Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 2, Randomized, Observer-blind, Controlled, Single Center Study to Evaluate the Safety and Immunogenicity of Three Formulations of the Novartis Vaccines Institute for Global Health (NVGH) Glycoconjugate Vaccine Against S. Typhi in Adult Subjects 18 to 40 Years of Age
Brief Summary: This trial is aimed to evaluate the safety and immunogenicity profiles of three formulations of Vi-CRM197 conjugate vaccine against S. Typhi in healthy human adults in comparison with the currently licensed Vi polysaccharide vaccine


Options:
A: Inclusion Criteria:

1. Males and females of age ≥18 to ≤40 years.
2. Individuals who, after the nature of the study have been explained to them, have given written consent according to local regulatory requirements.
3. Individuals in good health as determined by the outcome of medical history, physical examination and clinical judgment of the investigator.
4. Individuals with negative urine screening tests for drug addition (Opiate, Cocaine, Amph/Metamphetamine, Cannabinoides )
5. If women, use of birth control one month before study start, a negative pregnancy test and willingness to use birth control measures for the entire study duration.

Exclusion Criteria:

1. Individuals with 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.
2. Individuals with any progressive or severe neurological disorder, seizure disorder or Guillain-Barré syndrome.
3. Individuals who are not able to understand and to follow all required study procedures for the whole period of the study.
4. Individuals with history of any illness that, in the opinion of the investigator, might interfere with the results of the study or pose additional risk to the subjects due to participation in the study.
5. Individuals with known or suspected HIV infection or HIV related disease, with history of an autoimmune disorder or any other known or suspected impairment /alteration of the immune system, or under immunosuppressive therapy including use of systemic corticosteroids or chronic use of inhaled high-potency corticosteroids within the previous 30 days, or were in chemotherapy treatment within the past 6 months.
6. Individuals with a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time.
7. Individuals with any serious chronic or progressive disease according to judgment of the investigator (e.g., neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease).
8. Individuals who have any malignancy or lymphoproliferative disorder.
9. Individuals with history of allergy to vaccine components.
10. Individuals participating in any clinical trial with another investigational product 30 days prior to first study visit or intent to participate in another clinical study at any time during the conduct of this study.
11. Individuals who have previously received any vaccines against typhoid fever (either oral live attenuated or injectable vaccines).
12. Individuals who received any other vaccines within 4 weeks prior to enrolment in this study or who are planning to receive any vaccine within 4 weeks from the study vaccine.
13. Individuals who have received blood, blood products and/or plasma derivatives including parenteral immunoglobulin preparations in the past 12 weeks.
14. Individuals who are part of study personnel or close family members to the personnel conducting this study.
15. Individuals with body temperature \> 38.0 degrees Celsius within 3 days of intended study immunization.
16. BMI \> 35 kg/m2.
17. Individuals with history of substance or alcohol abuse within the past 2 years.
18. Women who are pregnant or breast-feeding or of childbearing age who have not used any birth control measure one month prior to study start or do not plan to use acceptable birth control measures, for the duration of the study.
19. Females with history of stillbirth, neonatal loss, or previous infant with anomaly.
20. Individuals who have a previously ascertained or suspected disease caused by S. Typhi.
21. Individuals who have had household contact with/and or intimate exposure to an individual with laboratory confirmed S. Typhi.
22. Any condition which, in the opinion of the investigator may interfere with the evaluation of the study objectives.
B: Inclusion Criteria:

1. Males and females of age ≥18 to ≤40 years.
2. Individuals who, after the nature of the study has been explained to them, have given written consent according to local regulatory requirements.
3. Individuals in good health as determined by the outcome of medical history, physical examination, hematological / hematochemical blood tests and urinalysis and clinical judgment of the investigator.
4. If women, a negative pregnancy test and willingness to use birth control measures for the entire study duration

Exclusion Criteria:

1. Individuals with 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.
2. Individuals with any progressive or severe neurological disorder, seizure disorder or Guillain-Barré syndrome.
3. Individuals who are not able to understand and to follow all required study procedures for the whole period of the study.
4. Individuals with history of any illness that, in the opinion of the investigator, might interfere with the results of the study or pose additional risk to the subjects due to participation in the study.
5. Individuals with known or suspected HIV infection or HIV related disease, with history of an autoimmune disorder or any other known or suspected impairment /alteration of the immune system, or under immunosuppressive therapy including use of systemic corticosteroids or chronic use of inhaled high-potency corticosteroids within the previous 30 days, or were in chemotherapy treatment within the past 6 months.
6. Individuals with a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time.
7. Individuals with any serious chronic or progressive disease according to judgment of the investigator.
8. Individuals who have any malignancy or lymphoproliferative disorder.
9. Individuals with history of allergy to vaccine components.
10. Individuals participating in any clinical trial with another investigational product 30 days prior to first study visit or intent to participate in another clinical study at any time during the conduct of this study.
11. Individuals who have previously received any vaccines against typhoid fever.
12. Individuals who received any other vaccines within 4 weeks prior to enrollment in this study or who are planning to receive any vaccine within 4 weeks from the study vaccine.
13. Individuals who have received blood, blood products and/or plasma derivatives including parenteral immunoglobulin preparations in the past 12 weeks.
14. Individuals with body temperature \> 38.0 degrees Celsius within 3 days of intended study immunization.
15. BMI \> 35 kg/m2.
16. Individuals with history of substance or alcohol abuse within the past 2 years.
17. Women who are pregnant or breast-feeding or of childbearing age who have not used or do not plan to use acceptable birth control measures, for the duration of the study.
18. Females with history of stillbirth, neonatal loss, or previous infant with anomaly.
19. Individuals who have a previously ascertained or suspected disease caused by S. Typhi.
20. Individuals who have had household contact with/and or intimate exposure to an individual with laboratory confirmed S. Typhi.
C: Inclusion criteria:

* Male or female aged 18 - 60 years inclusive and in good health.
* Have an abdominal ultrasound scan result documented demonstrating no evidence of gallbladder pathology.
* Willing to allow their general practitioner and/or hospital consultant (if relevant) and the Health Protection Unit to be notified of participation in the study.
* Agree to refrain from blood donation in the future if diagnosed with typhoid fever.
* Be willing to have 24-hour contact with study staff during the four weeks post-challenge.

Exclusion Criteria:

* Have previously received any typhoid vaccine, been resident in a typhoid endemic country for over 6 months, been diagnosed with probable or confirmed typhoid infection or been challenged with Salmonella Typhi or enrolled in a typhoid challenge study.
* Have any known or suspected impairment or alteration of immune function.
* History of significant cardiovascular disease.
* 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.
* 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.
* History of significant infectious disease.
* History of non-benign cancer.
* Presence of any implants or prostheses.
* 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 partner 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.
* 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.
* Scheduled elective surgery or other procedures requiring general anaesthesia during the vaccine/challenge period, at time of enrolment.
* Participants who have taken part in other research involving an investigational product (IMP) 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
* 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.
D: Inclusion Criteria:

Participants must satisfy all of the following criteria to be considered eligible for the study:

* Agree to give informed consent for participation in the study.
* Aged between 18 and 60 years inclusive at time of vaccination.
* In good health as determined by medical history, physical examination and clinical judgment of the study team.
* Agree (in the study team's opinion) to comply with all study requirements, including capacity to adhere to good personal hygiene and infection control precautions.
* Agree to allow his or her General Practitioner (and/or Consultant if appropriate), to be notified of participation in the study.
* Agree to allow study staff to contact his or her GP to access the participant's vaccination records.
* Agree to allow Public Health England to be informed of their participation in the study.
* Agree to give his or her close contacts written information informing them of the participant's involvement in the study and offer them voluntary screening for S. Typhi carriage.
* Agree to have 24-hour contact with study staff during the four weeks post challenge and are able to ensure that they are contactable by mobile phone for the duration of the challenge period until antibiotic completion.
* Have internet access to allow completion of the e-diary and real-time safety monitoring.
* Agree to avoid antipyretic/anti-inflammatory treatment from the time of challenge (Day 0) until advised by a study doctor or until 14 days after challenge.
* Agree to provide their National Insurance/Passport number for the purposes of TOPS registration and for payment of reimbursement expenses.

Exclusion Criteria:

The participant will not be enrolled if any of the following apply:

* History of significant organ/system disease that could interfere with trial conduct or completion. Including, for example, but not restricted to: Cardiovascular, respiratory, haematological, endocrine, Renal/bladder, biliary tract, gastro-intestinal, neurological, metabolic, autoimmune or infectious disease. Or Psychiatric illness requiring hospitalisation or known or suspected drug and/or alcohol misuse
* Have any known or suspected impairment of immune function, alteration of immune function, or prior immune exposure that may alter immune function to typhoid infection
* Moderate or severe depression or anxiety as classified by the Hospital Anxiety and Depression Score at screening or challenge that is deemed clinically significant by the study doctors .
* Weight less than 50kg
* Presence of implants or prosthesis.
* Anyone taking long-term medication that may affect symptom reporting or interpretation of the study results.
* Contraindication to ciprofloxacin or macrolide antibiotics.
* Female participants who are pregnant, lactating or who are unwilling to ensure that they or their partner use effective contraception one month prior to challenge and continue to do so until two negative stool samples, a minimum of 2 weeks after completion of antibiotic treatment, have been obtained.
* Occupations involving:

  * Direct contact with young children attending pre-school groups or nursery or aged under 2 years, or
  * Direct contact with highly susceptible patients or persons in whom typhoid infection would have particularly serious consequences (unless willing to avoid work until demonstrated not to be infected with typhoid in accordance with guidance from Public Health England)
* Occupations involving commercial food handling
* Close household contact with:

  * Young children (defined as those attending pre-school groups, nursery or those aged less than 2 years)
  * Immunocompromised individuals
* Scheduled elective surgery or other procedures requiring general anaesthesia during the study period.
* Participants who have participated in another research study involving an investigational product within the 30 days prior to enrolment
* Detection of any abnormal results from screening investigations (at the clinical discretion of the study team).
* Inability to comply with any of the study requirements
* Any other social, psychological or health issues which, in the opinion of the study staff, may

  * Put the participant or their contacts at risk because of participation in the study,
  * Adversely affect the interpretation of the primary endpoint data,
  * Impair the participant's ability to participate in the study.
* Having previously received any typhoid vaccine
* Having been resident in an enteric fever endemic country for 6 months or more.
* Have previously been diagnosed with laboratory-confirmed typhoid or paratyphoid infection or been given a diagnosis compatible with enteric fever.
* Have participated in previous typhoid or paratyphoid challenge studies
* Have received vaccination with tetanus toxoid containing vaccine within the past 12 months.
* Have any history of allergy to vaccine components
* Have a prolonged corrected QT interval (\>450 milliseconds) on ECG screening

Answer: A