and quality of new vaccines developed for HIV/AIDS, tuberculosis, malaria, leishmaniasis and other conditions. Increasingly, adjuvants will be developed to facilitate vaccine delivery to other sites in the body, such as mucosal surfaces.
Safety issues will require a thorough understanding of the effects of adjuvants on the immune response and related mechanisms. Current regulatory approaches will have to take into account the new scientific data available on vaccine adjuvants. Adjuvant safety is an important and neglected field. Since adjuvants have their own pharmacological properties, which might affect both the immunogenicity and the safety of vaccines, safety assessment is essential.
The meeting concluded that WHO will have an important role in facilitating dialogue between the scientific community, industry and regulatory agencies, and in establishing standards published in the Technical Report Series, to ensure a consistent regulatory approach in this complex area. Adverse events attributable to adjuvants need to be documented and reviewed, and the information made available. That is another important role for WHO. Since many of the new adjuvants are likely to be used in vaccines for conditions endemic in developing countries, scientists from those countries should be involved in these considerations. Systems for safety monitoring and the necessary training will be required.
In considering a framework for safety studies of adjuvants, attention was drawn to the limitations of animal models in predicting adjuvant safety. A number of the traditional methods and interpretations used in animal studies of (non-vaccine) drug safety are unlikely to apply in the specialized field of adjuvant safety. Nevertheless, animals cannot be dispensed with in the early consideration of a safety profile. No single experimental animal can provide the answer, nor do conventional dose–increment safety studies adequately address the immunological aspects of adjuvant safety (including tolerance effects, hypersensitivity and generation of autoimmunity). Validated animal models for adjuvant safety testing do not exist, yet they will be required for future vaccine research and development. Short-term and long-term safety evaluation and prediction are important, as is the evaluation of the pharmacokinetics of the adjuvant alone. WHO might promote research and further develop guidelines on adjuvant safety.
Safety testing of new adjuvants, once combined with a vaccine, necessitates improved and consistent standards for safety monitoring boards, post-licensure signal generation and evaluation, and surveillance of adverse immunological events. This includes unexpected safety issues. Phase IV studies should accommodate adverse reactions that cannot be anticipated from the biological actions of the vaccine and its adjuvant, including the rare and unusual adverse reactions that are not detected in animal work or in small pre-registration human studies. For this, clear case definitions are needed. All this requires a new clinical, scientific and regulatory approach, with attention to the short- and long-term safety of adjuvants.
It was suggested that WHO might serve as a repository for safety reports and as a forum for dialogue and guidance for the technical and scientific standards for adjuvants and their safety, for setting standards for such work, and for defining principles governing regulatory issues in adjuvant safety. The GACVS might collate such information, which should be evaluated and made widely available.
1. The discussions on the safety of adjuvants took place with additional experts who presented evidence, information and opinion, and participated in the discussions. However, the conclusions and recommendations reflected above are those of Committee members alone, taken in closed session.