COVID-19 vaccine in naive individuals and cancer patients

新冠病毒 (COVID-19) 疫苗用于初次接种者和癌症患者

• 批准号: 10926405
• 负责人: BARBARA K FELBER
• 金额: $ 85.2万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926405
• 关键词: 2019-nCoV; Anti-Inflammatory Agents; Antibodies; Antigens; B-Lymphocytes; Binding; Biological Markers; Biology; CCL2 gene; CCL22 gene; CCL3 gene; CCL4 gene; CCL8 gene; COVID-19; COVID-19 vaccination; COVID-19 vaccine; CXCL10 gene; CXCL13 gene; CXCR3 gene; Cancer Patient; Cells; Data; Development; Disease; Early identification; Effectiveness; Goals; HIV vaccine; Hematologic Neoplasms; Humoral Immunities; IL16 gene; IL8 gene; Immune; Immune response; Immunity; Immunocompromised Host; Immunologic Markers; Individual; Infection; Inflammatory; Innate Immune Response; Interferon Type II; Interleukin-15; Interleukin-16; Interleukin-6; Internships; Longevity; Longitudinal cohort; Messenger RNA; Nature; Participant; Patients; Persons; Pfizer-BioNTech COVID-19 vaccine; Population; RNA vaccination; RNA vaccine; Regimen; Role; SARS-CoV-2 immune response; SARS-CoV-2 infection; Shapes; Structure of germinal center of lymph node; TNF gene; Vaccinated; Vaccination; Vaccine Design; Vaccinee; Virus; adaptive immune response; adaptive immunity; anakinra; chemokine; cohort; cytokine; frontier; high risk; individual patient; microorganism; neutralizing antibody; novel; prognostic; research and development; response; vaccine development; vaccine efficacy; vaccine platform; vaccine strategy

We have been studying the immune response of COVID-19 cohorts longitudinally to characterize the nature and longevity of immune response (Rosati M, Am J Hematol: 97:E3, 2022; Rosati Frontiers Immunol 12: 793953, 2021; Thomopoulos, Viruses 1:1844; 2021; Terpos, Eur J Intern Med, 89:87,2021; Pappa, Microorganisms 9, 806, 2021; Terpos, Microorganisms. 8:1885, 2020). The analysis of natural infection is providing important information for the design of vaccine strategies. To characterize adaptive and innate immune responses in SARS-CoV2 vaccinated persons, we identified early responses to vaccination that are important in shaping both humoral and cellular protective immunity (Bergamaschi, Cell Rep 36:109504; 2021; Bergamaschi, Frontiers Immunol 3:899972, 2022). We characterized the cytokine and chemokine responses to BNT162b2 mRNA (Pfizer/BioNtech) vaccinations in antigen-naive and in previously COVID-19-infected individuals and in patients with hematological malignancies (NCT04743388). We identified a systemic signature including IL-15, IFN-gamma, IP-10/CXCL10, TNF-alpha and IL-6 (Bergamaschi, Cell Rep 36:109504; 2021). Transient increases in IL-15 and IFN-gamma levels early after boost correlated with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We expanded our studies to immunocompromised individuals including patients with hematological malignancies, a population at high risk of developing severe disease upon SARS-CoV-2 infection (Bergamaschi, Frontiers Immunol 3:899972, 2022). Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. Overall, the patients showed heterogeneous adaptive immune responses with lower humoral (binding and neutralizing antibodies) levels. In contrast to vaccination of a cohort of healthy participants, patients with hematological malignancies who had a lower anti-Spike response, also had a diminished systemic cytokine response (IFN-g, IL-15 and CXCL10/IP-10), and this correlated with the lower anti-Spike antibody levels. On the other hand, in patients who failed to develop antibodies, the innate systemic response showed a lack of the IL-15/IFN-g signature with responses dominated by CCL8/IL-8 and CCL3/MIP-1alpha. Thus, we concluded that successful development of an anti-Spike immune response was associated with a robust transient activation of the IL-15 signature, serving as a novel, prognostic approaches for potentiating the effectiveness of COVID-19 vaccination. We have been expanding our research of the development of adaptive and innate immune responses upon the third COVID-19 mRNA vaccination. In addition to the previously identified cytokine/chemokine responses, we detected induction of CXCL13, a biomarker for germinal center activation and a key regulator of B cells, found only after the 3rd vaccination. In contrast to the transient increase of the IL-15 signature cytokines, a set of pro-inflammatory cytokines (CCL3/MIP-1alpha, CCL4/MIP-1beta, MCP-1, CCL22/MDC, CXCL8/IL-8, IL-16) and the anti-inflammatory factor IL-1Ra remained at higher levels for up to one month post the 2nd and the 3rd vaccination, indicative of a state of longer-lasting innate immune change. Importantly, changes of the IL-15 signature and the inflammatory/anti-inflammatory cytokine profile correlated with neutralizing antibody levels also after the 3rd vaccination supporting their role as immune biomarkers for effective development of vaccine-induced humoral responses. Together, these data revealed that repeated BNT162b2 mRNA vaccination induced both rapid/transient as well as longer-lasting cytokine/chemokine changes. These results highlight the important role of innate responses to the BNT162b2 mRNA vaccination in shaping adaptive immunity. Together, our results show coordinated responses to the BNT162b2 mRNA vaccine and highlight the important role of a network of innate responses, centering on IL-15, in shaping adaptive immunity after vaccination. This study suggests that understanding the role of these biomarkers could also help the refinement of regimens to increase efficacy of other vaccine platforms including HIV vaccines.

我们一直在研究Covid-19人群的免疫反应，以表征免疫反应的性质和寿命（Rosati M，Am J Hematol：97：e3，2022; Rosati Frontiers Immunol 12：793953，2021; Thomopoulos，Thomopoulos，Thomopoulos，Viruses 1：1844; 2022; 2022; 2022; 2022; epos； Pappa，微生物9，806，2021;自然感染的分析为设计疫苗策略的设计提供了重要信息。为了表征SARS-COV2疫苗接种的人的适应性和先天免疫反应，我们确定了对疫苗接种的早期反应，这些反应对于塑造体液和细胞保护性免疫很重要（Bergamaschi，Cell Rep 36：109504; 2021; 2021; Bergamaschi，Frontiers immunol 3：899999999972，20222; 2021; Bergamaschi，Frontiers Immunol 3：我们表征了对抗原含量和先前共同感染的患者以及血液恶性肿瘤患者的细胞因子和趋化因子对BNT162B2 mRNA（辉瑞/Biontech）疫苗接种（NCT047433388）的反应。我们确定了一个系统性签名，包括IL-15，IFN-GAMMA，IP-10/CXCL10，TNF-ALPHA和IL-6（Bergamaschi，Cell Rep 36：109504; 2021）。增强后早期IL-15和IFN-GAMMA水平的瞬态增加与峰值抗体水平相关，从而支持它们用作疫苗接种的有效体液免疫发展的生物标志物。我们将研究扩展到免疫功能低下的个体，包括血液恶性肿瘤的患者，在SARS-COV-2感染后患有严重疾病的人群（Bergamaschi，Frontiers，Immunol 3：899972，2022）。疫苗接种提供的保护通常很低，导致疫苗疗效改变的生物学尚不完全了解。总体而言，患者显示出异质的适应性免疫反应，其体液（结合和中和抗体）水平较低。与众多健康参与者的疫苗接种相反，血液学恶性肿瘤患者的抗SPIKE反应较低，系统性细胞因子反应也降低（IFN-G，IL-15和CXCL10/IP-10），并且与较低的抗Spike抗体水平相关。另一方面，在未开发抗体的患者中，先天的系统性反应缺乏IL-15/IFN-G签名，其反应以CCL8/IL-8和CCL3/MIP-1Alpha为主。因此，我们得出的结论是，抗尖峰免疫反应的成功发展与IL-15特征的稳健瞬态激活有关，它是一种新型的预后方法，可增强Covid-19疫苗接种的有效性。我们一直在扩大对第三次Covid-19 mRNA疫苗接种的适应性和先天免疫反应发展的研究。除了先前鉴定的细胞因子/趋化因子反应外，我们还检测到CXCL13的诱导，这是一种生发中心活化的生物标志物和B细胞的关键调节剂，仅在第三次疫苗接种后才发现。与IL-15特征细胞因子的短暂增加相反，一组促炎性细胞因子（CCL3/MIP-1Alpha，Ccl4/Mip-1Beta，MCP-1，CCL22/MDC，CXCL8/CXCL8/IL-8，IL-8，IL-8，IL-16），IL-16）和抗抗激素级别的级别和较高的级别IL-1级别均为IL-1级别，以下均降低了3级，以下均为IL-1余地。疫苗接种，表明先天免疫变化持续持续的状态。重要的是，在第三次疫苗接种后，IL-15特征的变化和炎症/抗炎细胞因子谱也与中和抗体水平相关。总之，这些数据表明，重复的BNT162B2 mRNA疫苗接种诱导了快速/瞬变以及持续持续的细胞因子/趋化因子的变化。这些结果突出了对BNT162B2 mRNA疫苗接种在塑造适应性免疫方面的重要作用。总之，我们的结果表明，对BNT162B2 mRNA疫苗的协调反应，并突出了以IL-15为中心的先天反应网络在疫苗接种后塑造适应性免疫方面的重要作用。这项研究表明，了解这些生物标志物的作用也可以帮助改进方案以提高其他疫苗平台在内的疗效，包括HIV疫苗。

项目成果

A Phase II Study on the Use of Convalescent Plasma for the Treatment of Severe COVID-19- A Propensity Score-Matched Control Analysis.

• DOI: 10.3390/microorganisms9040806
• 发表时间: 2021-04-11
• 期刊: Microorganisms
• 影响因子: 4.5
• 作者: Pappa V;Bouchla A;Terpos E;Thomopoulos TP;Rosati M;Stellas D;Antoniadou A;Mentis A;Papageorgiou SG;Politou M;Kotanidou A;Kalomenidis I;Poulakou G;Jahaj E;Korompoki E;Grigoropoulou S;Hu X;Bear J;Karaliota S;Burns R;Pagoni M;Trontzas I;Grouzi E;Labropoulou S;Stamoulis K;Bamias A;Tsiodras S;Felber BK;Pavlakis GN;Dimopoulos MA
• 通讯作者: Dimopoulos MA

Systemic IL-15, IFN-γ, and IP-10/CXCL10 signature associated with effective immune response to SARS-CoV-2 in BNT162b2 mRNA vaccine recipients.

• DOI: 10.1016/j.celrep.2021.109504
• 发表时间: 2021-08-10
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Bergamaschi C;Terpos E;Rosati M;Angel M;Bear J;Stellas D;Karaliota S;Apostolakou F;Bagratuni T;Patseas D;Gumeni S;Trougakos IP;Dimopoulos MA;Felber BK;Pavlakis GN
• 通讯作者: Pavlakis GN

SARS-CoV-2 antibody kinetics eight months from COVID-19 onset: Persistence of spike antibodies but loss of neutralizing antibodies in 24% of convalescent plasma donors.

• DOI: 10.1016/j.ejim.2021.05.010
• 发表时间: 2021-07
• 期刊: European journal of internal medicine
• 影响因子: 8
• 作者: Terpos E;Stellas D;Rosati M;Sergentanis TN;Hu X;Politou M;Pappa V;Ntanasis-Stathopoulos I;Karaliota S;Bear J;Donohue D;Pagoni M;Grouzi E;Korompoki E;Pavlakis GN;Felber BK;Dimopoulos MA
• 通讯作者: Dimopoulos MA

Low Spike Antibody Levels and Impaired BA.4/5 Neutralization in Patients with Multiple Myeloma or Waldenstrom's Macroglobulinemia after BNT162b2 Booster Vaccination.

• DOI: 10.3390/cancers14235816
• 发表时间: 2022-11-25
• 期刊: Cancers
• 影响因子: 5.2

Sequential Analysis of Binding and Neutralizing Antibody in COVID-19 Convalescent Patients at 14 Months After SARS-CoV-2 Infection.

• DOI: 10.3389/fimmu.2021.793953
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Rosati M;Terpos E;Ntanasis-Stathopoulos I;Agarwal M;Bear J;Burns R;Hu X;Korompoki E;Donohue D;Venzon DJ;Dimopoulos MA;Pavlakis GN;Felber BK
• 通讯作者: Felber BK