Older vaccines made from live or killed whole organisms were effective, but suffered from high reactogenicity. As vaccine manufacturers developed safer, less reactogenic subunit vaccines, they found that with lower reactogenicity came reduced vaccine effectiveness. Somewhat ironically, the solution proposed to boost immunogenicity in modern vaccines is to add back immune-activating substances such as toll-like receptor agonists—the very same contaminants removed from old-style vaccines. This raises the question of whether the vaccine field is moving forward or backward. We propose that by avoiding adjuvants that work through toll-like receptor (TLR) pathways, and instead focusing on adjuvants stimulating B- and T-cell immunity directly, one can minimize inflammatory cytokine production and consequent reactogenicity. We present data on a polysaccharide-based adjuvant candidate, Advax, that enhances immunogenicity without reactogenicity, suggesting that potent and well-tolerated vaccines for both adult and pediatric use are indeed possible.
Vaccine-caused adverse effects can be separated into two types: local and systemic reactions. Local reactions range from injection site pain, inflammation, and swelling, to granulomas, sterile abscess formation, lymphadenopathy, and ulceration. Systemic vaccine reactions may include nausea, fever, adjuvant arthritis, uveitis, eosinophilia, allergic reactions, organ-specific toxicity, anaphylaxis, or immunotoxicity mediated by liberation of cytokines, immunosuppression, and induction of autoimmune diseases.1,2 While some systemic reactions such as allergy and anaphylaxis are clearly due to the antigen, others, such as adjuvant arthritis, may be caused directly by or exacerbated by the adjuvant. It can be difficult to identify which adverse reactions are mediated by the antigen, which by the adjuvant, and which by both.