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Typhoid FeverPhase 2VASTNCT02324751

Vaccines Against Salmonella Typhi

A Phase 2 study testing Vi-TCV and Vi-PS Vaccine in people with Typhoid Fever and Enteric Fever, run by University of Oxford at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 60 yearsHealthy volunteers can take part
Conditions the study is for
Typhoid Fever, Enteric Fever
What is being tested?
Vi-TCV and Vi-PS Vaccine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
112 participants
Where
1 siteUnited Kingdom
Study dates
Sep 2015to 27 Jun 2022
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site

  • Centre for Clinical Vaccinology and Tropical Medicine

    Oxford, Oxfordshire, OX3 7LE

Other trials in United Kingdom

About this study

Official title: A Phase IIb, Observer-blind, Randomised Controlled Trial to Assess the Immunogenicity and Protective Efficacy of Vi Conjugated (Vi-TCV) and Unconjugated (Vi-PS) Polysaccharide Vaccines in Preventing Typhoid Infection Compared to a Control Vaccine (Meningococcal ACWY), Using a Human Challenge Model of Typhoid Infection

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.

Read the detailed description

Typhoid fever is an infection caused by a bacterium, Salmonella Typhi, that only causes disease in humans. It is transmitted faecal-orally and causes more than 22 million infections every year in developing countries, such as areas of Asia, Africa and South America, where access to clean drinking water and sanitation facilities is limited. Although typhoid fever is treatable with effective antibiotics, there are more than 200,000 deaths every year in these resource-limited regions.

Salmonella Typhi could be eradicated but improving sanitation and living conditions in endemic regions is difficult. Vaccination to prevent the transmission of Salmonella Typhi could significantly reduce the burden of disease. The currently licensed typhoid vaccines are only moderately effective in preventing infection in people who have been immunised and no vaccines are licensed for use in young children. Novel typhoid vaccines have been developed to overcome these problems, but more research and information is needed to study how well these vaccines work before they can be routinely used.

This study proposes to investigate the protective effect of a novel typhoid vaccine (typhoid Vi polysaccharide capsule - tetanus toxoid conjugate vaccine) using a human challenge model of typhoid infection. Healthy adults will be vaccinated with the novel typhoid vaccine, a currently used typhoid vaccine (Vi polysaccharide capsule vaccine) or a control vaccine. One month after vaccination, participants will be exposed to live Salmonella Typhi by drinking a solution containing the bacteria. Participants will then be closely monitored to determine which participants develop infection and which are protected. In addition to assessing the protective effect of conjugated and unconjugated typhoid vaccines, the effect the vaccines have on the immune system and on the clinical course of typhoid infection will also be studied.

It is hoped that the knowledge gained from this study will contribute to the use of vaccines against Salmonella Typhi to help control this preventable disease.

Being tested
Vi-TCV, Vi-PS Vaccine, Control (Men ACWY)
Medical subject headings
Typhoid Fever

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Vi-TCVBiological

    Also called Typbar-TCV

    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

  • Vi-PS VaccineBiological

    Also called TYPHIM Vi

    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

  • Control (Men ACWY)Biological

    Also called MENVEO

    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

Study groups in NCT02324751
Study groupRoleWhat they receive
Vi-TCVExperimentalSingle intramuscular injection
Receives: Biological: Vi-TCV
Vi-PS VaccineActive comparatorSingle intramuscular injection
Receives: Biological: Vi-PS Vaccine
Control (Men ACWY)OtherSingle intramuscular injection
Receives: Biological: Control (Men ACWY)

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Up to 14 days after typhoid challenge dose administration

Secondary outcomes (5)

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

    In particular comparing control and typhoid vaccination groups regarding time to onset of symptoms, duration of illness, symptom severity, time to onset of bacteraemia, time to onset of stool shedding, and inflammatory response after typhoid challenge

    Measured: 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

  2. 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

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

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

    To assess variation in genomic response to vaccination with Vi-TCV, Vi-PS and control vaccine and subsequent Salmonella Typhi challenge

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

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

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

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

    Measured: From time of vaccination until 7 days post-vaccination

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Dec 2014 (estimated)
  2. Study startSep 2015
  3. Primary completion2 Dec 2017
  4. Study completion27 Jun 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Participant
Enrolment
112 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02324751
Sponsor's protocol ID
OVG 2014/08
Acronym
VAST
Status last verified
Feb 2018
First submitted
2 Dec 2014
Last updated
5 Jul 2022
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 37402153

  • 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.

    PubMed 36875126

  • 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.

    PubMed 31877141

  • 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.

    PubMed 28965718

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Vi-TCV and Vi-PS Vaccine in people with Typhoid Fever and Enteric Fever, run by University of Oxford at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Clinically or microbiologically proven typhoid infection (time frame: Up to 14 days after typhoid challenge dose administration). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02324751, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Jul 2022.

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