Adjuvants in the History of Vaccine Development
The word "vaccination" was coined by English scientist Edward Jenner in 1796, although early forms of vaccination have been documented as far back as the 17th century.1 Vaccination is used to generate a strong immune response to a specific administered antigen, providing long-term protection against infection.2 Demonstrated successes of vaccination include the global eradication of smallpox in the 20th century as well as the control of many other diseases, such as polio and measles.
Key challenges to developing vaccines are associated either with lack of efficacy or unacceptable reactogenicity, or the capacity to induce undesirable reactions.3 Reactogenicity associated with nonviable, whole microorganism vaccines frequently manifests as localized swelling and severe, fever-like symptoms. This has led to the development of purer vaccines that eliminate unwanted reactogenic material, while preserving efficacy. An unintended consequence of the use of purified vaccine components was the loss of immunogenicity, to the extent that many pure protein or carbohydrate-based vaccines were so poorly immunogenic that efficacy of these vaccines was reduced to unacceptable levels.
Effective modern vaccines therefore often require the addition of substances that enhance immunogenicity. Adjuvants are used to boost immunogenicity of these purified vaccines without significantly increasing reactogenicity. Although hundreds of materials with adjuvant activity have been identified to date, the majority of these do not meet standards for clinical use due to their inherent reactogenicity.3
What is an Adjuvant?
Immunological adjuvants are defined as molecules, compounds, or macromolecular complexes that boost the potency and longevity of specific immune response to antigens, but cause minimal toxicity or long-lasting immune effects on their own.4 The purpose of the adjuvant is to help the immune system (the Latin verb 'adjuvare' means 'to help') by increasing the immunogenicity of the coadministered microorganism, harmless protein or polysaccharide (antigen).5 Adjuvant mechanisms of action have long been enigmatic.
Early attempts to produce adjuvanted vaccines used crude oils or other materials that deposited material at the site of injection, often leading to local irritation and pathology.3 Adjuvants currently serve an expanded role in vaccine formulations by providing a number of functions:
- Enhancing immunogenicity of highly purified or recombinant antigens
- Reducing the amount of antigen or the number of immunizations needed for protective immunity
- Improving the efficacy of vaccines in newborns, the elderly, or immunocompromised persons
- As antigen delivery systems for the uptake of antigens by the mucosa2
Types of Adjuvants Used in Vaccines
Few adjuvants other than alum salts are widely accepted for human use. Alum, also known as aluminum hydroxide, was first described as an adjuvant by Glenny, et al., in 1926.6 Since then, aluminum hydroxide, aluminum phosphate, and aluminum potassium sulfate have been the preferred adjuvants for human vaccines, especially in the U.S. Oil-in-water emulsions and lipids are less common human vaccine adjuvant formulations. Oil-based adjuvants are common in veterinary vaccines but have only recently been approved for use in humans in extended clinical studies.3,
Why are New Adjuvants Needed?
New adjuvant development has been driven principally by the shortcomings of aluminum adjuvants. Alum adjuvants fail to stimulate mature, durable T cell responses, including those of critical cytotoxic T cells (CTL).4 An ideal adjuvant will elicit both humoral and cellular immune responses with no reactogenicity. This has yet to be identified, though research is ongoing to identify the best substance or combination of substances to elicit the correct immune response to target antigens.
Alum adjuvants have contributed to the success of the majority of current vaccines. Because new generation vaccine candidates to treat diseases such as AIDS, cancer, and infectious pathogens will increasingly contain highly purified antigens that may be poorly immunogenic, adjuvants with more potent immune responses will become increasingly important.7 New adjuvants will ideally confer response advantages, including more heterologous antibody responses to meet pathogen diversity, the induction of potent functional antibody responses to ensure pathogen neutralization, and the induction of more effective T cell responses for direct and indirect pathogen elimination.7
WHY ADJUVANTS MAY FAIL, AND HOW TO CONSIDER THEIR SUCCESSFUL APPLICATION IN VACCINES
Over more than 80 years of adjuvant research, identification of effective adjuvants has been relatively simple, while the constraint has been the lack of successful adjuvants safe enough for human use. Freund's Complete Adjuvant (FCA) is an example of the challenges inherent to adjuvant use in clinical vaccines. FCA is an extremely potent adjuvant, but may cause granulomas, inflammation at the inoculation site, and lesions, effectively excluding it from use in human vaccines.8 Beyond tolerability, other key factors can prevent an adjuvant from becoming an ingredient in vaccines. These include
- complex scaleup
- lack of reproducibility
- availability of material (or of the appropriate quality and grade)
- poor degradability
- incompatibility with the antigen or other ingredients in the formulation.7
When considering an adjuvant for a vaccine, tolerability must be defined in the context of the target, taking into consideration the severity of infection or disease, and the risk to the target population. While some adverse effects are acceptable when treating a cancer patient, those same effects might be unacceptable when vaccinating an infant against influenza.
Characteristics of an Optimal Adjuvant Candidate
In identifying or developing a new adjuvant, there is no one-size-fits-all process. Scientists must first determine the desired immune response for a given antigen, and adjuvant selection is wholly dependent on vaccine formulation and individual application. Efficacy and safety are the primary considerations in adjuvant selection, but other characteristics for successful adjuvants include:
- A compound that is stable, with a long shelf life
- Biodegradability
- Feasible cost to obtain or synthesize
- Does not induce immune responses against itself
- Promotes an appropriate immune response (i.e. cellular or antibody immunity against the target, depending on requirements for protection)2
The potential for limited immunogenicity of novel vaccine antigens and modalities has increased the urgent need for adjuvant research in vaccine development. Adjuvants will be needed to enhance and extend immune responses while reducing the amount of antigen necessary in each dose. In recent years, both the US and Europe have created initiatives to evaluate, compare, and develop adjuvants in the public, private, academic, and government sectors. Such initiatives will encourage these groups to continue working toward more effective adjuvants as part of a global health strategy to prepare for future infectious disease crises.
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