Pre-vaccination frequency of circulatory Tfh is associated with robust immune response to TV003 dengue vaccine.
Pre-vaccination frequency of circulatory Tfh is associated with robust immune response to TV003 dengue vaccine.
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DOI：
10.1371/journal.ppat.1009903
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发表时间：
2022-01
期刊：
影响因子：
6.7
通讯作者：
Haddad EK
中科院分区：
文献类型：
--
作者：
Izmirly AM;Pelletier AN;Connors J;Taramangalam B;Alturki SO;Gordon EA;Alturki SO;Mell JC;Swaminathan G;Karthik V;Kutzler MA;Kallas EG;Sekaly RP;Haddad EK
据估计，每年有超过3.9亿人感染登革热病毒;其中约9600万人感染导致临床病理学。迄今为止，只有一种基于病毒载体的许可的登革病毒疫苗CYD-TDV被批准用于登革流行地区。虽然最初批准用于与血清状态无关的给药，但当前指南仅建议将该疫苗用于血清阳性个体。因此，迫切需要研究登革病毒血清状态的影响和影响疫苗结果的免疫机制。在此，我们提供了对血清状态和宿主免疫因素的综合评价，这些因素与人类参与者的II期临床队列中对基于登革病毒载体的四价疫苗（TV 003）的稳健免疫应答相关。我们观察到血清阳性个体对TV 003疫苗表现出更强的免疫应答。我们的多层免疫分析显示，血清阳性受试者的循环T滤泡辅助细胞（cTfh）和Tfh相关趋化因子CXCL 13/BLC的基线/接种前频率增加。重要的是，该基线/接种前cTfh谱与接种者针对所有四种血清型登革热病毒发起中和抗体应答的能力相关，这是登革热疫苗临床试验的重要终点。总的来说，我们提供了新的见解，在登革病毒血清阳性个体中持续存在的有利的cTfh相关的免疫状态，与他们的能力，安装强大的疫苗特异性免疫应答。在临床疫苗学背景下对cTfh细胞生物学的这种详细询问将有助于揭示有利的免疫调节剂的机制和靶点。登革病毒（DENV）是一种全球性的威胁，造成重大的健康和经济负担。目前，在DENV疫苗的开发中存在几个挑战，包括存在四种不同的血清型，它们都能够引起疾病和抗体依赖性增强（ADE）。为了获得完全保护，疫苗必须能够产生针对所有4种血清型的中和抗体，以避免ADE。目前，有一种获得许可的DENV疫苗，CYD-TDV（DENGVAXIA）。然而，该疫苗仅在DENV血清阳性个体中有效预防严重疾病，因此必须进一步研究血清状态效应以用于最佳疫苗设计。已知称为T滤泡辅助（Tfh）细胞的CD 4 + T细胞亚群在帮助高亲和力抗体产生中起主要作用。因此，我们选择研究Tfh的亚群及其在人类血液中产生的细胞因子，这些细胞因子可以作为有效疫苗设计的生物标志物。我们发现，DENV血清阳性参与者在接种疫苗前Tfh细胞的频率增加，并且Tfh相关趋化因子CXCL 13/BLC的水平更高，该趋化因子在指导抗原特异性反应中起作用。然后，该接种前Tfh谱和CXCL 13/BLC与接种者产生针对DENV的所有四种血清型的中和抗体（应答宽度）的能力正相关，这是所有DENV疫苗试验的重要目标。
It has been estimated that more than 390 million people are infected with Dengue virus every year; around 96 millions of these infections result in clinical pathologies. To date, there is only one licensed viral vector-based Dengue virus vaccine CYD-TDV approved for use in dengue endemic areas. While initially approved for administration independent of serostatus, the current guidance only recommends the use of this vaccine for seropositive individuals. Therefore, there is a critical need for investigating the influence of Dengue virus serostatus and immunological mechanisms that influence vaccine outcome. Here, we provide comprehensive evaluation of sero-status and host immune factors that correlate with robust immune responses to a Dengue virus vector based tetravalent vaccine (TV003) in a Phase II clinical cohort of human participants. We observed that sero-positive individuals demonstrate a much stronger immune response to the TV003 vaccine. Our multi-layered immune profiling revealed that sero-positive subjects have increased baseline/pre-vaccination frequencies of circulating T follicular helper (cTfh) cells and the Tfh related chemokine CXCL13/BLC. Importantly, this baseline/pre-vaccination cTfh profile correlated with the vaccinees’ ability to launch neutralizing antibody response against all four sero-types of Dengue virus, an important endpoint for Dengue vaccine clinical trials. Overall, we provide novel insights into the favorable cTfh related immune status that persists in Dengue virus sero-positive individuals that correlate with their ability to mount robust vaccine specific immune responses. Such detailed interrogation of cTfh cell biology in the context of clinical vaccinology will help uncover mechanisms and targets for favorable immuno-modulatory agents. Dengue virus (DENV) is a worldwide threat that causes significant health and economic burden. Currently, there are several challenges in the development of a DENV vaccine including the existence of four different serotypes, which are all capable of causing disease and antibody dependent enhancement (ADE). For complete protection, a vaccine must be able to generate neutralizing antibodies against all 4 serotypes to avoid ADE. Currently, there is one licensed DENV vaccine, CYD-TDV (DENGVAXIA). However, this vaccine is only efficacious in protecting against severe disease in DENV seropositive individuals therefore serostatus effect must be further studied for optimal vaccine design. A subset of CD4+ T cells called T-follicular helper (Tfh) cells have been well known to play a major role in aiding high affinity antibody production. Therefore, we chose to look at subsets of Tfh and the cytokines they produce in human blood that can serve as biomarkers for effective vaccine design. We found that DENV sero-positive participants had increased pre-vaccination frequencies of Tfh cells and higher levels of the Tfh related chemokine CXCL13/BLC that plays a role in directing antigen-specific responses. This pre-vaccination Tfh profile and CXCL13/BLC are then correlated positively with the vaccinees’ ability to produce neutralizing antibody against all four sero-types (breadth of the Response) of DENV, an important goal for all DENV vaccine trials.
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