异源与同源加强免疫在移植受者中引发了性质不同、针对 BA.5 的交叉反应性 T 细胞。

Heterologous versus homologous boosting elicits qualitatively distinct, BA.5-cross-reactive T cells in transplant recipients.

机构信息

Department of Medicine.

Bloomberg~Kimmel Institute for Cancer Immunotherapy, and.

出版信息

JCI Insight. 2023 May 22;8(10):e168470. doi: 10.1172/jci.insight.168470.

DOI:10.1172/jci.insight.168470

PMID:37104041

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10322695/

Abstract

BackgroundThe SARS-CoV-2 Omicron BA.5 subvariant escapes vaccination-induced neutralizing antibodies because of mutations in the spike (S) protein. Solid organ transplant recipients (SOTRs) develop high COVID-19 morbidity and poor Omicron variant recognition after COVID-19 vaccination. T cell responses may provide a second line of defense. Therefore, understanding which vaccine regimens induce robust, conserved T cell responses is critical.MethodsWe evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4+ and CD8+ T cell responses from SOTRs in a national, prospective, observational trial (n = 75). Participants were selected if they received 3 doses of mRNA (homologous boosting) or 2 doses of mRNA followed by Ad26.COV2.S (heterologous boosting).ResultsHomologous boosting with 3 mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated lower pseudo-neutralization against BA.5 compared with the ancestral strain. In contrast, vaccine-induced S-specific T cells maintained cross-reactivity against BA.5 compared with ancestral recognition. Homologous boosting induced higher frequencies of activated polyfunctional CD4+ T cell responses, with polyfunctional IL-21+ peripheral T follicular helper cells increased in mRNA-1273 compared with BNT162b2. IL-21+ cells correlated with antibody titers. Heterologous boosting with Ad26.COV2.S did not increase CD8+ responses compared to homologous boosting.ConclusionBoosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants in SOTRs, but alternative vaccine strategies are required to induce robust CD8+ T cell responses.FundingBen-Dov Family; NIH National Institute of Allergy and Infectious Diseases (NIAID) K24AI144954, NIAID K08AI156021, NIAID K23AI157893, NIAID U01AI138897, National Institute of Diabetes and Digestive and Kidney Diseases T32DK007713, and National Cancer Institute 1U54CA260492; Johns Hopkins Vice Dean of Research Support for COVID-19 Research in Immunopathogenesis; and Emory COVID-19 research repository.

摘要

背景

由于刺突（S）蛋白的突变，SARS-CoV-2 的奥密克戎 BA.5 亚变体逃避了疫苗诱导的中和抗体。实体器官移植受者（SOTR）在 COVID-19 疫苗接种后会出现高 COVID-19 发病率和对奥密克戎变体的识别不良。T 细胞反应可能提供第二道防线。因此，了解哪种疫苗方案可诱导出强大、保守的 T 细胞反应至关重要。

方法

我们在一项全国性、前瞻性、观察性试验（n = 75）中评估了 SOTR 的抗-S IgG 滴度、亚变体假中和以及 S 特异性 CD4+和 CD8+T 细胞反应。如果参与者接受了 3 剂 mRNA（同源增强）或 2 剂 mRNA 后再接受 Ad26.COV2.S（异源增强），则选择他们。

结果

同源增强 3 剂 mRNA 可诱导最高的抗-S IgG 滴度。然而，两种疫苗方案诱导的抗体对 BA.5 的假中和作用均低于原始株。相比之下，疫苗诱导的 S 特异性 T 细胞对 BA.5 仍保持交叉反应性，与原始识别一致。同源增强诱导了更高频率的活化多效性 CD4+T 细胞反应，与 BNT162b2 相比，mRNA-1273 中增加了多效性 IL-21+外周 T 滤泡辅助细胞。IL-21+细胞与抗体滴度相关。与同源增强相比，Ad26.COV2.S 的异源增强并未增加 CD8+反应。

结论

用原始株增强可诱导 SOTR 中对新兴变体产生交叉反应性的 T 细胞反应，但需要替代疫苗策略来诱导强大的 CD8+T 细胞反应。

资助

本-多夫家族；美国国立卫生研究院过敏和传染病研究所（NIAID）K24AI144954、NIAID K08AI156021、NIAID K23AI157893、NIAID U01AI138897、国家糖尿病、消化和肾脏疾病研究所 T32DK007713 和国家癌症研究所 1U54CA260492；约翰霍普金斯大学研究支持副主任 COVID-19 免疫发病机制研究；和埃默里 COVID-19 研究存储库。