A Randomised, Double-blind, Placebo-controlled, Single-centre Phase IIb Trial as Part of the EU-funded UNISEC Project to Assess the Immunogenicity and Safety of Different Formulations and Dosing Regimens of FLU-v Vaccine in Healthy Adults
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 175
- 试验地点
- 2
- 主要终点
- IFN-gamma Responses Measured by ELISA
研究概览
简要总结
FLU-v is a vaccine that aims to protect against a wide range of flu viruses. The purpose of this study is to measure the immune responses induced by FLU-v vaccine. This study will look at how safe FLU-v is when administered and how successful it is in preventing flu or reducing the severity of the flu symptoms.
The study requires 222 healthy volunteers 18-60 years old. Participation in the study will take a maximum of 7 months and consists of 5 visits. During visit 1, subjects will be examined by a doctor to make sure they are eligible to enter the study. A 15ml blood sample (a tablespoon) will be taken to check general health followed by a general physical exam. Medical history and some personal information will be collected. Subjects that have received the traditional flu vaccine in the past 6 months, and those females who are pregnant or breastfeeding will not be allowed in the study. Subjects of childbearing age must agree to use effective contraceptive methods.
At visit 2, subjects will be randomly allocated to one of the four treatment groups summarised below:
- Treatment 1: FLU-v (test vaccine) at the start of the study (Day 0) and then again 21 days later
- Treatment 2: FLU-v (test vaccine) with an additional substance added [known as Montanide ISA 51] which improves the effect of the test vaccine. Injection will be given on Day 0 and then Placebo (no test vaccine) alone 21 days later
- Treatment 3: Placebo (no test vaccine) injection on Day 0 and then 21 days later
- Treatment 4: Placebo (no test vaccine) with an additional substance added [known as Montanide ISA 51] on Day 0 and then Placebo (no test vaccine) alone 21 days later Treatment will be injected under the skin in the upper arm on day 0 (visit 2) and 21 days later (visit 3). Blood samples will be taken before treatment (day 0), and on days 42 (visit 4) and 180 (visit 5) to the immune responses induced by the vaccine.
Subjects will be asked to complete a diary card to write down any side effects that they may experience after vaccination. Subjects will also be asked to complete another diary card to document any flu-like symptoms experienced between December 2016 and March 2017, this time is officially considered as the flu season. During this period, if the subject experiences flu-like symptoms, a collection of a nose and tonsil swab will be arranged by the study site to confirm whether they have the flu or not.
详细描述
Rationale: Current seasonal influenza vaccines mainly induce immune responses against viral membrane glycoproteins. These proteins, however, undergo continuous mutations by a process called antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy not only poses inconvenience and cost-inefficiency, but also results in poor protective effectiveness when the vaccinated strains are mismatched with the actual circulating strains. The latter point is especially of concern during a pandemic outbreak, when a large geographical area is affected and the general population is naïve to the newly re-assorted viral strain due to antigenic shift.
Objective: To evaluate the safety and immunogenicity of the influenza vaccine (FLU-v, as a suspension or adjuvanted as emulsion) targeting conserved immunogenic regions of influenza A and B viruses in healthy adults, in particular to show that the TH1 cytokine response at 42 and 180 days after the first injection is greater in the adjuvanted FLU-v and unadjuvanted FLU-v than in the placebo.
Study design: A total of 222 study participants will be recruited. The study follows a factorial design where the two factors are treatment (FLU-v / placebo) and formulation (unadjuvanted / suspension, adjuvanted / emulsion). Subjects will be randomised in two strata (age 18 to 40, age 41 to 60) to one of the following treatment regimens:
- Group 1 (n=74): FLU-v (unadjuvanted) as a suspension in pH neutral HCl/NaOH (0.5mL) on Day 0 and Day 21
- Group 2 (n=74): (0.5mL) ISA-51-adjuvanted FLU-v emulsified in water for injection (WFI) on Day 0, saline (0.5mL) on Day 21
- Group 3 (n=37): saline solution (0.5mL ) on Day 0 and Day 21
- Group 4 (n=37): WFI and ISA-51 emulsion (0.5mL) on Day 0, saline (0.5mL) on Day 21
Each administration will be given subcutaneously. Solicited and unsolicited adverse events (AEs) will be collected by AE questionnaire/diary card until day 42. Adverse events (AEs) and serious adverse events (SAEs) will be collected for the entire study period. The treatments will be administered starting in third quarter of 2016 in order to provide protection for the subsequent influenza season starting in December 2016. Blood samples will be taken from all subjects on day 0 (before FLU-v vaccination), 42 (21 days after the second dosing) and 180 (159 days after the second dosing) for the evaluation of FLU-v-specific cellular and humoral immune responses. Clinical symptom scores to ascertain severity and the incidence of RT-PCR-confirmed influenza A and/or B infection will be recorded during the subsequent influenza season (December 2016 to March 2017) to decide clinical efficacy of the tested vaccines.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy males or healthy non-pregnant females (as indicated by a negative blood pregnancy test done during the screening visit) between the ages of 18 and 60 years, inclusive;
- •Women of childbearing potential (not surgically sterile or postmenopausal for greater than or equal to one year) and men must agree to practice appropriate contraception (a combination of barrier and hormonal methods for women and a condom for men) from screening and until at least 30 days (up to Study Day 51 for females) and 90 days (up to Study Day 111 for males), after the last vaccination.
- •A subject is in good health, as determined by a comprehensive clinical assessment {vital signs (heart rate, blood pressure, oral temperature)}, blood chemistry test (electrolytes, renal/kidney function, liver function, C-reactive protein, complete blood count), medical history, general physical examination, self-reported illness} and the clinical judgment of the investigator;
- •Able to understand and comply with planned study procedures;
- •Provides signed informed consent form
排除标准
- •Has a known allergy to any of the components of the vaccine.
- •Has a history of severe reaction following immunization.
- •Persons with immune deficiency/disorder, whether due to genetic defect, immunodeficiency disease, or immunosuppressive therapy.
- •Women who have a positive pregnancy test during the screening visit or who are breastfeeding.
- •Has a history of any of the following (reported by subjects):
- •Acute disseminated encephalomyelitis (ADEM);
- •Neoplastic disease - current or previous;
- •Asthma or severe allergic disease;
- •Bleeding disorders
- •Chronic Hepatitis B and/or C infection;
- •Chronic liver disease;
- •Diabetes mellitus;
- •Guillain-Barré syndrome;
- •Rheumatoid arthritis or other autoimmune diseases;
- •Severe renal disease;
- •Transplant recipients;
- •Unstable or progressive neurological disorders.
- •Receipt of medicines/treatments that may affect evaluation of immunogenicity such as:
- •Oral or parenteral steroids, high-dose inhaled steroids (greater than 800 micrograms/day of beclomethasone dipropionate or equivalent) or other immunosuppressive or cytotoxic drugs (azathioprine (Imuran), cyclosporine (Neoral, Sandimmune, SangCya); monoclonal antibodies such as basiliximab (Simulect), daclizumab (Zinbryta), infliximab (Remicade), rituximab (MabThera), alemtuzumab (Campath and Lemtrada), omalizumab (Xolair), abatacept (Orencia), adalimumab (Humira and Exemptia) and etanercept (Enbrel)basiliximab (Simulect), daclizumab (Zenapax), and muromonab (Orthoclone OKT3); corticosteroids such as prednisone (Deltasone, Orasone); tacrolimus (Prograf, Advagraf, Protopic); Glatiramer acetate (Copaxone); Mycopehnolate (Cellcept); Sirolimus (Rapamune); (within 6 months of vaccination in this study)
- •Immunoglobulin or other blood products (plasma, blood cells, coagulation factors, haemoglobin)(within 3 months of vaccination in this study);
- •An experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month of vaccination in this study, or expects to receive an experimental agent (during the study period).
- •Influenza antiviral medication (Amantadine (Symmetrel); Rimantadine (Flumadine); Zanamivir (Relenza), Oseltamivir (Tamiflu) (within 4 weeks of vaccination in this study).
- •Has received any influenza vaccine within 6 months of vaccination in this study.
- •Has influenza-like illness (a sudden onset of symptoms and at least one of the four systemic symptoms-fever or feverishness, malaise, headache, myalgia and at least one of the three respiratory symptoms-cough, sore throat, shortness of breath) or acute respiratory infection (a sudden onset of symptoms and at least one of the four respiratory symptoms-cough, sore throat, shortness of breath, coryza (Rhinitis) and a clinician's judgement that the illness is due to an infection) within 6 months prior to vaccination in this study. These symptoms must have stopped the subject from carrying out their normal daily activities such as attending work or school for a period of at least 3 days.
- •Has an acute illness, including an oral temperature greater than 38 degrees Celsius, within 1 week of vaccination.
- •Has a history of alcohol or drug abuse within the last 2 years deemed unsuitable for inclusion by the investigator.
- •Any abnormal haematology values and/or serum chemistries judged by the Investigator as clinically significant.
结局指标
主要结局
IFN-gamma Responses Measured by ELISA
时间窗: day 0 to day 42, day 0 to day 180
Median fold change in IFN-gamma secretion from PBMCs stimulated in vitro with FLU-v antigens. IFN-gamma secretion was measured by ELISA.Fold change was measured as secretion on day 42 divided by secretion on day 0, and secretion on day 180 divided by secretion on day 0.
Percentage of Responders on Day 42 and Day 180 for IFNgamma Secretion by PBMCs
时间窗: prevaccination (day 0) to postvaccination (day 42 and day 180)
Responders were defined as subjects having at least a two-fold increase in the amount of IFNg secreted on day 42 and day 180 compared the amount secreted on day 0. IFNg was measured by ELISA
CD4+ and CD8+ Th1 Cellular Immunogenicity on Day 42
时间窗: day 0 to day 42
Comparison of the TH1 response in the treatment arms compared to placebo from baseline to day 42 following vaccination, calculated as the median fold change in the number of CD4+ and CD8+ T cells positive for IFN-gamma, TNF-alpha, IL-2 and CD107a. Fold change is calculated as the number of cells on day 42 divided by number of cells on day 0.
CD4+ and CD8+ Th1 Cellular Immunogenicity on Day 180
时间窗: Day 0 to day 180
Comparison of the TH1 response in the treatment arms compared to placebo from baseline to day 180 following vaccination, calculated as the median fold change in the number of CD4+ and CD8+ T cells positive for IFN-gamma, TNF-alpha, IL-2 and CD107a. Fold change is calculated as the number of cells on day 180 divided by number of cells on day 0.
Percentage of TH1 Cytokine Responders (Responders Defined as Those With >2 Fold Median Increase From Baseline in CD4+ and CD8+ T-cells Positive for Particular Cytokine)
时间窗: prevaccination, day 42 (21 days after last vaccination) and day 180.
To compare the number of subjects that showed at least a two-fold increase on day 42 and day 180 following vaccination in the number of CD4+and CD8+ T-cells secreting TH1 cytokines in all groups.
Percentage of CD4+ and CD8+ TH1 Cytokine Responders Determined by Mixture Models for Single-cell Assays (MIMOSA)
时间窗: day 0 to day 42 and day 180
To compare the number of subjects identified as responders for cytokine markers as determined by MIMOSA analysis (Responders based on a false discovery rate derived P-value \<0.05).
Solicited AEs
时间窗: until 21 days after the last dosing of the study vaccine
To evaluate the solicited AEs in all subjects
次要结局
- Antibody Responses to FLU-v(prevaccination, day 42 (21 days after last vaccination) and day 180.)
- Th2 Cytokine Responses (IL-4)(prevaccination, day 42 (21 days after last vaccination) and day 180.)