Lympho-geographical concepts in vaccine delivery.

The key triggers and regulators of immune responses are antigens and their appearance in immune-privileged secondary lymphatic organs. Currently, the majority of vaccines are administered intramuscularly or subcutaneously, although neither the muscular tissue nor the subcutis is particularly rich in immuno-competent cells. Thus, introducing antigens at sites with a higher density of immune-competent cells, such as the dermis, lymph nodes, or afferent lymphatic conducts, with appropriate formulations and injection devices may induce more efficacious immune responses and protection. In this work, we first reviewed the geographical and functional map of the most important lymphatic elements that play a key role in the induction of a specific immune response, such as site of injection, choice of adjuvants and etc. In a first set of experiments, we demonstrated that short intervals of boosting (daily versus weekly) increase the production of IgG2a antibody against the injected model antigen, while increasing rather than constant booster doses increase the number of antigen-specific CD8(+) IFN-γ producing cells. Such antigen presentation patterns reflect the initially increasing amounts of antigen associated with natural infections by highly virulent and replicating pathogens. In a second set of experiments, we studied the importance of administration route (subcutaneous, intradermal, intramuscular, intralymphatic) for the induction of antigen-specific IgG2a, and of IFN-γ produced by antigen-specific lymphocytes when using PLGA microparticles for delivery of antigen. Interestingly, both IgG2a and IFN-γ production were significantly enhanced after intramuscular and intra-lymph node administration when compared to the other two routes. In conclusion, the results suggest that traditional vaccination schedules and administration routes should be reconsidered in vaccine development, particularly when using more advanced formulations and delivery systems such as micro- and nanoparticles or combinations of antigen and immune-response modifiers.