The GACVS reviewed 2 published papers alleging that aluminium in vaccines is associated with autism spectrum disorders^{3, 4} and the evidence generated from quantitative risk assessment by a US FDA pharmacokinetic model of aluminium-containing vaccines.

GACVS considers that these 2 studies^{3, 4} are seriously flawed. The core argument made in these studies is based on ecological comparisons of aluminium content in vaccines and rates of autism spectrum disorders in several countries. In general, ecological studies cannot be used to assert a causal association because they do not link exposure to outcome in individuals, and only make correlations of exposure and outcomes on population averages. Therefore their value is primarily for hypothesis generation. However, there are additional concerns with those studies that limit any potential value for hypothesis generation. These include: incorrect assumptions about known associations of aluminium with neurological disease, uncertainty of the accuracy of the autism spectrum disorder prevalence rates in different countries, and accuracy of vaccination schedules and resulting calculations of aluminium doses in different countries.

The GACVS also reviewed the US FDA risk assessment model of aluminium in vaccines. The FDA calculations incorporate the most recently published aluminium risk assessments by adjusting for gastrointestinal absorption and uptake from the site of injection. The FDA analysis indicates that the body burden of aluminium following injections of aluminium-containing vaccines never exceeds safe US regulatory thresholds based on orally ingested aluminium even for low birth-weight infants. GACVS concludes that this comprehensive risk assessment further supports the clinical trial and epidemiological evidence of the safety of aluminium in vaccines. Current research on pharmacokinetics of aluminium in vaccines is ongoing and should be encouraged as a means of further validating and improving this model.

³Tomljenovic L, Shaw CA. Do aluminum vaccine adjuvants contribute to the rising prevalence of autism? Journal of Inorganic Biochemistry, 2011; 105: 1489–1499.

⁴Tomljenovic L, Shaw CA. Aluminum vaccine adjuvants: are they safe? Current Medicinal Chemistry, 2011; 18(17):2630–2637.

Full report of GACVS meeting of 6-7 June 2012, published in the WHO Weekly Epidemiological Record on 27 July 2012

Extract from report of GACVS meeting of 1-2 December 2005, published in the WHO Weekly Epidemiological Record on 13 January 2006

Adjuvant safety and the use of preclinical models to assess adjuvant safety were due to be discussed at the WHO conference on adjuvants on 4–8 December 2005. A WHO website on adjuvants in clinical evaluation including adjuvant safety, with a database of clinical trials, will be made available shortly.

Since a squalene-containing adjuvant is already used for one already licensed flu vaccine, and is also a candidate adjuvant for pandemic influenza vaccines, it would be important to assure the safety of squalene in that context. An authoritative information source on adjuvants, including a review of the scientific data to support adjuvant safety for vaccines that might be used in pandemic influenza vaccine, should be developed.

Full report of GACVS meeting of 1-2 December 2005, published in the WHO Weekly Epidemiological Record on 13 January 2006

The Committee considered the safety of adjuvants used in vaccines. This hitherto neglected subject is becoming increasingly important given modern advances in vaccine development and manufacture. WHO is developing a website to make available all relevant preclinical and clinical trial information pertaining to the safety of vaccine adjuvants. With the development of vaccines for malaria, human immunodeficiency virus (HIV), human papillomavirus and hepatitis B and of other complex modern vaccines, adjuvant safety has become a central issue. Increasingly in the future there will be a need in developing countries for surveillance of vaccine adjuvant safety following vaccine registration. This applies not only to new vaccines but also to vaccines already available and used for new indications. GACVS will participate in developing such safety surveillance.

Full report of GACVS meeting of 2-3 December 2004, published in the WHO Weekly Epidemiological Record on 7 January 2005

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.

*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.

Full report of GACVS meeting of 10-11 June 2004, published in the WHO Weekly Epidemiological Record on 16 July 2004