Robust induction of TRMs by combinatorial nanoshells confers cross-strain sterilizing immunity against lethal influenza viruses

Molecular Therapy: Methods & Clinical Development

Che-Ming Jack Hu¹  Hung-Chih Yang²  Hui-Wen Chen³  Pei-Jer Chen⁴  Yu-Sung Hsu⁵  Chieh-Yu Liang⁵  Yi-Hsuan Lin⁵  Ching-Fu Pan⁵  Pin-Hung Lin⁵  Bing-Yu Yao⁶  Yu-Han Liu⁶  Li-Ling Wu⁷ 

[1] Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan;Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan;Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan;Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan;Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan;Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan;Institute of Physiology, National Yang-Ming Chiao-Tung University, Taipei City, Taiwan;

关键词: resident memory T cell;    nanoshell;    T cell vaccine;    peptide vaccine;    influenza virus;    universal influenza vaccine;   

DOI  :  

来源: DOAJ

【 摘 要 】

Antigen-specific lung-resident memory T cells (TRMs) constitute the first line of defense that mediates rapid protection against respiratory pathogens and inspires novel vaccine designs against infectious pandemic threats, yet effective means of inducing TRMs, particularly via non-viral vectors, remain challenging. Here, we demonstrate safe and potent induction of lung-resident TRMs using a biodegradable polymeric nanoshell that co-encapsulates antigenic peptides and TLR9 agonist CpG-oligodeoxynucleotide (CpG-ODN) in a virus-mimicking structure. Through subcutaneous priming and intranasal boosting, the combinatorial nanoshell vaccine elicits prominent lung-resident CD4+ and CD8+ T cells that surprisingly show better durability than live viral infections. In particular, nanoshells containing CpG-ODN and a pair of conserved class I and II major histocompatibility complex-restricted influenza nucleoprotein-derived antigenic peptides are demonstrated to induce near-sterilizing immunity against lethal infections with influenza A viruses of different strains and subtypes in mice, resulting in rapid elimination of replicating viruses. We further examine the pulmonary transport dynamic and optimal composition of the nanoshell vaccine conducive for robust TRM induction as well as the benefit of subcutaneous priming on TRM replenishment. The study presents a practical vaccination strategy for inducing protective TRM-mediated immunity, offering a compelling platform and critical insights in the ongoing quest toward a broadly protective vaccine against universal influenza as well as other respiratory pathogens.

【 授权许可】

Unknown