Development of Vaccine Adjuvants: a Historical Perspective

Since the earliest attempts to raise signifi cant immune responses against nonliving agents, investigators have tried to identify useful additives that can be combined with antigens to enhance immune responses. Such immuneenhancing additives are known as adjuvants. Virtually all adjuvant systems developed to date have focused on one of two mechanisms: specifi c immune activation or the delivery–depot effect. Although many adjuvant systems have been developed and tested in preclinical models, few have actually proved useful for human vaccines. The primary limitations for the use of new adjuvant systems with human vaccines revolve around safety issues. Whereas the toxicity of adjuvants has been reduced systematically through research and development efforts over the last 80 years, the safety barriers presented by regulatory and liability issues have continued to increase. Adjuvants to be used with prophylactic vaccines in normal, healthy populations need to have virtually pristine safety profi les. The fact that most vaccines today are given to infants or children heightens the safety concerns of vaccine adjuvants. In this chapter we review the history of vaccine adjuvant development from the beginning studies of the early twentieth century through to the present day. We recognize four periods of adjuvant development: (1) the initial