COVID-19 vaccine development

COVID-19 疫苗开发

• 批准号: 10487068
• 负责人: George N. Pavlakis
• 金额: $ 66.18万
• 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/10487068
• 关键词: 2019-nCoV; Animals; Antibodies; Antibody titer measurement; Antigens; Biological Markers; COVID-19; COVID-19 vaccine; CXCL10 gene; Cellular Immunity; Clinical; Clinical Trials; Collaborations; Collection; DNA; Development; Dose; Ebola; Effectiveness; Frequencies; Future; Generations; Goals; Greece; Human; Humoral Immunities; Immune; Immune response; Immunotherapy; Individual; Infection; Interferon Type II; Interleukin-15; Interleukin-6; Kinetics; Knowledge; Lead; Longevity; Longitudinal Studies; Macaca; Maintenance; Maps; Messenger RNA; Middle East Respiratory Syndrome; Nature; Patients; Pfizer-BioNTech COVID-19 vaccine; Plasma; Preventive vaccine; Procedures; Public Health; Recommendation; SARS-CoV-2 antibody; SARS-CoV-2 antigen; SARS-CoV-2 infection; Sampling; Secondary Immunization; Severe Acute Respiratory Syndrome; TNF gene; Technology; Testing; Vaccination; Vaccine Design; Vaccines; Virus; Virus Diseases; adaptive immunity; base; cellular longevity; chemokine; cohort; compare effectiveness; convalescent plasma; cytokine; flu; interest; neutralizing antibody; novel coronavirus; response; vaccination outcome; vaccine development; vector; vector-induced

A collection of human samples is being analyzed to examine in detail humoral and cellular immunity after natural infection. These patients recovered from infection and accepted to donate convalescent plasma for transfer to hospitalized patients in an approved clinical trial. The immune response of these cohort is studied longitudinally to identify the nature and longevity of immune response. In addition, the recipient patients will be studied in an effort to identify benefits of immunotherapy after plasma transfer. The results of analysis of natural infection will be important in the design of vaccine strategies. The identification of patients with high titers of neutralizing antibodies will also support the selection of plasma collection for transfer to hospitalized patients as immunotherapy. We studied SARS-CoV-2 antibody maintenance in this cohort of infected convalescent people in Athens, Greece. 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 was observed. We continue to follow this cohort for 14 months and we determine Antibody longevity and neutralizing activity. In collaboration with Dr. Felber's Section we have developed DNA vectors that induced strong immune response in macaques after two vaccinations. Our strategy is to induce both neutralizing Ab and also cellular immunity able to optimally suppress virus infection. Several forms of SARS-CoV-2 antigens were expressed in DNA vectors and were tested in animals after characterization. Macaque vaccination showed that the animals develop robust immune responses. We showed that these responses to be protective after virus challenge, thus giving the opportunity to develop prophylactic vaccines against SARS-CoV-2 based on DNA technology that also provides much higher cellular immune responses. These responses may lead to vaccines with superior longevity and effectiveness compared with the current generation. We characterized the cytokine and chemokine responses to the 1st and 2nd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in antigen-naive and in previously coronavirus disease 2019 (COVID-19)-infected individuals (NCT04743388). Transient increases in interleukin-15 (IL-15) and interferon gamma (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 identified a systemic signature including increases in IL-15, IFN-gamma, and IP-10/CXCL10 after the 1st vaccination, which were enriched by tumor necrosis factor alpha (TNF-alpha) and IL-6 after the 2nd vaccination. In previously COVID-19-infected individuals, a single vaccination resulted in both strong cytokine induction and antibody titers similar to the ones observed upon booster vaccination in antigen-naive individuals, a result with potential implication for future public health recommendations.

正在分析人类样品的集合，以详细检查自然感染后的体液和细胞免疫。这些患者从感染中恢复过来，并接受了在批准的临床试验中捐赠疗养血浆，以转移给住院的患者。对这些队列的免疫反应进行了纵向研究，以识别免疫反应的性质和寿命。此外，将研究接受者患者，以确定血浆转移后免疫疗法的益处。自然感染分析的结果在疫苗策略的设计中很重要。鉴定中和抗体较高滴度的患者还将支持选择血浆收集，以转移到住院的患者作为免疫疗法。我们研究了希腊雅典受感染康复的人群中的SARS-COV-2抗体维持。 SARS-COV-2抗体动力学从COVID-19发作八个月：峰值抗体的持久性，但观察到24％的疗养血浆供体中中和抗体的丧失。我们继续跟随该队列14个月，并确定抗体寿命和中和活性。与Felber博士的部分合作，我们开发了DNA载体，这些载体在两次疫苗接种后诱导了猕猴的强烈免疫反应。我们的策略是诱导中和AB和细胞免疫，能够最佳地抑制病毒感染。在DNA载体中表达了几种形式的SARS-COV-2抗原，并在表征后在动物中进行了测试。猕猴的疫苗接种表明，动物会产生强大的免疫反应。我们表明，这些对病毒挑战后具有保护性的反应，因此有机会基于DNA技术开发针对SARS-COV-2的预防性疫苗，该技术也提供了更高的细胞免疫反应。与当前一代相比，这些反应可能导致具有更高寿命和有效性的疫苗。我们表征了对抗原剂中的Bnt162b2 mRNA（Pfizer/Biontech）疫苗的第一剂和第二剂量的细胞因子和趋化因子反应，以及先前的冠状病毒疾病2019（VoVID-19）（VoVID-19）的疫苗（NCT047443388）。升高后，白细胞介素15（IL-15）和干扰素γ（IFN-gamma）水平的短暂增加与峰值抗体水平相关，从而支持它们用作疫苗响应疫苗的有效体液免疫发展的生物标志物。我们确定了第1次疫苗接种后IL-15，IFN-GAMMA和IP-10/CXCL10的增加，包括在第二次疫苗接种后富含肿瘤坏死因子α（TNF-Alpha）和IL-6后IL-10/CXCL10的增加。在以前的199个感染者中，单个疫苗接种导致强烈的细胞因子诱导和抗体滴度，类似于抗原侵害个体促进疫苗接种时观察到的抗体滴度，这一结果可能对未来的公共卫生建议产生潜在影响。