Harnessing Human DC Subsets for Improved Muscosal Vaccines

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Vaccination represents one of the major successes of medicine as it has spared countless people from polio, tetanus and other acute infections. Yet, improved immunization strategies are needed to make vaccines for microbes that cause considerable morbidity . To identify novel strategies for protective vaccination we will study dendritic cells (DCs) which specialized to capture and process antigens in vivo, presenting the MHC molecules to T cells. DCs also present antigens to B cells. Maturation and subsets allow DCs to control diverse immune responses. Our long-term goal is to develop novel human vaccines based on in vivo DC-targeting. Our hypothesis is that Human Dendritic cells subsets express distinct uptake and signaling receptors that need to be mobilized in concert to provide durable immune responses leading to increased resistance to microbes at the mucosal port of entry. To this end, we have made high affinity monoclonal antibodies against several DC surface molecules and conjugated them to several influenza virus proteins. We have shown that antigens delivered to a single type of human DCs through different surface lectins induce distinct types of antigen-specific CD4+ T cell responses. The current focus is on mucosal immunity because mucosa is a major site of invasion as well as replication of pathogens, including influenza virus. Thus, the induction/activation of two major effectors, B cells and CD8+ T cells, with mucosal homing capacity is expected to limit viral replication, resulting in reduced disease burden. Furthermore, induction of CD4+ T cells with helper functions for B cells or CTLs will enhance the longevity of memory cells and the magnitude and the quality of mucosal homing effectors. We view the candidate vaccine as a bispecific antibody a) binding to two different cell surface antigens, such as specific lectin for antigen delivery and CD40 for activation, or to two different DC subsets, to harness their capacity to induce different type of immune effectors, and in addition b)TLR agonists as DC activators. We propose four projects and two technical development components which will be supported by six cores.