Cutaneous STING pathway agonism enhances the immunogenicity of a SARS-CoV-2 ferritin nanoparticle vaccine in both young and aged mice

Summary: Abstract Body: Low thermotolerance, waning immunity, limited breadth, and age-dependent immunogenicity of existing SARS-CoV-2 vaccines justify the development of new thermostable vaccines capable of inducing durable protection against existing and future coronaviruses across the lifespan. Here, we report a thermotolerant coronavirus vaccine candidate combining SARS-CoV-2 Spike protein Ferritin Nanoparticle (SpFN) and the rationally selected STING pathway agonist ADU-S100 in a microneedle patch (MNP). We demonstrate that skin delivery of SpFN+ADU-S100 MNP elicits improved humoral responses in young and aged mice without any systemic reactogenicity, compared to either intramuscular injection of SpFN or MNP administration of monomeric SARS-CoV-2 Spike protein. Co-delivery of ADU-S100 with SpFN in the same MNP improves antigen-specific adaptive immune responses by inducing Th1-predominant pro-inflammatory cytokines and chemokines (IFNβ1, CCL2, CXCL10) in the vaccine-targeted skin microenvironment. Skin vaccination with SpFN+ADU-S100 MNP generates robust, durable, and broadly neutralizing antibodies, as well as potent systemic and pulmonary cellular responses against coronaviruses. Notably, the key immunopotentiating benefits of ADU-S100 as a skin adjuvant is evident in both young and aged mice, as well as in translational studies using human skin models. Together, SpFN+ADU-S100 MNP supports the utility of emerging bioengineering platforms and adjuvants for the development of a next-generation coronavirus vaccine focused on addressing the limitations of authorized SARS-CoV-2 vaccines. Sanpreet Singh¹, Stephen Balmert¹, Saniya Mahendiratta¹, Cara D. Carey¹, Ashish Dhayani¹, Jiying Zhang¹, Agnes Hajduczki^{2, 3}, William C. Chang^{2, 3}, Phyllis A. Rees^{2, 3}, M G. Joyce^{2, 3}, Emrullah Korkmaz^{1, 4}, Louis D. Falo, Jr.^{1, 4} 1. Dermatology, University of Pittsburgh, Pittsburgh, PA, United States. 2. Viral Disease Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States. 3. Henry M Jackson Foundation for the Advancement of Military Medicine Inc, Rockville, MD, United States. 4. Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States. Translational Studies: Preclinical