A major unsolved challenge in adjuvant development is how to achieve a potent adjuvant effect while avoiding reactogenicity
or toxicity.3 Most newer human adjuvants including MF59,4 ISCOMS,5 QS21,6 AS02,7 and AS048 have substantially higher local reactogenicity and systemic toxicity than alum. Even alum, despite being FDA-approved, has
significant adverse effects including injection site pain, inflammation, and lymphadenopathy, and less commonly injection-site
necrosis, granulomas, or sterile abscess.9 Although many adjuvant-caused vaccine reactions are not life-threatening and do resolve over time, they remain one of the
most important barriers to better community acceptance of routine prophylactic vaccination. This particularly applies to pediatric
vaccination where prolonged distress in the child due to increased reactogenicity may lead directly to parental and community
resistance to vaccination.10 Hence, particularly in the context of childhood prophylactic vaccines, it is critical that suitable adjuvants be developed
with lower reactogenicity and greater safety. Ideally, in addition to being safe and well tolerated, adjuvants should promote
an appropriate (humoral and/or cellular) immune response, have a long shelf-life, and should be stable, biodegradable, cheap
to produce, and not induce immune responses against themselves.11 A brief description and history of potential human adjuvants follows (Table 1).
Table 1. A range of human adjuvants under development with comparative features.
Aluminum Salts (Alum)
Mechanism of action.
While the exact mechanism of action of aluminum adjuvants remains uncertain, proposed mechanisms include formation of a local
antigen depot, efficient uptake of aluminum-adsorbed antigen particles by antigen-presenting cells due their particulate nature
and optimal size, stimulation of immune-competent cells of the body through activation of complement, induction of eosinophilia,
and activation of macrophages.12 Yet, none of these theories fail to adequately explain aluminum's adjuvant ability.
We propose an alternative unifying theory of aluminum action based on its toxicity. In our model, aluminum particles together
with absorbed antigen are phagocytosed by tissue macrophages, which then become activated and mobilize into the lymph. Aluminum,
once ingested, is toxic to cells13 and by the time they reach the draining lymph node most of the macrophages that have ingested aluminum particles will be
dead or dying. Once necrotic, the macrophages release their cytoplasmic contents, including alum-absorbed antigen and inflammatory
mediators such as IL-1 and TNF, into the lymph. This provides a source of macrophage cell debris, antigen, and co-stimulatory
cytokines flowing into the draining lymph node, a potent mix to stimulate antigen-specific plasma cells and antibody production.
Interestingly, a similar mechanism was proposed many years ago to explain the adjuvant action of beryllium, a compound which
is even more toxic to macrophages than aluminum, and has potent adjuvant activity.14
Limitations of alum.
Although aluminum salts remain the most commonly used adjuvants and the only ones currently approved for use in humans by
the FDA, they suffer from a number of downsides, including inability to induce cytotoxic T-lymphocyte (CTL) responses critical
in many cases for viral protection and clearance.15 Well-recognized problems of aluminum adjuvants include local injection site reactions, stimulation of eosinophilia, augmentation
of IgE antibody responses, ineffectiveness for some antigens, and failure to enhance CTL responses. Alum is reasonably well
tolerated when injected intramuscularly, with only mild to moderate injection pain and occasional granulomas. Risk of granulomas
becomes particularly high when alum-based vaccines are injected subcutaneously or intradermally. Consequently, alum-containing
vaccines are generally given by intramuscular injection.16,17