Vaccines Against Salmonella Typhi

NCT02324751 | Completed Phase 2 DMC

• 1 other identifier: OVG 2014/08
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 1

Brief Summary

Using an established model of human typhoid infection, whereby healthy adults are deliberately exposed to typhoid-causing bacteria, the investigators will determine how effective a new typhoid conjugate vaccine (Vi-TCV) is in preventing infection. The new typhoid vaccine will be compared with a control vaccine (meningococcal ACWY). The protective effect of a currently used typhoid polysaccharide vaccine (Vi-PS) will also be studied and compared with the control vaccine using this model of typhoid infection. A second component of this study will involve vaccinating 15-20 participants with Vi-PS. Serum will be obtained prior to vaccination and 4-6 weeks after vaccination. The post-vaccination serum will be pooled and used to create an anti-Vi IgG serum standard.

Conditions

Typhoid Fever; Enteric Fever

Outcome Measures

Primary Outcomes (1)

• Clinically or microbiologically proven typhoid infection

  Clinical (fever \>38 degrees for more than 12 hours) or microbiologically (blood culture positive) proven typhoid infection following oral challenge with Salmonella Typhi.

  Up to 14 days after typhoid challenge dose administration

Secondary Outcomes (5)

• Clinical manifestations of typhoid infection after typhoid challenge as determined by physical examination, participant symptom reporting and microbiological assays

  Clinical signs and solicited symptoms occurring during the 21 day period after challenge; microbiological assays and unsolicited symptoms followed up over the course of one year

• Host immune responses (including Geometric Mean Titres of Salmonella Typhi antigen specific antibodies, antigen specific cell frequencies) at baseline, post-vaccination and post-typhoid challenge time points

  From baseline (pre-vaccination) to final follow up visit at one year

• Laboratory and high-throughput assays to measure gene expression and protein translation at baseline, post-vaccination and post-challenge time points

  From baseline (pre-vaccination) to 28 days after challenge (total duration 2 months)

• Exploratory analysis of blood and faeces samples to investigate novel diagnostic methods for detecting Salmonella Typhi infection

  From time of challenge until time of typhoid diagnosis (maximum time frame of 14 days)

• Assessment of the number of participants reporting solicited local and systemic reactions, and unsolicited adverse events following vaccination with Vi-TCV

  From time of vaccination until 7 days post-vaccination

Other Outcomes (1)

• Producing an anti-Vi IgG serum standard from volunteers vaccinated with Vi-PS (Vi polysaccharide vaccine)

  From time of vaccination until 4-6 weeks post-vaccination

Study Arms (3)

Vi-TCV

EXPERIMENTAL

Single intramuscular injection

Biological: Vi-TCV

Vi-PS Vaccine

ACTIVE COMPARATOR

Single intramuscular injection

Biological: Vi-PS Vaccine

Control (Men ACWY)

OTHER

Single intramuscular injection

Biological: Control (Men ACWY)

Interventions

Vi-TCV BIOLOGICAL

Each 0.5mL vaccine dose contains 25μg of purified Vi capsular polysaccharide (S. Typhi Ty2 strain) conjugated to non-toxic tetanus toxoid. The vaccine will be administered 28 days prior to typhoid challenge

Also known as: Typbar-TCV

Vi-TCV

Vi-PS Vaccine BIOLOGICAL

Each 0.5 mL vaccine dose contains 25 μg of purified Vi capsular polysaccharide (S. Typhi Ty2 strain). The vaccine will be administered 28 days prior to typhoid challenge

Also known as: TYPHIM Vi

Vi-PS Vaccine

Control (Men ACWY) BIOLOGICAL

Each vaccine dose contains N. meningitidis oligosaccharides (10μg MenA oligosaccharide, 5μg of each of MenC, Men Y and MenW-135 oligosaccharides) conjugated to 32.7 μg to 64.1μg Diphtheria CRM197 protein with residual formaldehyde dose less than 0.30μg. The vaccine will be administered 28 days prior to typhoid challenge

Also known as: MENVEO

Control (Men ACWY)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Oxford: lead

Study Sites (1)

Centre for Clinical Vaccinology and Tropical Medicine

Oxford, Oxfordshire, OX3 7LE, United Kingdom

Location

Related Publications (4)

• Zhu H, Chelysheva I, Cross DL, Blackwell L, Jin C, Gibani MM, Jones E, Hill J, Truck J, Kelly DF, Blohmke CJ, Pollard AJ, O'Connor D. Molecular correlates of vaccine-induced protection against typhoid fever. J Clin Invest. 2023 Aug 15;133(16):e169676. doi: 10.1172/JCI169676.

  PMID: 37402153 DERIVED

• Li K, Dodds M, Spreng RL, Abraha M, Huntwork RHC, Dahora LC, Nyanhete T, Dutta S, Wille-Reece U, Jongert E, Ewer KJ, Hill AVS, Jin C, Hill J, Pollard AJ, Munir Alam S, Tomaras GD, Dennison SM. A tool for evaluating heterogeneity in avidity of polyclonal antibodies. Front Immunol. 2023 Feb 16;14:1049673. doi: 10.3389/fimmu.2023.1049673. eCollection 2023.

  PMID: 36875126 DERIVED

• Jin C, Gibani MM, Pennington SH, Liu X, Ardrey A, Aljayyoussi G, Moore M, Angus B, Parry CM, Biagini GA, Feasey NA, Pollard AJ. Treatment responses to Azithromycin and Ciprofloxacin in uncomplicated Salmonella Typhi infection: A comparison of Clinical and Microbiological Data from a Controlled Human Infection Model. PLoS Negl Trop Dis. 2019 Dec 26;13(12):e0007955. doi: 10.1371/journal.pntd.0007955. eCollection 2019 Dec.

  PMID: 31877141 DERIVED

• Jin C, Gibani MM, Moore M, Juel HB, Jones E, Meiring J, Harris V, Gardner J, Nebykova A, Kerridge SA, Hill J, Thomaides-Brears H, Blohmke CJ, Yu LM, Angus B, Pollard AJ. Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet. 2017 Dec 2;390(10111):2472-2480. doi: 10.1016/S0140-6736(17)32149-9. Epub 2017 Sep 28.

  PMID: 28965718 DERIVED

Related Links

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MeSH Terms

Conditions

Typhoid Fever

Interventions

Vi polysaccharide vaccine, typhoid; Meningococcal Vaccines

Condition Hierarchy (Ancestors)

Salmonella Infections; Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures

Study Officials

• Andrew J Pollard, FRCPCH, PhD

  Oxford Vaccine Group, The University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 2, 2014
• First Posted: December 24, 2014
• Study Start: September 1, 2015
• Primary Completion: December 2, 2017
• Study Completion: June 27, 2022
• Last Updated: July 5, 2022

Record last verified: 2018-02

Locations

GB (1)