Th2 and Th17-associated immunopathology following SARS-CoV-2 breakthrough infection in Spike-vaccinated ACE2-humanized mice.
Th2 and Th17-associated immunopathology following SARS-CoV-2 breakthrough infection in Spike-vaccinated ACE2-humanized mice.
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Spike 疫苗接种的 ACE2 人源化小鼠中 SARS-CoV-2 突破性感染后的 Th2 和 Th17 相关免疫病理学。
DOI：
10.1002/jmv.29408
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发表时间：
2024
影响因子：
12.7
通讯作者：
Huang,Weishan
中科院分区：
文献类型：
--
作者：
Zhang,Tianyi;Magazine,Nicholas;McGee,MichaelC;Carossino,Mariano;Veggiani,Gianluca;Kousoulas,KonstantinG;August,Avery;Huang,Weishan
疫苗在预防COVID-19方面表现出显着的有效性;然而，在突破性感染后出现了对疫苗相关增强性呼吸道疾病（VAERD）的担忧。SARS-CoV-2的刺突蛋白亚单位疫苗在仓鼠中诱导VAERD，其中铝佐剂促进Th 2偏向的免疫应答，导致具有突破性感染的动物中2型肺部炎症增加。为了更深入地了解VAERD的潜在风险和潜在机制，我们用含铝和CpG‐ODN佐剂的SARS‐CoV‐2刺突蛋白免疫ACE 2人源化小鼠。随后，我们将他们暴露于增加剂量的SARS-CoV-2，以建立突破性感染。该疫苗引起了强烈的中和抗体反应，降低了病毒滴度，并提高了宿主存活率。然而，在突破性感染后，接种疫苗的动物表现出严重的肺部免疫病理学，其特征在于嗜酸性粒细胞和CD 4 +T细胞的显著血管周围浸润，沿着Th 2/Th 17细胞因子表达增加。细胞内流式细胞术分析显示全身性Th 17炎症反应，特别是在肺部。我们的数据表明，铝/CpG佐剂诱导了针对COVID-19的强抗体和Th 1相关免疫，但也引发了强烈的Th 2/Th 17炎症反应，这可能有助于突破性感染后T细胞介导的肺部免疫病理学的快速发作。这些发现强调了进一步研究的必要性，以揭示COVID-19中VAERD的复杂性，并增强疫苗配方，以获得广泛的保护和最大的安全性。
Vaccines have demonstrated remarkable effectiveness in protecting against COVID‐19; however, concerns regarding vaccine‐associated enhanced respiratory diseases (VAERD) following breakthrough infections have emerged. Spike protein subunit vaccines for SARS‐CoV‐2 induce VAERD in hamsters, where aluminum adjuvants promote a Th2‐biased immune response, leading to increased type 2 pulmonary inflammation in animals with breakthrough infections. To gain a deeper understanding of the potential risks and the underlying mechanisms of VAERD, we immunized ACE2‐humanized mice with SARS‐CoV‐2 Spike protein adjuvanted with aluminum and CpG‐ODN. Subsequently, we exposed them to increasing doses of SARS‐CoV‐2 to establish a breakthrough infection. The vaccine elicited robust neutralizing antibody responses, reduced viral titers, and enhanced host survival. However, following a breakthrough infection, vaccinated animals exhibited severe pulmonary immunopathology, characterized by a significant perivascular infiltration of eosinophils and CD4+T cells, along with increased expression of Th2/Th17 cytokines. Intracellular flow cytometric analysis revealed a systemic Th17 inflammatory response, particularly pronounced in the lungs. Our data demonstrate that aluminum/CpG adjuvants induce strong antibody and Th1‐associated immunity against COVID‐19 but also prime a robust Th2/Th17 inflammatory response, which may contribute to the rapid onset of T cell‐mediated pulmonary immunopathology following a breakthrough infection. These findings underscore the necessity for further research to unravel the complexities of VAERD in COVID‐19 and to enhance vaccine formulations for broad protection and maximum safety.
影响因子：
11.8
作者：
Choe PG;Kang CK;Suh HJ;Jung J;Song KH;Bang JH;Kim ES;Kim HB;Park SW;Kim NJ;Park WB;Oh MD
通讯作者：
Oh MD
影响因子：
30.3
作者：
Chen K;Eddens T;Trevejo-Nunez G;Way EE;Elsegeiny W;Ricks DM;Garg AV;Erb CJ;Bo M;Wang T;Chen W;Lee JS;Gaffen SL;Kolls JK
通讯作者：
Kolls JK
影响因子：
8.4
作者：
Grana, Carolina;Ghosn, Lina;Evrenoglou, Theodoros;Jarde, Alexander;Minozzi, Silvia;Bergman, Hanna;Buckley, Brian S.;Probyn, Katrin;Villanueva, Gemma;Henschke, Nicholas;Bonnet, Hillary;Assi, Rouba;Menon, Sonia;Marti, Melanie;Devane, Declan;Mallon, Patrick;Lelievre, Jean-Daniel;Askie, Lisa M.;Kredo, Tamara;Ferrand, Gabriel;Davidson, Mauricia;Riveros, Carolina;Tovey, David;Meerpohl, Joerg J.;Grasselli, Giacomo;Rada, Gabriel;Hrobjartsson, Asbjorn;Ravaud, Philippe;Chaimani, Anna;Boutron, Isabelle
通讯作者：
Boutron, Isabelle