Yellow Fever Heavy Water: Turnover of Antigen Specific Lymphocytes and Monocytes After Immunization With the 17D Yellow Fever Vaccine
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 27
- 试验地点
- 1
- 主要终点
- Decay Curve of Monocytes
研究概览
简要总结
The yellow fever vaccine is a live, attenuated virus that results in a robust immune response, especially in the T cell compartment. The researchers have been studying immune responses to live viral infections using the yellow fever vaccine as a model for a live viral infection. In this study, the researchers are interested in looking at the processing and lifespan of yellow fever specific CD8 T cell by measuring DNA replication and cell proliferation in humans using a naturally occurring stable isotope called deuterium.
详细描述
Yellow fever is a viral disease caused by the yellow fever virus (YFV). It is transmitted to humans through the bite of an infected mosquito and can result in a life-threatening infection with hepatitis, renal failure and coagulation abnormalities, and in severe cases, death. Yellow fever can be prevented by vaccination with the yellow fever vaccine (YFV-17D). Currently, the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommend vaccination for persons ≥ 9 months of age who are traveling to or living in a yellow fever endemic area.
A very interesting, but unexplained aspect of flavivirus biology is how infection with different members of the same virus family can lead to such diverse types of host-virus interactions and variable disease outcomes. For example, YFV infection can be fatal, but if the infected host survives, long-term protective immunity is seen. Alternatively, dengue virus causes an acute infection with associated acute disease manifestations; however, even more severe disease outcomes are observed following secondary infection with a distinct serologic type of dengue virus. Understanding why the human immune system can successfully contain one flavivirus infection, but not another is both a fascinating scientific enigma in human immunology and a topic with substantial practical importance to public health. Given the great global public health threats posed by epidemic and emerging flavivirus infections, and the need to define the biological basis of successful induction and maintenance of protective immunity by vaccination, elucidation of the immunologic mechanisms underlying the generation and maintenance of protective immunity to YFV vaccine should be extremely useful. Furthermore, definition of the attributes of such a highly effective vaccine should help expedite the development and evaluation of new and/or improved vaccines to prevent important prevalent and emerging infectious diseases.
The goal of this study is to use the live attenuated yellow fever vaccine, YFV-17D (YF-VAX®, Sanofi Pasteur) as a safe and effective model to study a primary, acute viral infection in humans. Yellow fever virus vaccine is the viral infection model that the researchers have chosen for the following reasons:
- The 17D attenuated yellow fever vaccine strain is one of the most efficacious vaccines available and has been in use since the 1930s.
- YFV vaccination leads to limited infection without causing the disease.
- Since most of the US population is not exposed to yellow fever virus, immunization of adult participants with the 17D vaccine strain allows for examination of the innate immunity and the naïve T and B cell response in humans during primary infection and the subsequent development of memory T cells after resolution of the primary infection.
- The YFV-17D vaccine induces long-term immunity that lasts for decades. By studying how the human immune system responds to an effective vaccine such as the YFV-17D vaccine, the researchers hope to learn more about the normal functioning of the immune system so that it might be possible to design new, more effective vaccines to prevent important infectious diseases. Therefore, this vaccine can serve as an ideal model to help decipher the properties that make a vaccine effective.
YFV-17D is known to stimulate broad-spectrum immune responses, including cytotoxic T cells and Th1 and Th2 responses, as well as neutralizing antibody titers that can persist for up to 30 years, after a single vaccination. Despite the great success of this empiric vaccine, there has been relatively little understanding of the mechanisms by which YFV-17D induces such robust protective immune responses.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Able to understand and give informed consent
- •Age 18-45 years
- •Participant agrees not to take any live vaccines 30 days before or after (14 days for inactivated, including coronavirus disease 2019 (COVID-19) vaccination) yellow fever vaccination (not applicable to Group 3 and 4b participants)
- •Participant agrees to not receive any other vaccination during the 2H2O labeling period
- •Women of child bearing potential must agree to use effective birth control for the entire duration of the study. A negative urine pregnancy test must be documented prior to vaccination or 2H2O intake. Participants who have a history of surgical sterilization or post-menopausal status >1 year, are not required to have a pregnancy test.
- •Positive for the HLA-A2 allele (not applicable to Group 3 or 4 participants)
排除标准
- •Prior receipt of a yellow fever vaccine (not applicable for Group 2 participants)
- •Lived in a country/area which is endemic for yellow fever (not applicable to Group 2 participants)
- •Travel to country/area which is endemic for yellow fever. Subject to investigator discretion
- •History of previous West Nile, Dengue, St. Louis encephalitis, Japanese encephalitis vaccination or infection
- •Any history of allergy to eggs, chicken or gelatin or to any previous vaccine (not applicable to Group 2 (if received YFV-17D outside of study), 3 and 4b participants)
- •A history of a medical condition resulting in impaired immunity (such as HIV infection, cancer, particularly leukemia, lymphoma, use of immunosuppressive or antineoplastic drugs or X-ray treatment). Persons with previous skin cancers or cured non-lymphatic tumors are not excluded from the study.
- •History of HIV infection
- •Active Hepatitis B or Hepatitis C infection
- •COVID-19 infection within 30 days prior to enrollment. Symptoms of COVID-19 must be completely resolved before enrollment.
- •History of any chronic medical conditions that are considered progressive (ex, diabetes, heart disease, lung disease, liver disease, kidney disease, gastrointestinal diseases and uncontrolled hypertension). Use of systemic immunosuppressive medications (ex, prednisone) for 2 weeks or more in the past 3 months.
- •History of excessive alcohol consumption, drug abuse, psychiatric conditions, social conditions or occupational conditions that in the opinion of the investigator would preclude compliance with the trial
- •Thymus gland problems (such as myasthenia gravis, DiGeorge syndrome, thymoma) or removal of thymus gland or history of autoimmune disorder
- •History of neurological or neurodegenerative disorders (ex, Guillain-Barré, peripheral neuropathy, epilepsy, etc.). Subject to investigator assessment and discretion.
- •Receipt of a blood products or immune globulin product within 42 days of enrollment. Participants who received COVID monoclonal antibodies (mAbs) for treatment are not excluded.
- •Pregnant women and nursing mothers or women who are planning to become pregnant for the duration of the study.
- •Any condition in the opinion of the investigator that would interfere with the proper conduct of the trial.
研究组 & 干预措施
Group 3 - Drink deuterated water for up to 8 weeks without vaccination
To assess homeostatic turnover of CD8+ T lymphocytes in general, unvaccinated participants will be asked to drink deuterium (70% enriched 2H2O) labeled water for up to 8 weeks.
干预措施: Deuterium (70% enriched 2H2O) labeled water (Other)
Group 1a - Drink deuterated water on days 0 - 14 post-vaccination
Participants testing positive for human leukocyte antigen-A2 (HLA-A2) will be enrolled into one of the three Group 1 study arms. To assess the life span and decay of effector CD8+T cells, participants in group 1a will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water for 2 weeks, on Days 0 through 14 post-vaccination.
干预措施: Yellow fever vaccine (Biological)
Group 1a - Drink deuterated water on days 0 - 14 post-vaccination
Participants testing positive for human leukocyte antigen-A2 (HLA-A2) will be enrolled into one of the three Group 1 study arms. To assess the life span and decay of effector CD8+T cells, participants in group 1a will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water for 2 weeks, on Days 0 through 14 post-vaccination.
干预措施: Deuterium (70% enriched 2H2O) labeled water (Other)
Group 1b - Drink deuterated water on days 14 - 28 post-vaccination
Participants testing positive for HLA-A2 will be enrolled into one of the three Group 1 study arms. To assess the life span and decay of effector CD8+T cells, participants in group 1b will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water for 2 weeks, on Days 14 through 28 post-vaccination.
干预措施: Yellow fever vaccine (Biological)
Group 1b - Drink deuterated water on days 14 - 28 post-vaccination
Participants testing positive for HLA-A2 will be enrolled into one of the three Group 1 study arms. To assess the life span and decay of effector CD8+T cells, participants in group 1b will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water for 2 weeks, on Days 14 through 28 post-vaccination.
干预措施: Deuterium (70% enriched 2H2O) labeled water (Other)
Group 1c - Drink deuterated water on days 0 - 28 post-vaccination
Participants testing positive for HLA-A2 will be enrolled into one of the three Group 1 study arms. To assess the life span and decay of effector CD8+T cells, participants in group 1c will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water for 4 weeks, on Days 0 through 28 post-vaccination.
干预措施: Yellow fever vaccine (Biological)
Group 1c - Drink deuterated water on days 0 - 28 post-vaccination
Participants testing positive for HLA-A2 will be enrolled into one of the three Group 1 study arms. To assess the life span and decay of effector CD8+T cells, participants in group 1c will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water for 4 weeks, on Days 0 through 28 post-vaccination.
干预措施: Deuterium (70% enriched 2H2O) labeled water (Other)
Group 2a - Drink deuterated water 2 months post-vaccination
To assess the homeostatic proliferation of Memory CD8 T cells, participants in group 2a will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water 2 months post-vaccination.
干预措施: Yellow fever vaccine (Biological)
Group 2a - Drink deuterated water 2 months post-vaccination
To assess the homeostatic proliferation of Memory CD8 T cells, participants in group 2a will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water 2 months post-vaccination.
干预措施: Deuterium (70% enriched 2H2O) labeled water (Other)
Group 2b - Drink deuterated water 6 months post-vaccination
To assess the homeostatic proliferation of Memory CD8 T cells, participants in group 2b will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water 6 months post-vaccination.
干预措施: Yellow fever vaccine (Biological)
Group 2b - Drink deuterated water 6 months post-vaccination
To assess the homeostatic proliferation of Memory CD8 T cells, participants in group 2b will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water 6 months post-vaccination.
干预措施: Deuterium (70% enriched 2H2O) labeled water (Other)
Group 4a - Drink deuterated water on days 0 - 7 post-vaccination, with fine needle aspirate
To assess homeostatic turnover of monocytes participants in group 4a will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water on Days 0 through 7 post-vaccination. Participants will undergo two fine needle aspirate (FNA) procedures to examine the immune response in the lymph nodes.
干预措施: Yellow fever vaccine (Biological)
Group 4a - Drink deuterated water on days 0 - 7 post-vaccination, with fine needle aspirate
To assess homeostatic turnover of monocytes participants in group 4a will receive the 17D yellow fever vaccine and will be asked to drink deuterium (70% enriched 2H2O) labeled water on Days 0 through 7 post-vaccination. Participants will undergo two fine needle aspirate (FNA) procedures to examine the immune response in the lymph nodes.
干预措施: Deuterium (70% enriched 2H2O) labeled water (Other)
Group 4b - Drink deuterated water for 7 days without vaccination
To assess homeostatic turnover of monocytes participants in group 4b, unvaccinated participants will will be asked to drink deuterium (70% enriched 2H2O) labeled water for 7 days post enrollment.
干预措施: Deuterium (70% enriched 2H2O) labeled water (Other)
结局指标
主要结局
Decay Curve of Monocytes
时间窗: Up to Month 12
The decay curve of monocytes after immunization with 17D yellow fever vaccine is measured in days. The schedule of follow up visits depends on the study arm that the participant is in.
Lifespan of Effector CD8 T Cells
时间窗: Up to Month 12
The life span of effector CD8 T cells after immunization with 17D yellow fever vaccine is measured in days. The schedule of follow up visits depends on the study arm that the participant is in.
Homeostatic Turnover of Memory CD8 T Cells
时间窗: Up to Month 12
The rate of homeostatic turnover of memory CD8 T cells after immunization with 17D yellow fever vaccine. The schedule of follow up visits depends on the study arm that the participant is in.
Decay Curve of Effector CD8 T Cells
时间窗: Up to Month 12
The decay curve of effector CD8 T cells after immunization with 17D yellow fever vaccine is measured in days. The schedule of follow up visits depends on the study arm that the participant is in.
Lifespan of Monocytes
时间窗: Up to Month 12
The life span of monocytes after immunization with 17D yellow fever vaccine is measured in days. The schedule of follow up visits depends on the study arm that the participant is in.
次要结局
- Kinetics of T Cell Responses(Up to Month 12)
- Magnitude of B Cell Responses(Up to Month 12)
- Magnitude of Monocytes(Up to Month 12)
- Magnitude of T Cell Responses(Up to Month 12)
- Kinetics of B Cell Responses(Up to Month 12)
- Turnover of Epstein-Barr Virus (EBV)-Specific CD8 T Cells(Up to Month 12)
- Kinetics of Monocytes(Up to Month 12)
- Turnover of Cytomegalovirus (CMV)-Specific CD8 T Cells(Up to Month 12)
研究者
Sri Edupuganti
Professor
Emory University