The word "vaccination" was first 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 eradication of smallpox and the control of many other diseases, such as polio and measles.
Major difficulties of vaccination are associated with either lack of efficacy or unacceptable reactogenicity.3 The reactogenicity associated with non-living, whole microorganism vaccines frequently appear as localized swelling and severe, fever-like symptoms. This resulted in the development of purer vaccines that eliminate unwanted reactogenic material, while retaining efficacy due to the protective antigens associated with them. An unintended consequence of the use of purified vaccine components was the loss of immunogenicity to the extent that pure protein or carbohydrate-based vaccines were so poorly immunogenic that efficacy levels of the vaccine was reduced to unacceptable levels.
At this point, vaccine developers considered adding materials to enhance immunogenicity. Adjuvants were tasked with enhancing the immunogenicity of these purified vaccines without significantly increasing reactogenicity. To this day, hundreds of materials with adjuvant activity have been identified, but the majority of these fail for human use due to their own inherent reactogenicity.3
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 (Latin verb 'adjuvare' means 'to help') by increasing the immunogenicity of the coadministered microorganism, harmless protein or polysaccharide (antigen).5 To this day, the explanation as to how many adjuvants function is still a mystery. Adjuvant mechanisms of action have long been enigmatic, leading noted Yale University immunologist Charles Janeway Jr. to offer the famous quote refering to adjuvants as 'the dirty little secret of immunologists'.5
Early attempts to produce adjuvanted vaccines used crude oils or other materials that deposited material at the site of injection, usually leading to local irritation and pathology.3 Currently adjuvants serve an expanded role in vaccine formulations by providing a number of functions:
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, both aluminum hydroxide and aluminum phosphate have been used as the preferred adjuvants for human vaccines, especially in the U.S. Oil-based adjuvants are used in veterinary vaccines but only recently have been approved for use in humans in extended clinical studies.3
New adjuvant development has been driven principally by the shortcomings of aluminum adjuvants. The primary problem with the alum adjuvants is their failure to stimulate T cell responses, including cytotoxic T cells (CTL).4 Research continues to strive to identify the best adjuvant or combination of adjuvants to elicit the correct immune response for a given antigen. Currently adjuvant/antigen combinations are designed to work together to provide ideal immunogenicity and minimize reactogenicity. An ideal adjuvant will elicit both humoral and cellular immune responses with no reactogenicity, but one has yet to be identified and may not exist.
Alum adjuvants have contributed to the success of the majority of current vaccines. But because new generation vaccine candidates such as AIDS and cancer will increasingly contain highly purified proteins that are poorly immunogenic, adjuvants with more potent immune responses will become more necessary.7 "New adjuvants will need to offer advantages, including more heterologous antibody responses to cover pathogen diversity, the induction of potent functional antibody responses to ensure pathogen killing, or neutralization and the induction of more effective T cell responses for direct and indirect pathogen killing."7
In the 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 a great example of the challenges to adjuvant usage. FCA is an extremely potent adjuvant, yet it may cause granulomas, inflammation at the inoculation site and lesions, effectively excluding it from use in human vaccines.8 A number of other key factors besides tolerability and adverse local reactions can prevent an adjuvant from being successful, including complex scaleup, lack of reproducibility, lack of material or quality material, lack of degradability, antigen incompatibility, and inflexibility with the formulation.7 When considering an adjuvant for a vaccine the tolerability must be defined in the context of the target, taking into consideration the severity of infection or disease. While some adverse effects are acceptable when treating a cancer patient, those same effects would be unacceptable when vaccinating an infant against influenza.
In identifying or developing a new adjuvant, there is no clear recipe or protocol to follow. Scientists must determine the exact immune response desired for a given antigen. Adjuvant selection is greatly dependent on vaccine formulation and individual application. Effectiveness and safety are of primary importance in adjuvant selection, yet a number of other characteristics for successful adjuvants must be considered including the following:
The limited immunogenicity of new and novel vaccine antigens has increased the importance of 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. These initiatives will encourage these groups to continue working toward more effective adjuvants as part of a global health strategy to prepare for a possible future pandemic.
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