Skin-targeted polyphosphazene adjuvanted vaccines

Summary: Abstract Body: Driven by their affordability, ease of manufacture, and safety, subunit antigens have been a cornerstone of modern vaccinology. However, their poor immunogenicity necessitates the development of strategies to enhance their effectiveness. Here, we present polyphosphazene (PPZ)-adjuvanted microneedle patches (MNPs) as a strategically developed skin vaccination platform to increase the immunogenicity of subunit antigens. This platform employs two strategies: (1) co-delivery of the clinically viable PPZ adjuvant with antigen and (2) targeting vaccine components (antigen and adjuvant) to the skin, a highly potent site for immunization compared to traditional sites such as muscle. In murine studies, we evaluated two common PPZ macromolecules, PCEP and PCPP, delivered via a dissolvable MNP format to compare their potency as skin adjuvants. While both PCEP and PCPP enhanced the immunogenicity of subunit antigens, PCEP exhibited superior skin adjuvanticity to PCPP. Mice vaccinated with PCEP MNP loaded with the subunit antigen (PCEP MNP-VAX) exhibited significantly higher levels of antigen-specific IgG antibodies compared to those immunized with PCPP MNP integrating the same antigen (PCPP MNP-VAX). Moreover, PCEP MNP-VAX elicited stronger cellular immune responses, with immune signatures skewed towards Th1-associated responses, in contrast to the responses observed with PCPP MNP-VAX. In translationally relevant studies, PCEP MNP-VAX also induced immunostimulatory migratory antigen-presenting cells in human skin. Collectively these results support the clinical development of PCEP MNPs as a safe and effective subunit vaccine platform for combating emerging and re-emerging pathogens. Saniya Mahendiratta¹, Stephen Balmert¹, Cara D. Carey¹, Sanpreet Singh¹, Alexander Marin², Antony S. Dimitrov³, Alexander K. Andrianov², Emrullah Korkmaz¹, Christopher C. Broder³, Louis D. Falo, Jr.¹ 1. Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, United States. 2. Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD, United States. 3. Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, United States. Translational Studies: Preclinical