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- Study Description
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- Instructions for requestors
- Data Use Certification (DUC) Agreement
- Talking Glossary of Genetic Terms
Vaccine development against Salmonella enterica serovar Typhi (S. Typhi) requires a better understanding of interaction between human host and the resident microbial consortia in gastrointestinal tract. Healthy adult volunteers received either Ty21a, M01ZH09 or placebo, and underwent challenges with wt S. Typhi. Stool samples were collected at the screening interview (Baseline 1), prior to the first vaccination visit (Baseline 2), during vaccination (Day -28 and -26 for placebo and M01ZH09 groups; Day -32, -30, -28, -26 for Ty21a group), prior to challenge with S. Typhi (Day 0), and after challenge (day 0 12h, day 1, day 3, day 7, and day 10). 16S rRNA and messenger RNA were extracted from stool and sequenced on the Illumina Miseq and HiSeq 2000 platforms, respectively.
- Study Design:
- Prospective Longitudinal Cohort
- Study Type:
- Longitudinal
- Total number of consented subjects: 99
- Subject Sample Telemetry Report (SSTR)
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- Publicly Available Data (Public ftp)
- Study Inclusion/Exclusion Criteria
Participants must satisfy each of the following criteria to be eligible for study inclusion:
- Male or female aged 18 - 60 years inclusive.
- Willing and able to give informed consent for participation after the nature of the study has been explained.
- In good health as determined by: a) Medical history, b) History-directed physical examination, and c) Clinical judgment of the investigators.
- Have an abdominal ultrasound scan result documented demonstrating no evidence of gallbladder pathology or cholelithiasis/gall stones.
- Able and willing (in the opinion of the investigators) to comply with all study requirements, including capacity for good personal hygiene.
- Able and willing to remain in England for 21 days after vaccination.
- Willing to allow their general practitioner and/or hospital consultant (if relevant) to be notified of participation in the study.
- Willing to allow the Health Protection Unit to be informed of participation in the study.
- For those involved in provision of health or social care to vulnerable groups only - willing to allow their employer to be notified of participation in the study.
- Willing to give their close contacts (defined as someone who is likely to have been exposed to the excreta of a challenged participant, usually a household or sexual contact) letters informing them of the participants involvement in the study and offering the contacts screening for Salmonella Typhi carriage.
- Agree to refrain from blood donation (to the National Blood Service) in the future if they are diagnosed with typhoid fever.
- Be willing to have 24-hour contact with study staff during the four weeks post challenge.
The participant may not enter the study if ANY of the following apply:
- Are unwilling or unable to give written informed consent to participate in the study.
- Have previously received any typhoid vaccine.
- Have previously been resident in a typhoid endemic country for >6 months.
- Have previously been diagnosed with probable or confirmed typhoid infection.
- Have previously been challenged with Salmonella Typhi or enrolled in a typhoid challenge study.
- Have any known or suspected impairment or alteration of immune function, resulting from, for example:
- Congenital or acquired immunodeficiency (including IgA deficiency),
- Human Immunodeficiency Virus infection or symptoms/signs suggestive of an HIV-associated condition,
- Autoimmune disease.
- History of significant cardiovascular disease [including congenital heart disease, previous myocardial infarction, valvular heart disease (or history of rheumatic fever), previous bacterial endocarditis, history of cardiac surgery (including pacemaker insertion), personal or family history of cardiomyopathy or sudden adult death].
- History of significant respiratory disease (e.g., uncontrolled asthma, chronic obstructive pulmonary disease).
- History of significant endocrine disorder (e.g., diabetes mellitus, Addison's disease).
- History of significant renal or bladder disease (including history of renal calculi).
- History of biliary tract disease (including biliary colic and/or gallstones, and asymptomatic gallstones detected by ultrasound screening).
- History of significant gastrointestinal disease [including inflammatory bowel disease, abdominal surgery, coeliac disease, liver disease (including hepatitis B or C infection, as determined by detected hepatitis B surface antigen or hepatitis C antibody), or requirement for H2-receptor antagonists, proton pump inhibitors or laxatives].
- History of significant neurological disease (including seizures and myasthenia gravis).
- History of significant metabolic disease (e.g., glucose-6-phosphate dehydrogenase deficiency).
- History of significant haematological diagnosis (including anaemia, bleeding diathesis and sickle cell disease).
- History of psychiatric illness requiring hospitalization, current known or suspected drug or alcohol misuse (defined as an alcohol intake exceeding 42 units per week).
- Moderate or severe depression or anxiety as classified by the Hospital Anxiety and Depression Score at challenge, that is deemed clinical significant by the Chief Investigator or consultant physician. If elevated scores are due to temporary life events, the questionnaire may be repeated after resolution of the event with a view to inclusion if normalized.
- History of significant infectious disease [e.g., previous or current schistosomiasis infection, history of positive syphilis serology (determined by non-treponemal test), stool examination positive for an enteric pathogen at screening].
- History of non-benign cancer (except squamous cell or basal cell carcinoma of the skin and cervical carcinoma in situ).
- Presence of any implants or prostheses (e.g., artificial joints, pacemakers).
- Any clinically significant abnormal finding on biochemistry or haematology blood tests or urine analysis.
- Hypersensitivity to any component of the vaccine or are hypersensitive to two or more of the following antibiotics: ciprofloxacin, azithromycin, ampicillin, trimethoprim sulfamethoxazole.
- Female participant who is pregnant, lactating or who is unwilling to ensure that they or their partners use effective contraception one month prior to vaccination and continue to do so until two negative stool samples obtained a week apart, a minimum of 1 week after completion of antibiotic treatment have been obtained.
- Current occupation involving: clinical or social work with direct contact with young children (defined as those attending pre-school groups, nursery or aged less than 2 years), highly susceptible patients or persons in whom typhoid infection would have particularly serious consequences (i.e. those who are immunocompromised or debilitated), care work involving the elderly. Exemption: those willing not to work from point of vaccination until demonstrated to not be infected with Salmonella Typhi (in accordance with Health Protection Agency guidance).
- Current occupation as a commercial food handler involving the preparation or serving of unwrapped foods not subjected to further heating.
- Household contact with a young child (defined as above).
- Household/close contact who is immunocompromised (due to treatment, e.g., chemotherapy, or illness, e.g., HIV infection).
- Scheduled elective surgery or other procedures requiring general anesthesia during the vaccine/challenge period, at time of enrolment.
- Participants who have taken part in other research involving an investigational product (IMP) that might affect risk of typhoid infection or compromise the integrity of the study within the 30 days prior to enrolment (e.g., significant volumes of blood already taken in previous study), as assessed by both participant questioning and 'The Over Volunteering Prevention System' (TOPS) database.
- Have received blood, blood products and/or plasma derivatives including parenteral immunoglobulin preparations in the previous 3 months
- Any other significant disease or disorder which, in the opinion of the investigator, may put the participants at risk because of participation in the study, may influence the result of the study, or affect the participant's ability to participate in the study.
Temporary exclusion criteria for vaccination visits:
- Fever >37.5°C within 24-hours prior to vaccination.
- Acute gastrointestinal illness within 24-hours prior to vaccination.
- Antibiotic therapy during the 14 days prior to vaccination or plan to take antibiotics in the period of vaccination until 14 days after the last dose of vaccine has been administered.
- Receipt of immunosuppressive treatment/therapy such as chemo- or radiotherapy within the preceding 6 months or long-term systemic corticosteroid therapy, iv, or any systemic corticosteroid (or equivalent) treatment within 14 days prior to challenge, or for more than 7 days consecutively within the previous 3 months.
- Receipt of another live vaccine within 4 weeks prior to vaccination or a killed vaccine within 7 days prior to vaccination
- Plan to receive any vaccine other than the study vaccine within 4 weeks following vaccination.
- Therapy with antacids, proton pump inhibitors or H2-receptor antagonists in the 24- hours prior to vaccination.
- Unavailable for challenge visit at 28 days (+/- 5 days) following vaccination.
- Significant blood donation within the preceding 3 months (e.g., to the National Blood Service).
Temporary exclusion criteria to challenge with S. Typhi (Quailes strain):
- Have experienced significant acute or exacerbation of chronic infection within the previous 7 days or have experienced fever (>37.5°C) within the previous 3 days or on the day of challenge (enrolment).
- History of antibiotic therapy within the previous 14 days.
- Any significant corticosteroid treatment (such as prednisolone or equivalent) within the 14 days prior to challenge, or for more than seven consecutive days within the previous 3 months.
- Therapy with antacids, proton pump inhibitors or H2-receptor antagonists within 24- hours prior to challenge.
- Molecular Data
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Type Source Platform Number of Oligos/SNPs SNP Batch Id Comment 16S rRNA Seqencing Illumina MiSeq N/A N/A Transcriptome Sequencing Illumina HiSeq 2000 N/A N/A - Selected Publications
- Diseases/Traits Related to Study (MeSH terms)
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- Primary Phenotype: Microbiota
- Links to Related Resources
- Authorized Data Access Requests
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See research articles citing use of the data from this study
- Study Attribution
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Principal Investigator
- Marcelo B. Sztein, MD. Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
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Co-Investigator
- Claire M. Fraser. Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.
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Funding Source
- R01 AI-036525. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
- U19 AI-082655. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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Principal Investigator