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编码保守非刺突抗原的 T 细胞定向疫苗 BNT162b4 可保护动物免受严重的 SARS-CoV-2 感染。

The T-cell-directed vaccine BNT162b4 encoding conserved non-spike antigens protects animals from severe SARS-CoV-2 infection.

机构信息

BioNTech US, 40 Erie Street, Cambridge, MA 02139, USA.

BioNTech US, 40 Erie Street, Cambridge, MA 02139, USA.

出版信息

Cell. 2023 May 25;186(11):2392-2409.e21. doi: 10.1016/j.cell.2023.04.007. Epub 2023 Apr 13.

DOI:10.1016/j.cell.2023.04.007
PMID:37164012
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10099181/
Abstract

T cell responses play an important role in protection against beta-coronavirus infections, including SARS-CoV-2, where they associate with decreased COVID-19 disease severity and duration. To enhance T cell immunity across epitopes infrequently altered in SARS-CoV-2 variants, we designed BNT162b4, an mRNA vaccine component that is intended to be combined with BNT162b2, the spike-protein-encoding vaccine. BNT162b4 encodes variant-conserved, immunogenic segments of the SARS-CoV-2 nucleocapsid, membrane, and ORF1ab proteins, targeting diverse HLA alleles. BNT162b4 elicits polyfunctional CD4 and CD8 T cell responses to diverse epitopes in animal models, alone or when co-administered with BNT162b2 while preserving spike-specific immunity. Importantly, we demonstrate that BNT162b4 protects hamsters from severe disease and reduces viral titers following challenge with viral variants. These data suggest that a combination of BNT162b2 and BNT162b4 could reduce COVID-19 disease severity and duration caused by circulating or future variants. BNT162b4 is currently being clinically evaluated in combination with the BA.4/BA.5 Omicron-updated bivalent BNT162b2 (NCT05541861).

摘要

T 细胞反应在预防β冠状病毒感染（包括 SARS-CoV-2）中发挥着重要作用，它们与降低 COVID-19 疾病严重程度和持续时间有关。为了增强针对 SARS-CoV-2 变体中很少改变的表位的 T 细胞免疫，我们设计了 BNT162b4，这是一种 mRNA 疫苗成分，旨在与编码刺突蛋白的 BNT162b2 联合使用。BNT162b4 编码 SARS-CoV-2 核衣壳、膜和 ORF1ab 蛋白中变异保守、具有免疫原性的片段，针对多种 HLA 等位基因。BNT162b4 在动物模型中单独或与 BNT162b2 联合使用时，可引发针对多种表位的多功能 CD4 和 CD8 T 细胞反应，同时保持对刺突蛋白的特异性免疫。重要的是，我们证明 BNT162b4 可保护仓鼠免受严重疾病的侵害，并降低在受到病毒变体挑战后的病毒滴度。这些数据表明，BNT162b2 和 BNT162b4 的联合使用可能会降低由循环或未来变体引起的 COVID-19 疾病严重程度和持续时间。BNT162b4 目前正在与 BA.4/BA.5 奥密克戎更新的二价 BNT162b2 （NCT05541861）联合进行临床评估。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/cfb951615e1d/figs7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/ae9f62d684b7/fx1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/08a3aad04699/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/16161bb9a180/figs1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/460d11581412/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/16d7f7f78a7b/figs2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/449660cb9933/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/c302c1949b99/figs3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/fd8097faef25/figs4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/76be908b0d24/figs5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/3bd2d383e59d/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/c682264b4ebb/figs6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/e84b664e5da0/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/73a080ad0f3d/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/cfb951615e1d/figs7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/ae9f62d684b7/fx1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/08a3aad04699/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/16161bb9a180/figs1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/460d11581412/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/16d7f7f78a7b/figs2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/449660cb9933/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/c302c1949b99/figs3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/fd8097faef25/figs4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/76be908b0d24/figs5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/3bd2d383e59d/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/c682264b4ebb/figs6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/e84b664e5da0/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/73a080ad0f3d/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6810/10099181/cfb951615e1d/figs7_lrg.jpg

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本文引用的文献

[1]
CD4+ and CD8+ T cells and antibodies are associated with protection against Delta vaccine breakthrough infection: a nested case-control study within the PITCH study.

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