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Here, we show that a biodegradable hyaluronic acid (HA)\u2010scaffold, termed HA cryogel, mediates sustained antigen and adjuvant release in vivo leading to a durable immune response. Delivery from subcutaneously injected HA cryogels was assessed and a formulation which enhanced the immune response while minimizing the inflammation associated with the foreign body response was identified, termed CpG\u2010OVA\u2010HAC2. Dose escalation studies with CpG\u2010OVA\u2010HAC2 demonstrated that both the antibody and T cell responses were dose\u2010dependent and influenced by the\u00a0competency of neutrophils to perform oxidative burst. In immunodeficient post\u2010hematopoietic stem cell transplanted mice, immunization with CpG\u2010OVA\u2010HAC2 elicited a strong antibody response, three orders of magnitude higher than dose\u2010matched bolus injection. In a melanoma model, CpG\u2010OVA\u2010HAC2 induced dose\u2010responsive prophylactic protection, slowing the tumor growth rate and enhancing overall survival. Upon rechallenge, none of the mice developed new tumors suggesting the development of robust immunological memory and long\u2010lasting protection against repeat infections. CpG\u2010OVA\u2010HAC2 also enhanced survival in mice with established tumors. The results from this work support the potential for CpG\u2010OVA\u2010HAC2 to enhance vaccine delivery.<\/jats:p>","DOI":"10.1002\/btm2.10591","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T05:32:16Z","timestamp":1692682336000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Biodegradable scaffolds for enhancing vaccine delivery"],"prefix":"10.1002","volume":"8","author":[{"given":"Matthew D.","family":"Kerr","sequence":"first","affiliation":[{"name":"Department of Nanoengineering University of California San Diego  La Jolla California USA"},{"name":"Chemical Engineering Program University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wade T.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Nanoengineering University of California San Diego  La Jolla California 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