Sidney John, Kim A-Reum, de Vries Rory D, Peters Bjoern, Meade Philip S, Krammer Florian, Grifoni Alba, Sette Alessandro
Center for Vaccine Innovation, La Jolla Institute for Immunology (LJI), La Jolla, California, USA.
Department of Viroscience, Erasmus University Medical Centre, Rotterdam, the Netherlands.
mBio. 2025 Feb 5;16(2):e0347924. doi: 10.1128/mbio.03479-24. Epub 2024 Dec 23.
Frequent recent spillovers of subtype H5N1 clade 2.3.4.4b highly pathogenic avian influenza (HPAI) virus into poultry and mammals, especially dairy cattle, including several human cases, increased concerns over a possible future pandemic. Here, we performed an analysis of epitope data curated in the Immune Epitope Database (IEDB). We found that the patterns of immunodominance of seasonal influenza viruses circulating in humans and H5N1 are similar. We further conclude that a significant fraction of the T-cell epitopes is conserved at a level associated with cross-reactivity between avian and seasonal sequences, and we further experimentally demonstrate extensive cross-reactivity in the most dominant T-cell epitopes curated in the IEDB. Based on these observations, and the overall similarity of the neuraminidase (NA) N1 subtype encoded in both HPAI and seasonal H1N1 influenza virus as well as cross-reactive group 1 HA stalk-reactive antibodies, we expect that a degree of pre-existing immunity is present in the general human population that could blunt the severity of human H5N1 infections.IMPORTANCEInfluenza A viruses (IAVs) cause pandemics that can result in millions of deaths. The highly pathogenic avian influenza (HPAI) virus of the H5N1 subtype is presently among the top viruses of pandemic concern, according to the WHO and the National Institute of Allergy and Infectious Diseases (NIAID). Previous exposure by infection and/or vaccination to a given IAV subtype or clade influences immune responses to a different subtype or clade. Analysis of human CD4 and CD8 T-cell epitope conservation between HPAI H5N1 and seasonal IAV sequences revealed levels of identity and conservation conducive to T cell cross-reactivity, suggesting that pre-existing T cell immune memory should, to a large extent, cross-recognize avian influenza viruses. This observation was experimentally verified by testing responses from human T cells to non-avian IAV and their HPAI H5N1 counterparts. Accordingly, should a more widespread HPAI H5N1 outbreak occur, we hypothesize that cross-reactive T-cell responses might be able to limit disease severity.
近期，H5N1亚型2.3.4.4b高致病性禽流感（HPAI）病毒频繁传播到家禽和哺乳动物，尤其是奶牛，还导致了数起人类感染病例，这增加了人们对未来可能发生大流行的担忧。在此，我们对免疫表位数据库（IEDB）中整理的表位数据进行了分析。我们发现，人类中流行的季节性流感病毒和H5N1的免疫优势模式相似。我们进一步得出结论，相当一部分T细胞表位在与禽类和季节性序列之间的交叉反应相关的水平上是保守的，并且我们通过实验进一步证明了IEDB中整理的最主要T细胞表位具有广泛的交叉反应性。基于这些观察结果，以及高致病性禽流感病毒和季节性H1N1流感病毒中编码的神经氨酸酶（NA）N1亚型的总体相似性以及交叉反应性1组HA茎反应性抗体，我们预计普通人群中存在一定程度的预存免疫力，这可能会减轻人类H5N1感染的严重程度。
重要性
甲型流感病毒（IAV）会引发大流行，可能导致数百万人死亡。根据世界卫生组织和美国国家过敏和传染病研究所（NIAID）的说法，H5N1亚型高致病性禽流感（HPAI）病毒目前是最受关注的大流行病毒之一。先前通过感染和/或接种疫苗接触给定的IAV亚型或进化枝会影响对不同亚型或进化枝的免疫反应。对高致病性禽流感H5N1和季节性IAV序列之间的人类CD4和CD8 T细胞表位保守性分析显示，其同一性和保守性水平有利于T细胞交叉反应，这表明预先存在的T细胞免疫记忆在很大程度上应该能够交叉识别禽流感病毒。通过测试人类T细胞对非禽类IAV及其高致病性禽流感H5N1对应物的反应，对这一观察结果进行了实验验证。因此，我们假设，如果发生更广泛的高致病性禽流感H5N1疫情，交叉反应性T细胞反应可能能够限制疾病的严重程度。
