Diversifying T-cell responses: safeguarding against pandemic influenza with mosaic nucleoprotein.

IF 4 2区 医学 Q2 VIROLOGY
Journal of Virology Pub Date : 2025-03-18 Epub Date: 2025-02-03 DOI:10.1128/jvi.00867-24
Hongtae Park, Brock Kingstad-Bakke, Thomas Cleven, Myunghwan Jung, Yoshihiro Kawaoka, M Suresh
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引用次数: 0

Abstract

Pre-existing T-cell responses have been linked to reduced disease severity and better clinical outcomes during the 2009 influenza pandemic and the recent COVID-19 pandemic. We hypothesized that diversifying T-cell responses, particularly targeting conserved viral proteins such as the influenza A virus (IAV) nucleoprotein (NP), could protect against both epidemic and pandemic IAV strains. To test this, we created a mosaic nucleoprotein (MNP) by synthesizing a sequence that maximized the representation of 9-mer epitopes from 7422 NP sequences across human, swine, and avian IAVs. Notably, the MNP sequence showed high homology with the NP of the H5N1 strain affecting dairy cows in the ongoing outbreak. Mucosal immunization with the adjuvanted MNP vaccine induced robust CD8 and CD4 T-cell responses against both known immunodominant and in silico predicted subdominant epitopes. MNP-vaccinated mice challenged with epidemic H1N1 and H3N2 strains, which shared immunodominant CD8 and/or CD4 T-cell epitopes, showed a significant (~4 log) reduction in lung viral load. Importantly, MNP-vaccinated mice challenged with a pandemic H1N1 strain lacking shared immunodominant CD8 or CD4 epitopes exhibited a superior reduction in lung viral load, linked to T-cell responses targeting subdominant epitopes present in both the MNP and pandemic strain NP. These results suggest that a diversified T-cell response induced by the MNP vaccine could provide broad protection against severe disease from both current and emerging IAV strains.

Importance: The World Health Organization (WHO) estimates that seasonal influenza causes 3-5 million cases of severe illness annually. The influenza virus frequently undergoes genetic changes through antigenic drift and antigenic shift, resulting in annual epidemics and occasional pandemics. Consequently, a major public health objective is to develop a universal influenza vaccine that offers broad protection against both current and pandemic influenza A strains. In this study, we designed a nucleoprotein (NP) antigen (termed mosaic NP) comprising antigenic regions found in thousands of influenza viruses, aiming to use it as a vaccine to induce broad anti-influenza T-cell responses. Our findings indicate that the mosaic NP vaccine provided significant protection against seasonal H1N1 and H3N2, as well as the pandemic H1N1 strain, demonstrating its effectiveness across various influenza subtypes. These findings suggest that the mosaic NP is a potential universal influenza vaccine antigen, capable of protecting against diverse strains of influenza viruses.

多样化的t细胞反应:用花叶核蛋白防御大流行性流感。
在2009年流感大流行和最近的COVID-19大流行期间,预先存在的t细胞反应与降低疾病严重程度和改善临床结果有关。我们假设多样化的t细胞反应,特别是针对保守的病毒蛋白,如甲型流感病毒(IAV)核蛋白(NP),可以预防流行和大流行的IAV毒株。为了验证这一点,我们通过合成一个序列来创建一个镶嵌核蛋白(MNP),该序列最大限度地代表了人类、猪和鸟类的7422个NP序列中的9-mer表位。值得注意的是,MNP序列与正在暴发的影响奶牛的H5N1毒株的NP具有高度同源性。使用佐剂MNP疫苗进行粘膜免疫可诱导针对已知免疫显性和计算机预测的亚显性表位的强大CD8和CD4 t细胞应答。接种mnp疫苗的小鼠,用具有免疫优势的CD8和/或CD4 t细胞表位的H1N1和H3N2毒株攻击,肺病毒载量显著(~4 log)降低。重要的是,接种MNP疫苗的小鼠受到缺乏共享免疫显性CD8或CD4表位的大流行性H1N1毒株的攻击,表现出肺部病毒载量的显著降低,这与针对MNP和大流行性毒株NP中存在的亚显性表位的t细胞应答有关。这些结果表明,MNP疫苗诱导的多样化t细胞反应可以为当前和新出现的IAV株的严重疾病提供广泛的保护。重要性:世界卫生组织(世卫组织)估计,季节性流感每年导致300万至500万例严重疾病。流感病毒经常通过抗原漂移和抗原转移发生遗传变化,导致每年流行和偶尔大流行。因此,一个主要的公共卫生目标是开发一种通用流感疫苗,对当前和大流行性甲型流感毒株提供广泛的保护。在这项研究中,我们设计了一种核蛋白(NP)抗原(称为马赛克NP),包含数千种流感病毒中发现的抗原区域,旨在将其用作疫苗来诱导广泛的抗流感t细胞反应。我们的研究结果表明,马赛克NP疫苗对季节性H1N1和H3N2以及H1N1大流行毒株具有显著的保护作用,表明其对各种流感亚型的有效性。这些发现表明,马赛克NP是一种潜在的通用流感疫苗抗原,能够保护多种流感病毒株。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
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