Prophylactic immunization has substantially improved human health. While vaccines have been a major achievement in advancing human health, adjuvant options for vaccines are extremely limited. While alum-based adjuvants are the main immunostimulants used in vaccines, the mechanisms of action remain poorly understood, especially relating to the long-lasting immune effects on the immature neonatal and infant immune system. Until now, the focus on mechanism of action of alum has centered around antigen-specific effects in boosting immunity to the immunogen delivered with alum. Our preliminary data demonstrate that immunization of 21 day old mice with hepatits B virus (HB) alum vaccine alters the response to subsequent inhalation exposure to newly introduced immunogens. Mice that had not been previously immunized with the alum-based vaccine developed tolerogenic immune responses to the novel immunogen. Alternatively, mice that received the alum vaccine were predisposed to developing Th2-polarized immune responses to the novel immunogen which led to allergic reactions to challenge. Here, we aim to determine the contribution of alum-driven bystander effects on immune responses to newly introduced immunogens. This proposal is designed to generate proof-of-concept that early life immunization with alum results in Th2 imprinting that does not occur following alum immunization later in life. We propose to test our hypothesis that early life immunization with alum prolongs the Th2-bias of the neonatal immune system by 1) determining the impact of age at the time of alum immunization on maintenance of a Th2- biased immune system and 2) defining the mechanism by which immunization with the HB-alum vaccine modulates immune responses to subsequently introduced immunogens. Thus, furthering our understanding of how early life immunization with alum-based vaccines maintain a Th2-biased immune system is important for rational vaccine design as well as implementation of vaccine schedules. This is especially important to understand as infants receiving many vaccines which contain alum, including the HB vaccine which is given at birth. Definition of the mechanisms of action of adjuvants in early-life compared to later in life may lead to the development of age-specific adjuvants in order to maintain the public health benefit of vaccination while reducing broad effects on the immune system that may lead to immune pathologies later in life.
Despite the fact that the infant immune system is immature and has an inherent Th2 bias, all previous studies addressing immune effects of aluminium (alum) adjuvanted vaccines have used adult mice and therefore have not been well-suited to determine how early-life alum immunization affects the developing immune system. This proposal will elucidate the mechanisms by which early-life immunization with alum results in a predisposition to develop Th2-biased immune responses to subsequently introduced immunogens. Because immune dysfunction that predisposes the development of Th2-polarized immunity may lead to the development of allergic diseases or reduced efficacy of subsequently administered vaccines, further understanding of the effects of early-life alum immunization will be critical for improving vaccine safety.
