Small circular mRNA vaccines

小环状 mRNA 疫苗

• 批准号: 10558626
• 负责人: Guizhi Zhu
• 金额: $ 55.22万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10558626
• 关键词: Address; Adjuvant; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Beds; Benchmarking; Biodistribution; CD8-Positive T-Lymphocytes; COVID-19; Cells; Chemicals; Chronic; Cold Chains; Communicable Diseases; Complex; DNA; Data; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Elements; Engineering; Exonuclease; Foundations; Freezing; Genomics; Guidelines; Half-Life; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Immune; Immune response; Immunity; Immunization; Immunologic Receptors; Immunologic Stimulation; In Vitro; Infection; Innate Immune Response; Internal Ribosome Entry Site; Kinetics; Life; Liposomes; Malignant Neoplasms; Maps; Mediating; Messenger RNA; Modeling; Modification; Mus; Mutate; Mutation; Natural Immunity; Nucleotides; Outcome; Peptides; Production; Prophylactic treatment; Proteins; Proteomics; RNA; RNA Editing; RNA vaccine; Research Personnel; Risk; Safety; Series; Structure; T cell response; T-Lymphocyte; Technology; Temperature; Testing; Tissues; Toxic effect; Transgenic Mice; Translating; Translation Initiation; Translations; Transportation; Treatment Efficacy; Vaccines; Viral Vector; Virulent; Virus; adaptive immunity; aged; chemical synthesis; circular RNA; immunogenicity; immunoregulation; improved; improved outcome; in vivo; innovation; lymph nodes; mRNA sequencing; manufacture; nanocarrier; nanoparticle; nanoparticle delivery; nanoparticulate; neoplasm immunotherapy; novel; pathogen; prevent; prophylactic; single-cell RNA sequencing; success; tumor; vaccine access; vaccine efficacy; vector; young adult

Small circular mRNA vaccines Abstract: Vaccines save numerous lives each year. Conventional vaccines based on pathogens, DNA, proteins, or peptides are associated with poor pharmacokinetics, limited biostability, preexisting anti-viral-vector immunity, weak immunogenicity, or safety concerns over genomic integration or virulent reversion. The emerging mRNA vaccines hold the potential to overcome the above issues with pharmacokinetics and safety using mRNA and advanced drug delivery systems. However, despite efficient delivery, current mRNA vaccines rely on long mRNA that is still associated with 1) limited biostability, though extensively modified, and the resulting limited shelf-life even using cold chains and poor antigen translation efficiency, and 2) complicated enzymatic production. To address these limitations, we propose developing antigen-encoding small circular mRNA (circRNA), which are highly biostable and efficiently delivered by existing nanocarriers, as a novel platform of mRNA vaccines. Small circRNA is comprised of minimal RNA elements to translate peptide antigens. Our preliminary data showed several notable features of small circRNA vaccines: 1) in contrast to long mRNA, small circRNA leverages automated RNA synthesizers for fast, efficient, and precise chemical synthesis and versatile functional modifications; 2) even without any biostabilizing modifications, terminus-free circRNA prevents exonuclease degradation and prolongs its in vivo half-life and shelf-life under freezing, fridge, and ambient temperatures; as a result, circRNA showed efficient antigen translation and immunomodulation; 3) small circRNA vaccines leverage current drug delivery systems for efficient delivery to desired tissues and cells, and the small circRNA sizes can increase its loading capacity in nanocarriers, relative to bulky mRNA; 4) circRNA vaccine is self- adjuvanted due to intrinsic immunostimulation; 5) in cells, circRNA produces long genuine peptide antigens that elicit potent immunity; and 6) the modularity of circRNA vaccine allows its easy adaption for wide application. As a result, low-dose circRNA nanoparticles elicited potent immune responses in both young adult mice and aged mice, protected mice from target cell challenge, and mediated robust tumor immunotherapy. In this application, Aim 1 will optimize the antigen translation and presentation of biostable small circRNA vaccines by circRNA engineering; Aim 2 will study nanoparticle delivery of circRNA into immune tissues and cells, and the stability, integrity, and antigen translation kinetics of circRNA vaccines upon delivery to target cells; Aim 3 will decipher the immunomodulation mechanism by nanoparticle-delivered small circRNA vaccines; and Aim 4 will use human papillomavirus (HPV)-associated cancer as a test bed to assess the prophylaxis and therapeutic efficacy of nanoparticulate small circRNA vaccine in syngeneic and transgenic mouse tumor models. The PI (Early Stage Investigator) has assembled a team with complementary expertise to conduct this study. If successful, this study will lay the foundation to develop circRNA as a novel platform of mRNA vaccines for wide application in the prophylaxis and treatment of diseases, such as cancer and infectious diseases. Page 1

小环状mRNA疫苗