Inflammatory/Noninflammatory Adjuvants and Nanotechnology-The Secret to Vaccine Design

Abstract Vaccination is an efficient, safe, and cost-effective medical intervention. Historically, vaccines have been successfully developed for bacterial pathogens, however, there are still numerous complex pathogens, such as human immunodeficiency virus and malaria parasites, for which a vaccine is not available. Most vaccines rely on adjuvants to enhance the immune response, the most common being alum. Traditionally, adjuvants promote immune responses by the induction of inflammation at the injection site, or systematically, though persistent inflammation can be detrimental and has been linked to the acquisition of autoimmune or autoinflammatory syndromes. Herein we review the mechanism of actions of conventional pro-inflammatory adjuvants approved for human use such as alum, MF59, and specific toll-like receptor (TLR) agonists such as monophosphoryl lipid A (MPL-A). In addition, we discuss the differences in the types of immune responses induced by each of the adjuvants. Moreover, current research in vaccinology further acknowledges the potential usefulness of novel adjuvant systems that induce high levels of cellular and humoral immunity, in the absence of a pro-inflammatory environment. Nanoparticles are becoming increasingly popular as adjuvant candidates, due to their unique physiochemical properties, offering nontoxic and stable formulations. Some nanoparticle-based vaccines (nanovaccines) are noninflammatory in that they do not induce the classical inflammation associated cytokines [ie, tumor necrosis factor (TNF), interleukin 1 (IL-1) and IL-6]. Nanoparticle-based adjuvants, mostly in a viral size range, can increase recognition and uptake by dendritic cells, and increase innate cell activity, potentially through unconventional (nonclassical inflammation promoting) cell-signaling pathways. Therefore, incorporating nanoparticles as vaccine adjuvants may provide an answer to induce long lasting and broad immune responses against complex pathogens or diseases, in the absence of inflammation. We further review the possible mode of actions of nanoparticle-based adjuvants, current trends, and opportunities to develop diverse nanovaccines.