Fc Receptor Signaling in Vaccine Design for the Elderly

描述（由申请人提供）：在老年人中，细胞和体液免疫均显著下降，导致免疫功能失调，或免疫衰老。免疫衰老损害了对传染病的保护，并导致老年人对感染的易感性增加。此外，免疫衰老是老年人对疫苗接种反应减弱的原因。因此，老年人尤其脆弱，在发生生物恐怖袭击时面临更大的风险。老年人对流感病毒感染和疫苗接种的反应受损可能在临床上最相关。老年人对流感疫苗的反应明显减弱。老年人对流感疫苗的一抗和二抗反应减弱。即使流感疫苗与流行病毒之间的抗原匹配非常接近，接种疫苗也只能为30 - 40%的65岁人群提供保护，而65岁以下人群的这一比例为70-90%。目前可获得的三价灭活流感疫苗在预防患有相关慢性病的老年人死亡方面尤其无效，这突出表明需要对最需要疫苗的老年人更有效的流感疫苗。

DESCRIPTION (provided by applicant): In the elderly, there is a significant decline in both cellular and humoral immunity, leading to a state of dysregulated immune functions, or immunosenescence. Immunosenescence compromises protection against infectious diseases and contributes to the increased susceptibility of the elderly to infection. Furthermore, immunosenescence is responsible for the diminished responsiveness of the elderly to vaccination. Thus, the elderly are particularly vulnerable and are at greater risk in the event of a bioterror attack. An impaired response to influenza virus infection and vaccination in the elderly may be clinically most relevant. The responses to influenza vaccination are significantly impaired in aged people. Both primary and secondary antibody responses to influenza vaccination are diminished in the elderly. Even when the antigenic match between influenza vaccine and circulating virus is close, vaccination provides protection for only 30%- 40% of subjects aged >= 65 years, compared with 70-90% of those aged < 65 years. The currently available trivalent inactivated influenza vaccines are particularly ineffective in preventing deaths among elderly persons with associated chronic conditions, underscoring the need for influenza vaccines that are more effective in elderly persons who need them most. Fc receptors (FcR) link the humoral and cellular branches of the immune system and have crucial functions in the activation and modulation of immune responses. Our recent studies indicate that immunization with immune complexes (IC) can correct the age-related deficiency in humoral and cellular immune responses to model antigens as well as influenza vaccines in mice. We have also demonstrated that the inhibitory Fc receptor, Fcgamma IIB, can be selectively ablated by RNA interference using small interfering RNA (siRNA). Thus, manipulating FcR signaling and vaccination with IC may constitute a novel immunization strategy to provide effective protection to immune compromised elderly population against influenza infection. In this project, we propose the following specific aims: Aim 1. Determine the mechanisms by which immune responses are regulated by IC Aim 2. Study the modulation of immune responses by selective signaling Fc receptors Aim 3. Determine the effectiveness of 1C vaccines in overcoming age-related immune deficiency.