| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prophylaxis for Salmonella enterica serovar Typhi (S. Typhi) disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| vaccination to protect against typhoid fever |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039446 |
| E.1.2 | Term | Salmonella typhi infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Using an established model of human typhoid infection, where healthy adults are deliberately infected with typhoid-causing bacteria, we will determine how effective a new typhoid vaccine (Vi-CRM197, Novartis Vaccine Institute for Global Health) is in preventing infection. |
|
| E.2.2 | Secondary objectives of the trial |
| 1) To describe the clinical and laboratory features of the response to typhoid infection in participants who have previously been vaccinated with Vi-CRM197 vaccine or Vi-PS (Typherix)vaccine. These features will include the course of the illness, the point at which participants may develop typhoid bloodstream infection, excretion of bacteria in stool, and the level of inflammation produced in response to infection. 2) To describe the response of the immune systems to vaccination and typhoid infection in participants who have previously been vaccinated with Vi-CRM197 vaccine or Vi-PS (Typherix)vaccine. 3)To assess the safety and side effects of the novel vaccine (Vi-CRM197) and the licensed vaccine Vi-PS (Typherix). 4) To develop new methods for diagnosing typhoid infection 5) To explore how the genetic response (which protein encoding genes within the participants DNA are switched on and off) to vaccination in both groups varies. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion 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 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 proximity to Oxford for 14 days after challenge or until well on antibiotic treatment, at the discretion of the lead study doctor, nurse or chief investigator. • 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 or occupational health department 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 S Typhi carriage. • Agree to refrain from blood donation (to the National Blood Service) indefinitely 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, and to keep a 24-hour contact informed of their whereabouts. |
|
| E.4 | Principal exclusion criteria |
| 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 S. Typhi or enrolled in a typhoid challenge study. • Have received vaccination with a vaccine containing either CRM197 or diphtheria toxoid within the past 12 months • Have had previous confirmed infection due to C. diphtheriae in the past 5 years • Have any known or suspected impairment or alteration of immune function, resulting from, for example: Congenital or acquired immunodeficiency (including IgA deficiency); Receipt of immunosuppressive treatment/therapy such as chemo- or radiotherapy within the preceding 6 months or long-term systemic corticosteroid therapy; 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 • History of significant endocrine disorder • History of significant renal or bladder disease • History of biliary tract disease • 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 • History of significant metabolic disease • History of significant haematological diagnosis • History of psychiatric illness requiring hospitalisation, current known or suspected drug or alcohol misuse • 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 normalised • History of significant infectious disease (e.g., previous or current schistosomiasis infection, history of positive syphilis serology (determined by non-treponemal test)) • 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 • Known hypersensitivity to any component of the vaccine or hypersensitivity to ciprofloxacin (or other fluoroquinolone antibiotics) or azithromycin (or other macrolides). Hypersensitivity to other antibiotics will be reviewed on a case by case basis • Female participant who is pregnant, lactating or who is unwilling to ensure that they or their partner use effective contraception 28 days prior to vaccination and continue to do so until two negative stool samples obtained a week apart, a minimum of 3 weeks after completion of antibiotic treatment have been obtained • Current occupation or educational studies 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 • 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 anaesthesia during the study period • Participants who have taken part in other research involving an investigational medicinal product (IMP) that might affect risk of typhoid infection or compromise the integrity of the study within the 30 days prior to enrolment • Have received blood, blood products and/or plasma derivatives including parenteral immunoglobulin preparations in the previous 3 months |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of participants developing typhoid fever after challenge with S. Typhi (Quailes strain) given 28 days after vaccination with NVGH Vi-CRM197 vaccine. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| For the purposes of analysing data relating to the primary endpoint and for notification of cases to the Health Protection Unit, typhoid infection will be defined as: • A positive blood culture for S. Typhi collected from Day 7 post-challenge OR, • A positive blood culture for S. Typhi collected before Day 7 post-challenge with objective signs/symptoms of typhoid infection (such as a recorded temperature ≥38 C) OR, • Oral temperature ≥38 C, persisting continuously for at least 12-hours in the absence of anti-pyretic medication, occurring from 72-hours after challenge. |
|
| E.5.2 | Secondary end point(s) |
| After vaccination - Immunological 1) The geometric mean serum IgG, IgM, and IgA antibody concentrations to the Vi antigen at vaccination (day -28) and challenge(day 0), and to Citrobacter sp. Vi antigen at vaccination and challenge 2) Mean fold rise in IgG, IgM and IgA antibody concentrations to the Vi antigen from vaccination to day -21(visit Va) and day -14(visit Vb) 3) Proportion of participants demonstrating a 4-fold or greater rise in IgG, IgM and IgA antibody concentrations to Vi antigen between vaccination and day 0 (challenge) (i.e. 28 days after completion of vaccine course) and subsequent timepoints 4) Geometric mean S. Typhi specific serum bactericidal antibody (SBA) titres at days -28, -21 (Va), -14 (Vb) and 0 5) Geometric mean faecal IgG and IgA antibody concentrations to Vi antigen at vaccination and challenge 6) Geometric mean salivary IgA antibody levels at vaccination and challenge - Inflammatory mediators and genomics 7) The mean serum concentration of pro-inflammatory cytokines (including, but not limited to IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, TNF-α and IFN-γ) at day -28 (vaccination), 6 hours (V0+6h) and 24 hours (day -27) post-vaccination, and days -21, -14 and day 0 (challenge) 8) The relative abundance of gene expression (measured by gene expression microarrays and/or mRNA-sep technologies) at day -28, 6 hours (V0+6h) and 24 hours (day -27) post-vaccination, days -21,-14 and 0 - Clinical monitoring of vaccine safety Within seven days post-vaccination severity of Malaise; Fatigue; Myalgia; Arthralgia; Itching; Rash; Nausea; Headache; Fever (oral temperature ≥38˚C); Local reactogenicity; specifically pain, erythema, swelling and induration will be graded as none, mild, moderate or severe. After challenge - Clinical response to challenge After challenge, until completion of the antibiotic course, severity of Malaise; Headache; Myalgia; Arthralgia; Anorexia/ Loss of appetite; Nausea; Abdominal pain; Cough; Fever (oral temperature ≥ 38˚C); Rash will graded as none, mild, moderate or severe. Median time from challenge to clinical diagnosis of typhoid fever (oral temperature ≥380C for ≥12 hours, not development of bacteraemia) will also be recorded. - Microbiology 1) Individual and median time to Salmonella Typhi bacteraemia (by blood culture) 2) The number and proportion of volunteers developing S. Typhi bacteraemia, detected by positive blood culture in each group 3) The number and proportion of volunteers developing S. Typhi bacteraemia, detected by PCR, measured from days 0-14 4) The number and proportion of volunteers developing primary S. Typhi bacteraemia, detected by positive blood culture or PCR, within 4 days of challenge in each group 5) Mean number of S. Typhi CFU in blood at diagnosis (hour 0) of typhoid fever 6) The number and proportion of volunteers with the presence of S. Typhi detectable in stool pre-challenge and days 1,3,4,5, 7, 10, 14, 21 and 28 post challenge - Immunology 1) The geometric mean serum IgG, IgM, and IgA antibody concentrations to Salmonella Typhi O, H and Vi antigens at days 0 (challenge), 7, 10, 28 and 365, and to Citrobacter sp. Vi antigen at day 180 and 365. 2) Mean fold-rise and proportion of participants achieving a 4-fold or greater rise in IgG, IgM and IgA antibody concentrations to Salmonella Typhi O, H and Vi antigens between day 0 and subsequent time points 3) Geometric mean Vi polysaccharide specific serum bactericidal antibody (SBA)titres at days 0, 7, 10, 28 and 365 - Inflammatory mediators and genomics 1) The mean serum concentration of pro-inflammatory cytokines(including, but not limited to IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, TNF-α and IFN-γ) at days 0, +6hrs, +24hrs, 3, 5, 6, 7, 10, 14, 28, 60, 90, and 365. 2) The relative abundance of gene expression (measured by gene expression microarrays and/or mRNA-sep technologies) at days 0+6hrs, +24hrs, days 3,5,6,7,8, 9, 10, 11, 12, 13, 14 ,28, 60, 90 and 365. For all participants who are diagnosed with typhoid fever: 1) Median time from challenge to clinical diagnosis of typhoid fever (oral temperature ≥38 C for ≥12 hours, not development of bacteraemia) 2) Individual and median time to S. Typhi bacteraemia (by blood culture) 3) Geometric mean S. Typhi specific serum bactericidal antibody (SBA) titres at hours 0, 48 and 96 after diagnosis of typhoid fever 4) C-reactive protein (CRP) at hours 0, 24, 48 and 96 after diagnosis of typhoid 5) Mean number of S. Typhi CFU in blood at diagnosis (hour 0) of typhoid 6) The geometric mean serum IgG, IgM and IgA antibody concentrations to S. Typhi antigens at hours 48 and 96 after diagnosis of typhoid 7) Measurement of the relative abundance of gene expression (measured by gene expression microarrays and/or mRNA-sep technologies) at diagnosis of typhoid and hours 6,12, 24, 48, 72, and 96 after diagnosis of typhoid fever. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints for the evaluation of the secondary endpoints: - Secondary endpoints after vaccination (timepoints between vaccination and challenge): vaccination (day -28); vaccination+6 hours: vaccination+24 hours (day -27); day -21 (visit Va); day -14 (visit Vb); challenge (day 0) - Secondary endpoints after challenge (timepoints following challenge): 6 hours (V0+6h) and days 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 60, 90, 180, and 365 post challenge Also at diagnosis of typhoid fever and hours 6, 12, 24, 48, 72 and 96 after diagnosis of typhoid fever |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Correlating clinical and immune response to vaccination and challenge |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Historical unvaccinated typhoid-challenged controls |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of trial will be when the last participant sample has been processed. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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