da Silva Antunes Ricardo, Garrigan Emily, Quiambao Lorenzo G, Dhanda Sandeep Kumar, Marrama Daniel, Westernberg Luise, Wang Eric, Sutherland Aaron, Armstrong Sandra K, Brickman Timothy J, Sidney John, Frazier April, Merkel Tod, Peters Bjoern, Sette Alessandro
Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, San Diego, California, USA.
Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
bioRxiv. 2023 Mar 25:2023.03.24.534182. doi: 10.1101/2023.03.24.534182.
The incidence of whooping cough (pertussis), the respiratory disease caused by (BP) has increased in recent years, and it is suspected that the switch from whole-cell pertussis (wP) to acellular pertussis (aP) vaccines may be a contributing factor to the rise in morbidity. While a growing body of evidence indicates that T cells play a role in the control and prevention of symptomatic disease, nearly all data on human BP-specific T cells is related to the four antigens contained in the aP vaccines, and data detailing T cell responses to additional non-aP antigens, are lacking. Here, we derived a full-genome map of human BP-specific CD4+ T cell responses using a high-throughput Activation Induced Marker (AIM) assay, to screen a peptide library spanning over 3000 different BP ORFs. First, our data show that BP specific-CD4+ T cells are associated with a large and previously unrecognized breadth of responses, including hundreds of targets. Notably, fifteen distinct non-aP vaccine antigens were associated with reactivity comparable to that of the aP vaccine antigens. Second, the overall pattern and magnitude of CD4+ T cell reactivity to aP and non-aP vaccine antigens was similar regardless of aP vs wP childhood vaccination history, suggesting that the profile of T cell reactivity in adults is not driven by vaccination, but rather is likely driven by subsequent asymptomatic or sub-clinical infections. Finally, while aP vaccine responses were Th1/Th2 polarized as a function of childhood vaccination, CD4+ T cell responses to non-aP BP antigens vaccine responses were not, suggesting that these antigens could be used to avoid the Th2 bias associated with aP vaccination. Overall, these findings enhance our understanding of human T cell responses against BP and suggest potential targets for designing next-generation pertussis vaccines.
由百日咳博德特氏菌（BP）引起的呼吸道疾病百日咳的发病率近年来有所上升，人们怀疑从全细胞百日咳（wP）疫苗向无细胞百日咳（aP）疫苗的转变可能是发病率上升的一个促成因素。虽然越来越多的证据表明T细胞在控制和预防症状性疾病中发挥作用，但几乎所有关于人类BP特异性T细胞的数据都与aP疫苗中包含的四种抗原有关，而缺乏详细描述T细胞对其他非aP抗原反应的数据。在这里，我们使用高通量激活诱导标记（AIM）分析得出了人类BP特异性CD4+T细胞反应的全基因组图谱，以筛选一个涵盖3000多个不同BP开放阅读框的肽库。首先，我们的数据表明，BP特异性CD4+T细胞与大量以前未被认识到的广泛反应相关，包括数百个靶点。值得注意的是，十五种不同的非aP疫苗抗原与aP疫苗抗原的反应性相当。其次，无论儿童期接种aP还是wP疫苗的历史如何，CD4+T细胞对aP和非aP疫苗抗原反应的总体模式和强度相似，这表明成年人T细胞反应的特征不是由疫苗接种驱动的，而是可能由随后的无症状或亚临床感染驱动的。最后，虽然aP疫苗反应根据儿童期接种情况呈Th1/Th2极化，但CD4+T细胞对非aP BP抗原疫苗反应并非如此，这表明这些抗原可用于避免与aP疫苗接种相关的Th2偏差。总体而言，这些发现增强了我们对人类针对BP的T细胞反应的理解，并为设计下一代百日咳疫苗提出了潜在靶点。
