The studies described in this proposal integrate bioengineering with immunology to generate new knowledge on how biomaterials interact with immune cells and tissues. This insight will contribute towards the development of new vaccines as well as towards better understanding the modulating the immune responses towards implanted biomaterials. Immune responses are mediated by inter-connected signaling pathways coordinated in lymph nodes (LNs). Thus, all vaccines must reach LNs to be effective. Biomaterials, such as synthetic polymers, are being intensely studied as vaccine carriers because they offer controlled release and co-delivery of cargo. Several biomaterials have recently been associated with intrinsic properties that activate inflammatory immune pathways, even in the absence of other immune signals. However, direct information on the impact of biomaterials in LNs or the mechanisms by which these effects modulate immunity is largely lacking. This knowledge gap persists due to the inefficiency (< 1% of dose) with which biomaterial vaccines reach LNs after injection at peripheral locations (e.g., muscle).
The overall hypothesis is that both the physicochemical properties of biomaterials and the combinations and delivery kinetics of incorporated immune signals define the impact on the LN microenvironment and the resulting systemic immune response. To address it, the PI will exploit a new platform that directly delivers biomaterials to LNs to control the concentration and delivery kinetics of biomaterials and vaccine components in LNs. The specific aims are to 1) quantify the impact of biomaterials with different stabilities on LN activation and systemic response in the absence of other immune signals, 2) study the role of antigen and adjuvant released from biomaterial particles in activating LNs, 3) dissect the influence of the density of antigen/adjuvant presentation in and across LNs, and 4) compare signaling pathways activated by biomaterial carriers to profiles associated with clinically approved vaccine adjuvants.
Intellectual merit: The proposed studies will address how polymers impact LN activation to shape immunity, which has significant ramifications in vaccine development and in understanding and modulating the immune response towards biomaterials. More specifically, the proposed studies will provide 1) fundamental information of how biomaterials impact local LN structure in the absence and presence of immune signals, 2) knowledge of how local changes in LNs modulate systemic immunity, 3) the relative roles that controlled release and inherent polymer immune activity of biomaterials play in inducing responses, and 4) signaling profiles of two classes of key biomaterials compared with approved adjuvants.
Broader impacts: Vaccines have had an extraordinary impact on global health, but challenging diseases such as HIV and cancer still circumvent vaccine efficacy. The proposed studies will have a significant impact on the vaccine field and, more generally, on understanding the immune response towards biomaterials in the absence and presence of immune signals. In particular, the proposed studies may help overcome current technical limitations in vaccine development, while generating fundamental knowledge on the interactions between biomaterials and LNs. The proposed studies are integrated with an education plan to promote research exposure and awareness of career opportunities incorporating biomaterials, immunology, and vaccines. This will be accomplished through partnering with high-need schools, supporting community outreach programs, and training of undergraduate, graduate, and postdoctoral researchers. These education and outreach activities will help increase enrolment of high school students in STEM degree and research programs and will provide training opportunities in research education for undergraduate, graduate, and postdoctoral researchers.