Efficacy, Safety and Immunogenicity of GVGH Shigella Sonnei Vaccine (1790GAHB) in a Human Challenge Study of Healthy Non-immune Adults
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 71
- 试验地点
- 1
- 主要终点
- Percentage of Subjects With at Least One Episode of Shigellosis According to the Protocol Primary Case Definition
研究概览
简要总结
The purpose of this study is to evaluate the efficacy, safety and immunogenicity of the GSK3536852A vaccine, which was designed to protect against shigellosis caused by Shigella sonnei (S. sonnei) and is using the new Generalized Modules for Membrane Antigens (GMMA) platform technology developed by GlaxoSmithKline (GSK) Vaccines Institute for Global Health (GVGH).
The study vaccine could be the stepping stone for the development of a multivalent broadly protective Shigella vaccine for vaccination of impoverished communities where shigellosis is endemic. However, a standalone monovalent vaccine against S. sonnei could be used to protect travelers against diarrheal shigellosis, as the vast majority of travelers' shigellosis is caused by S. sonnei, and even to protect infants in endemic regions where shigellosis is primarily caused by S. sonnei.
The GSK3536852A vaccine has been tested in two Phase I dose escalation studies in Europe to assess its safety and immunogenicity via three routes of administration: intramuscular (IM), intranasal (IN) and intradermal (ID). The results from the first study (dose escalation with IM vaccination) have shown that the vaccine has an acceptable safety profile and is well-tolerated up to a dose of 100 micrograms (µg). The results from the second study (dose escalation with ID, IN and IM vaccination) showed that GSK3536852A vaccine is well-tolerated also when administered by the ID and IN routes of vaccination. However, immunogenicity data have shown that GSK3536852A vaccine administered by the ID and IN routes is not as immunogenic as GSK3536852A vaccine administered by the IM route. Therefore, it has been decided to proceed with the clinical development program of this vaccine only using the IM vaccination route. In terms of dosage, the regimen tested in Phase I studies (three doses given one month apart) did not show any significant benefit from the third dose in terms of immunogenicity, therefore a two dose schedule was selected for next studies.
A Phase IIa study, conducted in endemic regions of Africa (i.e., Kenya), has been completed and confirmed the acceptable safety profile and immunogenicity of GSK3536852A vaccine.
Performing this vaccine-human challenge study may give the opportunity to establish evidence of clinical protection induced by the candidate S. sonnei vaccine (GSK3536852A vaccine) at an early development stage.
详细描述
The original study protocol has been amended due to requests from the Food and Drug Administration (FDA), requests from the funder of the study, Bill & Melinda Gates Foundation (BMGF), to add an additional interim analysis for immunogenicity data that will accelerate the release of key results to help the planning of other studies, and to further align the protocol to other GSK studies and to the challenge model established at the Cincinnati Children's Hospital Medical Centre.
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)
盲法说明
Observer-blind The subject, the site and sponsor personnel involved in the clinical evaluation of the subjects are blinded while other study personnel may be aware of the treatment assignment.
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
- •Written informed consent obtained from the subject prior to performing any study specific procedure.
- •Individuals who, after the nature of the study has been explained to them, have shown adequate comprehension of the study procedures and knowledge of study.
- •A male or female between, and including, 18 and 50 years of age at the time of the first vaccination.
- •Healthy subjects as established by medical history and clinical examination before entering into the study.
- •Seronegative for human immunodeficiency virus (HIV), hepatitis B and C.
- •Female subjects of non-childbearing potential may be enrolled in the study.
- •Female subjects of childbearing potential may be enrolled in the study, if the subject:
- •Has practiced adequate contraception for 30 days prior to vaccination, and
- •Has a negative pregnancy test on the day of vaccination, and
- •Has agreed to continue adequate contraception during the entire study period.
排除标准
- •Received an investigational or non-registered medicinal product within 30 days prior to informed consent, or planned use during the study period.
- •Any behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the subject's ability to participate in the study.
- •History of any neurological disorders or seizures.
- •Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the subject due to participation in the study.
- •Human Leukocyte Antigen (HLA)-B27 positive test at screening and/or with history of reactive arthritis.
- •Clinical conditions representing a contraindication to intramuscular vaccination and blood draws.
- •Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine/placebo dose. For corticosteroids, this will mean prednisone ≥ 20 milligrams (mg)/day, or equivalent. Inhaled except for doses > 800 µg/day and topical steroids are allowed.
- •Administration of long-acting immune-modifying drugs at any time during the study period. Subjects may be on chronic or as needed medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition.
- •Known bleeding diathesis or any condition that may be associated with a prolonged bleeding time.
- •Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product.
- •History of having participated in a previous Shigella challenge study.
- •Individuals who have a previously laboratory confirmed case of disease caused by S. sonnei or serology positive for local anti S. sonnei LPS IgG Screening-ELISA at screening.
- •History of any serious chronic or progressive disease according to judgment of the investigator.
- •History of any malignancy or lymphoproliferative disorder.
- •Known to be part of study personnel or being a close family member to the personnel conducting this study.
- •History of anaphylactic reaction or allergy to vaccine/placebo or challenge agent components or any other allergies deemed by the investigator to increase the risk of an AE if they were to participate in the study.
- •Known allergy to ciprofloxacin or the other antibiotics used for treatment as deemed by the investigator.
- •Individuals receiving a course of antibiotics within a week of the challenge will be ineligible to receive the challenge strain.
- •History of gastric acid hyper-secretory disorders as assessed and judged by the investigator or any other significant intestinal disorder.
- •Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
- •Family history of congenital or hereditary immunodeficiency.
- •History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine/placebo or challenge agent.
- •Acute disease and/or fever at the time of enrolment.
- •Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests. Chronic medical diagnoses or conditions should be stable for the last 60 days. This includes no change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic medical diagnosis or condition in the 60 days prior to enrolment.
- •A clinically significant sign or symptoms of acute illness, significant anomalies in vital signs.
- •Known to handle food as part of work related activities.
- •Hepatomegaly, right upper quadrant abdominal pain or tenderness.
- •Received immunoglobulins or any blood products within 180 days prior to informed consent or planned administration during the study period.
- •Pregnant or lactating female.
- •Female planning to become pregnant or planning to discontinue contraceptive precautions.
- •Females with history of stillbirth, neonatal loss, or previous infant with anomaly, except those who have had a planned termination of pregnancy, hysterectomy or bilateral tubal ligation.
- •History of chronic alcohol consumption and/or drug abuse. Chronic alcohol consumption is defined as: a prolonged period of frequent, heavy alcohol use; the inability to control drinking once it has begun; physical dependence manifested by withdrawal symptoms when the individual stops using alcohol; tolerance, or the need to use more and more alcohol to achieve the same effects; a variety of social and/or legal problems arising from alcohol use.
- •Known to have close household or professional contacts with people with immunosuppressive condition.
- •Documented HIV, hepatitis B and C positive subject.
- •Any condition which, in the opinion of the investigator, may pose an increased and unreasonable safety risk to the subject if they participated in the study.
- •Subjects with a baseline neutrophil count below 1800 cells per microliter (cells/µL) lower limit of normal range (LLN) OR with clinically significant abnormalities in other laboratory values, according to local reference ranges and investigator judgment.
- •Previous history of Benign Ethnic Neutropenia, or drug related Neutropenia.
- •Concomitant treatment with neutropenic agents.
研究组 & 干预措施
S. sonnei Group
Male or female subjects between, and including, 18 and 50 years of age at the time of the first vaccination, received 2 doses of the S. sonnei study vaccine at Day 1 and Day 29 respectively, by intramuscular injection into the upper deltoid region of the non-dominant arm. At 28 days after the second dose (Day 57), subjects received the challenge dose of S. sonnei 53G strain, orally.
干预措施: S.sonnei vaccine (Biological)
S. sonnei Group
Male or female subjects between, and including, 18 and 50 years of age at the time of the first vaccination, received 2 doses of the S. sonnei study vaccine at Day 1 and Day 29 respectively, by intramuscular injection into the upper deltoid region of the non-dominant arm. At 28 days after the second dose (Day 57), subjects received the challenge dose of S. sonnei 53G strain, orally.
干预措施: S. sonnei 53G challenge strain (Biological)
Placebo Group
Male or female subjects between, and including, 18 and 50 years of age at the time of the first vaccination, received 2 doses of the placebo at Day 1 and Day 29 respectively, by intramuscular injection into the upper deltoid region of the non-dominant arm. At 28 days after the second dose (Day 57), subjects received the challenge dose of S. sonnei 53G strain, orally.
干预措施: Placebo (Drug)
Placebo Group
Male or female subjects between, and including, 18 and 50 years of age at the time of the first vaccination, received 2 doses of the placebo at Day 1 and Day 29 respectively, by intramuscular injection into the upper deltoid region of the non-dominant arm. At 28 days after the second dose (Day 57), subjects received the challenge dose of S. sonnei 53G strain, orally.
干预措施: S. sonnei 53G challenge strain (Biological)
结局指标
主要结局
Percentage of Subjects With at Least One Episode of Shigellosis According to the Protocol Primary Case Definition
时间窗: Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64)
Attack rate of shigellosis expressed as percentage of subjects with at least one episode of shigellosis after challenge, and 90% confidence interval (CI) (Clopper-Pearson method). Episodes of shigellosis fulfilling primary case definition: Shedding of S. sonnei 53G accompanied by moderate or severe diarrhea OR shedding with oral temperature greater than or equal to (≥) 38.5°C. Moderate diarrhea consists of 4 to 5 loose or watery (Grade \[G\]3 to 5) stools or 400 to 800 grams of G3 to 5 stools within 24 hours. Severe diarrhea consists of 6 or more loose or watery (G3 to 5) stools or \> 800 grams of G3 to 5 stools within 24 hours or required medical intervention. In case of severe diarrhea, medical intervention is defined as intravenous fluids administration or anticipation of antibiotic treatment before the 5th day after challenge. G3 = viscous opaque liquid or semi-liquid which assumes the shape of the bowl; G4 = watery opaque liquid; G5 = clear watery or mucoid liquid.
次要结局
- Weight of Grade 3-5 Stools(Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64))
- Number of Subjects With Any Solicited Systemic AEs(During the 7-day period after each vaccination (vaccine/placebo administered at Day 1 and Day 29))
- Percentage of Subjects With at Least One Episode of Shigellosis According to Controlled Human Infection Model (CHIM) Working Group Case Definition for Shigellosis(Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64))
- Percentage of Subjects With at Least One Episode of Shigellosis(Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64))
- Time (Days) From Challenge Administration to Onset of Shigellosis, According to the Primary Case Definition(Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64))
- Number of Subjects With Any Solicited Local Adverse Events (AEs)(During the 7-day period after each vaccination (vaccine/placebo administered at Day 1 and Day 29))
- Number of Subjects With Any Unsolicited AEs During the 28-day Post-vaccination Period(During the 28-day period across doses (vaccine/placebo administered at Day 1 and Day 29))
- Number of Subjects With Any Serious Adverse Events (SAEs) and Related SAEs(From Day 1 up to study end at Day 237)
- Percentage of Subjects With at Least One Episode of More Severe Shigellosis(Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64))
- Percentage of Subjects With Specific Disease Symptoms(Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64))
- Mean Number of Grade 3-5 Stools Per Subject(Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64))
- Number of Subjects With Any Unsolicited AEs During the 28-day Follow-up Period After Challenge(During the 28-day follow-up period after challenge (challenge administered at Day 57))
- Number of Subjects With Change From Baseline in Hematological Laboratory Parameters With Respect to Normal Laboratory Ranges(At Day 8, at Day 36 and at Day 237)
- Anti-S. Sonnei Lipopolysaccharide (LPS) Immunoglobulin G (IgG) Antibody Concentrations at Pre-vaccination and After the First and Second Vaccination(At Day 1 (pre-vaccination), at Day 8 (7 days after the first vaccination), at Day 29 (28 days after the first vaccination), at Day 36 (7 days after the second vaccination) and at Day 56 (27 days after the second vaccination))
- Number of Subjects With Any Adverse Events of Special Interest (AESI) (i.e., Symptomatic Neutropenia)(From Day 1 up to study end at Day 237)
- Anti-S. Sonnei LPS IgG Antibody Concentrations at Pre-challenge and After Challenge(At Day 56 (pre-challenge), at Day 64 (7 days after challenge) and at Day 85 (28 days after challenge))
- Number of Subjects Achieving a Post-vaccination Anti-S. Sonnei LPS Concentration ≥ 268 EU/mL(At Day 29 (28 days after the first vaccination) and at Day 56 (27 days after the second vaccination))
- Number of Seroresponders for Anti-S. Sonnei LPS(At Day 29 (28 days after the first vaccination) and at Day 56 (27 days after the second vaccination))