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Vaccination remains an important public health tool for disease control. Live vaccines typically induce potent immune responses and complete protection. However, live vaccines have been associated with a number of safety concerns, including reversion to virulence, resulting in disease and other adverse effects ranging from simple headache or fever (influenza, hepatitis A and B, and yellow fever) to more severe encephalitis (measles mumps rubella), intussusception (rotavirus), vaccine-associated paralysis (polio) or even death (smallpox) [1]. Primarily for safety reasons, a major trend in vaccinology has been to move towards the use of subunit vaccines, which are composed of highly purified proteins that can be targeted by the immune system. However, the major drawback of subunit vaccines is that they are poorly immunogenic, and often result in poor or suboptimal vaccine efficacy. In order to be effective, subunit vaccines require coadministration with adjuvants. With very few exceptions, currently available vaccines contain a single adjuvant. Although some vaccines with a single adjuvant provide optimal protection, in many cases, the adjuvant has a number of limitations, including induction of immune responses of low potency or of inappropriate quality. This is especially the case for human vaccines where there is a limited choice of clinically approved adjuvants. Alum, which was until recently the only clinically used adjuvant in humans, typically induces Th2- but not Th1-type immune responses, and therefore does not induce sufficient protection from some infections such as influenza. Even some promising experimental adjuvants have their own limitations. Using multiple adjuvants in combination can overcome these limitations. Indeed, there is evidence demonstrating that selected adjuvant combinations can be complementary or even synergistic. This approach may be beneficial for improving a number of vaccines. For example, addition of a Toll-like receptor (TLR) agonist to an alum-containing vaccine may significantly improve the efficacy of such a vaccine. As discussed later, a number of vaccines containing various combinations of adjuvants have been evaluated. This approach is promising and may improve a number of currently available vaccines whose efficacy is less than optimal. This approach may be particularly beneficial for vaccines against specific populations, such as newborns and the elderly. In neonates, vaccination generally induces a default Th2 response and adjuvants that promote Th1 responses are required. Immune responses decrease with advancing age, partly as a result of thymic involution, which results in reduced output of naive T cells [2]. Strong adjuvants may provide an approach to boost immune responses in the elderly. However, strong adjuvant formulations have the potential to induce undesirable side effects such as inflammation at the injection site. Thus, rigorous safety evaluations will be required for formulations based on adjuvant combinations.