Vaccine Adjuvants: Mode of Action

Abstract

Vaccines were first introduced more than 200 years ago and have since played a key role in the reduction of morbidity and mortality caused by infectious diseases. Many of the safest and most effective vaccines in use today are based on attenuated live viruses, as they mimic a live infection without causing disease. However, it is not always practical to take this approach, such as when it may not be safe to do so (e.g., for viruses that cause chronic infections such as HIV) or may not be feasible to manufacture (e.g., for viruses that do not grow well in cell culture such as HCV). In addition, it may preferable in some cases to target immune responses toward specific antigens from the pathogen, rather than the entirety of the genome. In these cases, subunit vaccines consisting of antigens purified from the pathogen or produced by recombinant DNA technology are being developed. However, highly purified proteins are typically not inherently immunogenic, as they usually lack the means to directly stimulate the innate immune system, and often require the addition of adjuvants to enhance vaccine potency. Despite more than a century of human use, only a few adjuvants are licensed today. However many adjuvants have been tested in humans and are in advanced stages of development. Much of the early work on adjuvants discovery and development was empirical producing safe and effective products, but without a clear understanding of how they worked. Recent insight into the functioning of the innate immune system has demonstrated its important role in triggering and shaping the adaptive immune response to vaccines.

Oil-in-Water Emulsion MF59 Increases Germinal Center B Cell Differentiation and Persistence in Response to Vaccination

“…Differences between MF59 and alum in shaping the GC responses may reflect their different mechanisms of action to activate the innate immune system [extensively reviewed by De Gregorio et al (11)]. Whereas alum efficiently delivers the Ag to conventional DC (9,35), MF59 generates an immunocompetent environment at the injection site that favors the trafficking and activation of monocytes (14,15,36).…”

“…In particular, alum was shown to bind lipids on the surface of APCs and trigger cellular activation cascades leading to initiation of an immune response, but without itself being internalized by the cells (9), suggesting an indirect role in delivering Ag into the Agprocessing pathway; however, other studies have shown that alum is internalized by APCs, resulting in endosomal destabilization (10). In contrast, MF59 primary mechanism of action resides in the generation of an immunocompetent environment at the injection site (muscle), characterized by the release of local extracellular ATP, expression of activation makers on resident DC, and secretion of chemokines that strongly increase phagocytic cells trafficking toward the injection site and the draining lymph nodes (LNs) (11)(12)(13)(14)(15). Unlike alum, MF59 does not directly activate DC, but rather promotes cell migration, a more efficient Ag uptake, and more Ag-loaded APCs in draining LNs compared with alum or nonadjuvanted vaccines (12,13,15).…”

A cell culture-derived whole virus influenza A vaccine based on magnetic sulfated cellulose particles confers protection in mice against lethal influenza A virus infection

“…Afterwards, aMSCP were washed 5x with 500 µl PFB to remove residual DVH 165 solution. Finally, aMSCP were suspended in 700 µl formulation buffer (FB) consisting of PFB 166 with 250 µg polyinosinic:polycytidylic acid (poly I:C)/ml (Invivogen, Toulouse, France) and 167 250 µg CpG/ml (Eurofins Genomics, Ebersberg, Germany) as adjuvant [29]. The aMSCP system 168 was optimized to contain a minimum antigen content of [30].…”

Induction of Potent Adaptive Immunity by the Novel Polyion Complex Nanoparticles

“…Removal or eradication of intracellular pathogens by the cell-mediated immune response is highly desired for the next generation of vaccines (3,4). Several lines of evidence suggest that an appropriate adjuvant can strongly enhance the immunogenicity of antigens (5)(6)(7). Such adjuvants must be first recognized by the innate immune cells in order to induce adaptive immunity.…”

“…Alum-based adjuvants (alum) that are approved for clinical use in humans can increase humoral immune responses without unacceptable side effects. However, they elicit cell-mediated immune responses only poorly (1,5). Therefore, ideal adjuvants are expected to effectively induce not only humoral but also cell-mediated immune responses.…”