Vaccines remain the most effective medical intervention to disease in which effective vaccines are available. Designing vaccines that elicit protective immunity while minimizing adverse events is difficult. Exacerbating the challenges of vaccine design is the increased emphasis on using pure preparation of antigens that alleviate safety concerns but also show decreased potency. Therefore the need for safe adjuvants to boost immunity of subunit immunizations is great. This work demonstrates the capability of a novel bio-erodible polyanhydride particle platform to enhance humoral and cellular immunity. Encapsulation of 25 µg of Ovalbumin (Ova) antigen in microparticles elicits humoral immune responses equivalent to 1600, 400, and 100 µg dosages of Ova. Characterizing the persistence of the nanoparticle platform shows that in vivo persistence and immunomodulatory activity can be tailored by altering copolymer chemistry. Polyanhydride nanoparticle vaccines against Ova show an increased ability to expand CD8+ T cells as compared to Alum and soluble Ova. These same polyanhydride nanoparticle vaccines expand CD4+ T cells and promote a T follicular helper (CXCR5high PD-1high) cell phenotype important for germinal center formation. The polyanhydride platform designed vaccines against H5N1 using a stabilized trimeric H5 antigen were evaluated in multiple dose and route regimens and elicit neutralizing antibody activity and expanded CD4+ cellular recall responses when administered subcutaneously. These results demonstrate that the polyanhydride particle platform can be used to effectively enhance immune responses in subunit immunizations.