ABSTRACT
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.
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A major bottleneck in vaccine development is the lack of suitable adjuvants for adult and pediatric prophylactic vaccine use.
Aluminum salts were introduced for human use in the 1930s when the regulatory environment was less stringent. The desire for
new and improved adjuvants stems not only from the need to make existing inactivated vaccines more potent, but also to gain
features such as antigen-sparing ability, more rapid seroprotection, stimulation of T-cell immunity, and longer-lasting protective
immunity. Significant regulatory and other hurdles exist for developing new adjuvants, as evidenced by the complete absence
of new FDA-approved adjuvants.
Safety and tolerability are critical regulatory issues confronting new adjuvants, and pose the greatest barrier to new adjuvant
approvals. In addition to preclinical studies on the adjuvant itself, the combined antigen–adjuvant formulation must pass
animal toxicology screens in at least two species at a dose and frequency similar to, or higher than, the proposed human dose,
and using the same route of administration, to assess safety and tolerability before clinical tests can begin. Therefore,
the benefits of incorporating any adjuvant into vaccines must be balanced against any increased reactogenicity or risk of
adverse reactions. Unfortunately, in most cases, increased adjuvant potency is associated with increased reactogenicity and
toxicity. The best example of this is complete Freund's adjuvant (CFA). While it remains the gold standard in terms of adjuvant
potency, its extreme reactogenicity and toxicity precludes its use in human vaccines, and there have been discussions of banning
CFA even in veterinary vaccines. 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.
