Phase 1-2, Randomized, Multi-Center, Double-Blind, Placebo-Controlled, Safety, Immunogenicity, and Efficacy Study in Healthy Adults of Intramuscular Norovirus Bivalent Virus-like Particle Vaccine in Experimental Human Norovirus GII.4 Disease
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 132
- 试验地点
- 10
- 主要终点
- Percentage of Participants Experiencing Solicited Local Adverse Events Within 7 Days Post-Dose 1
研究概览
简要总结
The purpose of this study is to determine whether the norovirus vaccine is effective in preventing acute gastroenteritis due to the experimental human Norovirus GII.4 challenge dose. The purpose is also to evaluate the safety of the vaccine and the immunogenicity of the vaccine.
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 49 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •To be eligible to participate in this study, a subject must meet the following criteria:
- •Signed informed consent.
- •Age 18 to 50 years (e.g., not reached their 50th birthday).
- •Good general health as determined by a screening evaluation within 45 days of randomization.
- •Expressed interest, availability, and understanding to fulfill the study requirements including measures to prevent Norovirus contamination of the environment and spread of infection and illness to the community. The prospective subjects must pass (≥70 % correct answers) a written examination on all aspects of the study before enrollment.
- •Available to return for follow-up visits following discharge from the inpatient unit and able to deliver stool specimens to the investigative site promptly with no plan to move within the duration of the study.
- •Female subjects must be of non-childbearing potential, or if of childbearing potential (as determined by the investigator) must be practicing abstinence or using an effective licensed method of birth control (e.g. oral contraceptives; diaphragm or condom in combination with contraceptive jelly, cream, or foam; intrauterine contraceptive device, or Depo-Provera; skin patch; vaginal ring or cervical cap) for 30 days prior to vaccination and must agree to continue such precautions during the study and for 60 days after the Challenge visit. Male subjects must agree not to father a child from the day of vaccination until 60 days after the Challenge visit.
- •Have a serum antibody titer of ≤1:1600 to the GII.4 Norovirus challenge strain as measured by Immunoglobulin G (IgG) P Particle Enzyme-Linked Immunosorbent Assay (ELISA.)
- •Demonstrated to be H Type 1 secretor positive by Histoblood Group Antigen (HBGA) binding assay of their saliva test. [This saliva test may be done at anytime prior to enrollment and does not need to be repeated.]
- •Negative serology for hepatitis C antibody, Human Immune Deficiency Virus (HIV) antibody, hepatitis B surface antigen, and Rapid Plasma Reagin (RPR).
- •Agrees not to participate in another clinical trial with an investigational product for the duration of the study (12 months after the last dose of study vaccine or placebo i.e. 393 days).
排除标准
- •To be eligible to participate in this study, a subject must NOT meet any of the following criteria:
- •Living with or having daily contact with children age 5 years or less or a woman known to be pregnant. This includes significant contact at home, school, day-care, or equivalent facilities.
- •Nursing mother.
- •Living with or having daily contact with childcare workers.
- •Living with or having daily contact with elderly persons aged 70 years or more, or infirmed, diapered individuals, persons with disabilities or incontinent persons. This includes work or visits to nursing homes and day-care or equivalent facilities.
- •History of any gastroenteritis suggestive of Norovirus illness since screening serum antibody IgG P Particle ELISA testing was done.
- •History of any gastroenteritis within the past 2 weeks.
- •History of chronic functional dyspepsia, chronic gastroesophageal reflux disease, peptic ulcer disease, gastrointestinal hemorrhage, gall bladder disease, inflammatory bowel disease, irritable bowel syndrome, frequent diarrhea, chronic constipation, malabsorption, maldigestion, major Gastrointestinal (GI) surgery, or diverticulitis anytime during the subject's lifetime or any other chronic GI disorders that would interfere with interpretation of symptoms or evaluation during the study.
- •Routine use of medication other than oral contraceptive agents, anti-hypertensives, anti-depressants, vitamins and minerals. The use of any other medications should be discussed with the Sponsor and/or Central Safety Monitor (CSM).
- •History of any of the following medical illnesses:
- •Immunosuppression (disease or treatments that may affect immune system function)
- •Diabetes (including gestational diabetes during the pregnancy that required treatment other than dietary).
- •Cancer (malignancy other than a resolved or excised skin lesion).
- •Heart disease (hospitalization for a heart attack, arrhythmia, or syncope)
- •Unconsciousness (other than a single brief "concussion")
- •Seizures (other than febrile seizures as a child <5 years old)
- •Asthma requiring treatment with inhaler or medication in the past 2 years.
- •Neuro-inflammatory disease
- •Autoimmune disease
- •Eating disorder
- •Chronic headaches associated with vomiting
- •Chronic vomiting syndrome
- •Any current illness requiring daily medication other than vitamins, minerals, birth control, anti-hypertensives or anti-depressants. The use of any other medications should be discussed with the Sponsor and/or CSM.
- •Allergies or hypersensitivity to any component of the vaccine or challenge virus.
- •Any clinically significant abnormality detected on physical examination, including:
- •Murmur (other than a functional, ie normal, murmur)
- •Focal neurological abnormality
- •Hepatosplenomegaly
- •Lymphadenopathy
- •Hypertension defined as BP > 150/90 mm Hg on two separate measurements. Chronic stable well-controlled hypertension on medications is allowed.
- •History of 3 or more hospitalizations for invasive bacterial infections (pneumonia, meningitis), acute or chronic dermatitis (e.g. eczema, seborrhea, psoriasis) or collagen vascular disease (e.g. Systemic Lupus Erythematosus (SLE) or dermatomyositis).
- •Presence of serious chronic illness.
- •Positive stool/fecal culture for bacterial pathogens (salmonella, campylobacter, E. coli 0157:H7, yersinia, or shigella) or positive stool/fecal screen for ova and parasites.
- •Employment in the food service industry, such as restaurants or cafeteria facilities. Specifically, this will include persons whose employment requires food processing in the 4 weeks following challenge.
- •Health-care workers with patient contact expected in the 4 weeks following challenge.
- •Expected contact (through employment or at home) with immunocompromised persons (HIV-positive, receiving immunosuppressive medications such as oral steroids or anti-neoplastic agents) in the 4 weeks following challenge.
- •Employment as an airline flight attendant scheduled to work in the 4 weeks following challenge.
- •Persons planning on taking a cruise in the 4 weeks following challenge.
- •Persons who plan to be living in a confined environment (e.g. ship, camp, or dormitory) within 4 weeks following challenge.
- •Persons who have consumed or plan to consume raw shellfish (e.g. oysters) from screening through post challenge Day
- •Any of the following lab abnormalities (per the site local laboratory):
- •Absolute neutrophil count (ANC) outside the normal range
- •Total White Blood Cell Count (WBC) outside the normal range
- •Hemoglobin or hematocrit outside the normal range
- •Platelet count outside the normal range
- •Electrolytes [Sodium (Na), Potassium (K), Chloride (Cl), Carbon dioxide (CO2)], Blood Urea Nitrogen (BUN) and/or creatinine outside the normal range
- •Screening glucose > upper limit of normal (ULN). Fasting glucose is not required
- •Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), alkaline phosphatase, bilirubin (total and indirect), or Gamma Glutamyl Transferase (GGT) outside the upper limit of the normal range
- •Screening urinalysis with a value higher than "trace" positive for urine protein or urine glucose, or urine Red Blood Cells (RBCs) (≥3; other than women during menses).
- •All of the above labs may be repeated if outside the normal limits. If repeated and continue outside site normal ranges, may enroll if determined by the Principal Investigator (PI) to be not clinically significant and discussed with the Sponsor and/or CSM.
- 另有 19 项未显示
研究组 & 干预措施
Placebo
Saline Placebo (0.9% sodium chloride (NaCl) and preservative-free), intramuscular (IM), Days 0 and 28.
干预措施: Saline Comparator (Biological)
Norovirus Bivalent VLP Vaccine
Norovirus Bivalent virus like particle (VLP) Vaccine (50 μg of GI.1 Norwalk VLP and 50 μg of GII.4 cVLP) adjuvanted with MPL and AI(OH)3, intramuscular (IM), Days 0 and 28.
干预措施: Norovirus Bivalent Vaccine (Biological)
结局指标
主要结局
Percentage of Participants Experiencing Solicited Local Adverse Events Within 7 Days Post-Dose 1
时间窗: Within 7 days post-dose 1
Local Adverse Events included local injection site reactions/symptoms: pain, tenderness, redness, and swelling.
Percentage of Participants Experiencing Solicited Systemic Adverse Events Within 7 Days Post-Dose 2
时间窗: Within 7 days post-dose 2
Systemic signs or symptoms included: elevated fever, headache, fatigue, muscle aches, chills, joint aches and gastrointestinal symptoms of nausea, vomiting, diarrhea, abdominal cramps/pain.
Percentage of Participants With Viral AGE Clinical Illness and Fecal Virus Excretion Detected by RT-PCR OR 4-Fold Rise In Anti-GII.4 Norovirus P Particle Antibody Titer
时间窗: Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose)
Viral AGE due to Norovirus GII.4 strain during the inpatient stay that meets clinical illness definition 1,2 or 3 and positive for infection as measured by fecal virus excretion detected by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) OR a 4-fold rise in Immunoglobulin G Enzyme-Linked Immunosorbent Assay (IgG ELISA) anti-GII.4 norovirus P particle antibody titer from pre-challenge (Within 2 weeks of Challenge Day 0) to post-challenge (Challenge Day 30). The clinical illness definitions are 1: diarrhea (defined as ≥ 3 loose or liquid stools OR \>400-600 grams of loose or liquid stools produced in any 24-hour period), 2: vomiting (defined as ≥ 2 vomiting episodes in any 24-hour period) or 3. One Vomiting episode plus any loose or liquid stool in any 24-hour period OR one vomiting episode plus at least 2 of the following 5 events: nausea, fever ≥99.7°F orally, abdominal cramps or pains, abdominal gurgling or bloating, or myalgia in any 24-hour period.
Percentage of Participants Experiencing Solicited Local Adverse Events Within 7 Days Post-Dose 2
时间窗: Within 7 days post-dose 2
Local Adverse Events included local injection site reactions/symptoms: pain, tenderness, redness, and swelling.
Percentage of Participants Experiencing Solicited Systemic Adverse Events Within 7 Days Post-Dose 1
时间窗: Within 7 days post-dose 1
Systemic signs or symptoms included: elevated daily oral temperature (fever), headache, fatigue, muscle aches, chills, joint aches and gastrointestinal symptoms of nausea, vomiting, diarrhea, abdominal cramps/pain.
Percentage of Participants With Serious Adverse Events (SAEs) 365 Days Following the Last Study Vaccination
时间窗: 365 Days Following Dose 2 (Up to 393 days)
A SAE was any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
次要结局
- Percentage of Participants With GII.4 Seroresponse Rate (4-fold Rise) From Pre-challenge Day 0 to Post-Challenge Day 30(Pre Challenge to 30 Days Post Challenge)
- Pan-Ig ELISA - Anti-Norovirus GI.1 VLP Geometric Mean Titer (GMT)(Baseline, 28 days Post Dose 1 and 28 days Post Dose 2)
- Severity of Viral AGE Due to GII.4 Strain Assessed by Modified Vesikari Scoring System During the Inpatient Phase(Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose))
- Severity of Viral AGE Due to GII.4 Strain Assessed by Post-Challenge Symptom Collection During the Inpatient Phase(Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose))
- Pan-Ig ELISA - Anti-Norovirus GII.4 cVLP GMT(Baseline, 28 days post Dose 1 and 28 days post Dose 2)
- ELISA IgA- Anti-Norovirus GII.4 cVLP GMFR From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- Percentage of Participant With ELISA IgA- Anti-Norovirus GII.4 cVLP Seroresponse From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- Percentage of Participants With Unsolicited Non-Serious [i.e Other Than SAEs] Adverse Events (AEs)(Vaccination Stage: Initial vaccination until 28 days after second vaccination; or Challenge Stage: the day of challenge until 60 days after challenge)
- Percentage of Participants With 4-Fold Rise In Serum P-Particle Antibody Titer by ELISA or Detection of Norovirus GII.4 by RT-PCR in the Stool(Pre Challenge to 30 Days Post Challenge)
- Duration of Viral AGE Due to GII.4 Strain During the Inpatient Phase(Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose))
- Pan-Ig ELISA - Anti-Norovirus GI.1 VLP Geometric Mean Fold Rise (GMFR) From Baseline(Baseline to 28 days Post Dose 1 and 28 days Post Dose 2)
- Pan-Ig ELISA - Anti-Norovirus GII.4 cVLP GMFR From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- ELISA Immunoglobulin A (IgA)- Anti-Norovirus GI.1 VLP Geometric Mean Fold Rise (GMFR) From Baseline(Baseline to 28 days Post Dose 1 and 28 days Post Dose 2)
- Percentage of Participants With Pan-Ig ELISA - Anti-Norovirus GI.1 VLP Seroresponse (4-fold Rise) From Baseline(Baseline, 28 days Post Dose 1 and 28 days Post Dose 2)
- Percentage of Participants With ELISA IgA- Anti-Norovirus GI.1 VLP Seroresponse (4-fold Rise) From Baseline(Baseline to 28 days Post Dose 1 and 28 days Post Dose 2)
- HBGA (PGM) - Anti-Norovirus GII.4 cVLP GMFR From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- Percentage of Participants With GII.4 Norovirus Positive RT-PCR in the Stool During the Inpatient and /or Outpatient Phase(Pre Challenge to 30 Days Post Challenge)
- Percentage of Participants With Pan-Ig ELISA - Anti-Norovirus GII.4 cVLP Seroresponse From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- ELISA IgA- Anti-Norovirus GI.1 VLP Geometric Mean Titer (GMT)(Baseline, 28 days Post Dose 1 and 28 days Post Dose 2)
- ELISA IgA- Anti-Norovirus GII.4 cVLP GMT(Baseline, 28 days post Dose 1 and 28 days post Dose 2)
- Percentage of Participants With HBGA (PGM) - Anti-Norovirus GI.1 VLP Seroresponse From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- HBGA (PGM) - Anti-Norovirus GII.4 cVLP GMT(Baseline, 28 days post Dose 1 and 28 days post Dose 2)
- HBGA (PGM) - Anti-Norovirus GI.1 VLP GMFR From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- HBGA (PGM) - Anti-Norovirus GI.1 VLP GMT(Baseline, 28 days post Dose 1 and 28 days post Dose 2)
- Percentage of Participants With HBGA (PGM) - Anti-Norovirus GII.4 cVLP Seroresponse From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)