Vaccine Adjuvants

The widespread use of effective vaccines against infectious diseases has been one of the most important public health advances in the 20th and 21st centuries. Early vaccines consisting of attenuated or inactivated pathogens or toxins may elicit robust, protective immune responses, but this approach cannot always be used because it is impractical to culture large numbers of organisms, lack of efficacy, or because of safety concerns. In such cases subunits (eg, microbial proteins or carbohydrates) are being promoted as vaccine antigens. Subunit antigens are often poorly immunogenic on their own as they do not properly stimulate innate immunity. This is likely the cause of the reduced efficacy of the acellular pertussis vaccine. Adjuvants are molecules, compounds, or supramolecular 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. Adjuvants can be used to enhance immunogenicity, modulate the type of immune response, reduce the amount of antigen or the number of immunizations required for efficacy, and/or improve the efficacy of vaccines in specific populations (eg, newborns or elderly). To be maximally effective, adjuvants must be selected judiciously and formulated appropriately based on the desired immune response.

First generation adjuvants were empirically developed to augment the immune response to insufficiently immunogenic antigens. Of these, only aluminum salts—including aluminum oxyhydroxide and aluminum phosphate (collectively, alum)—and squalene based oil-in-water (o/w) emulsions (eg, AS03 or MF59™) have been included as part of FDA-licensed vaccines However, the number of adjuvants with acceptable efficacy and safety profiles is limited, and these proprietary molecules/compounds are in the hands of a few companies, as is most of the formulation expertise. Lack of access to appropriate adjuvants, and lack of know-how regarding the formulation and use of adjuvants is one of the primary barriers to the development of new effective vaccines and immune therapeutics.

Critical to the early emergence of effective immune responses is the engagement of the innate immune system, characterized by the involvement of innate pattern recognition receptors (PRR) such as the toll-like receptors (TLRs) or the RIG-I-like receptors (RLRs) that recognize pathogen associated molecular patterns (PAMPs), leading to the production of cytokines and chemokines. In turn, these activate antigen presenting cells (APC) in particular dendritic cells (DCs) that initiate a cascade of signals to cells of the adaptive immune response, preparing them for the development of antigen-specific immunity. Thus one key strategy for improving vaccine performance involves the stimulation of innate immunity that facilitate antigen uptake, stimulation of antigen presenting cells, and downstream adaptive immunity. However, many adjuvants fail during product development owing to factors such as manufacturability, stability, lack of efficacy, unacceptable levels of tolerability, or safety concerns.

This chapter outlines the potential benefits of adjuvants in current and future vaccines and describes the importance of formulation and mechanisms of action of adjuvants. Moreover, we emphasize safety considerations and other crucial aspects in the clinical development of effective adjuvants that will help facilitate effective next-generation vaccines against tuberculosis (TB) and other global vaccine challenges.