Clinical Trial Results:
Vaccines Against Salmonella Typhi: a phase IIb, single centre, 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
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Summary
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EudraCT number |
2014-002978-36 |
Trial protocol |
GB |
Global end of trial date |
27 Jun 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Jul 2023
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First version publication date |
12 Jul 2023
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
OVG2014/08
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02324751 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
IRAS: 162909 | ||
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Sponsors
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Sponsor organisation name |
University of Oxford, Research Governance, Ethics & Assurance Team (RGEA)
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Sponsor organisation address |
Boundary Brook House, Oxford, United Kingdom, OX3 7GB
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Public contact |
Andrew Pollard, University of Oxford, +44 1865611400, andrew.pollard@paediatrics.ox.ac.uk
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Scientific contact |
Andrew Pollard, University of Oxford, +44 1865611400, andrew.pollard@paediatrics.ox.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
02 Dec 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Jun 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Primary objective: To determine the relative protective effect of Vi-TCV or Vi-PS compared to control vaccine in a healthy adult typhoid challenge model
Secondary objectives:
i. Compare clinical and laboratory features following S. Typhi challenge in participants vaccinated with Vi-TCV, Vi-PS or control vaccine
ii. Compare the host immune response following vaccination with Vi-TCV, Vi-PS or control vaccine
iii. Compare the host immune response following S. Typhi challenge in Vi-TCV, Vi-PS and control groups
iv. Persistence of immunological markers following vaccination and S. Typhi challenge
v. Genomic response to vaccination with Vi-TCV, Vi-PS and control and subsequent S. Typhi challenge
vi. Novel diagnostic methods for detecting S. Typhi infection
vii. Compare clinical and microbiological data following treatment of typhoid fever with antibiotics
viii. Immunological correlates of protection for S. Typhi infection
ix. Safety and tolerability of Vi-TCV
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Protection of trial subjects |
The trial staff ensured that the participants' anonymity was maintained.
The general risks to the participants were linked to venepuncture, use of the vaccines and challenge with live-causing bacteria. In view of the low infectivity of S.Typhi without gastric suppression and the general level of hygiene and sanitation in the UK, secondary transmission of S.Typhi to household or other close contacts was highly unlikely.
Participants were instructed to complete a Diary Card, recording oral temperatures and describing any symptoms or usage of any medications daily. The diary card was completed from point of first vaccination for 7 days. After 7 days following vaccination, participants were asked to document additional details regarding any visits seeking medical advice (including GP and Emergency Department visits). The e-diary was reviewed by the study team and when participants attended post-vaccination visits.
Participant were issued with a Medic Alert-type card containing information including the antibiotic sensitivity of the S. Typhi strain, study doctor contact details and instruction for the research team to be contacted immediately in the event of illness/accident.
Participants did not have to remain on site between assessments but a rest area was provided which participants could use if they wished.
Participants had access to a study physician 24-hours a day, from the time of vaccination until they were deemed to be clear of S. Typhi infection. Following challenge, participants were encouraged to contact one of the study investigators on the 24-hour emergency telephone number if they developed symptoms of typhoid between regular clinical reviews, or when their temperature exceeded 38C. The investigators considered extra clinical reviews if the participants' symptoms were moderate or severe, or at their request. Severity of symptoms was assessed and if participants were unwell as a result of S. Typhi infection, they were visited in their homes.
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Background therapy |
Four weeks after completion of the immunisation course, participants were challenged with Salmonella Typhi (Quailes strain) at an infective dose (1-5x10^4 CFU) previously demonstrated to give the desired clinical/laboratory attack rate. The S. Typhi (Quailes strain) for inoculation of participants is stored as a frozen suspension in soya tryptone medium containing 10% sucrose. | ||
Evidence for comparator |
Current Licensed Vaccines: The virulence factor (Vi) capsular polysaccharide (Vi-PS) vaccine does not generate immunological memory. Additionally, subsequent vaccinations do not booster its effect on immunity. In common with other polysaccharide vaccines, the Vi-PS vaccine is non-immunogenic in children under 2 years of age and is only moderately efficacious. Its duration of efficacy is also very limited, with protection lasting only 2 to 3 years. As a live attenuated oral vaccine, Ty21a stimulates local mucosal immunity, within the gut, as well as systemic antibody and cell-mediated immune responses. Currently, it is the only licensed oral vaccine for the prevention of typhoid fever. Limitations include the multiple dosages required for full immunogenicity and efficacy to occur (a three dose, alternate day regimen or a four dose schedule). Furthermore, Ty21a is not licensed for use in children below 6 years of age. Similar to the Vi-PS vaccine, the Ty21a vaccine is only moderately efficacious. Currently licensed typhoid vaccines are either not immunogenic in early childhood (parenteral Vi capsular polysaccharide vaccine) or are unsuitable for administration in children younger than 5 years (the oral live attenuated typhoid vaccine Ty21a is unsuitable for use in children younger than 5 years because of its formulation in capsules, which are difficult for young children to swallow). By contrast, typhoid conjugate vaccines, which combine the Vi-polysaccharide capsule with a protein carrier, have improved immunological properties and can be used from early infancy. Vi-TCV is a Vi polysaccharide-conjugate vaccine. Similar to other tetanus toxoid conjugate vaccines used to prevent encapsulated bacterial infections, Vi-TCV induces a T-cell dependent immune response resulting in improved immunogenicity in infants and the potential to produce a durable immune response by inducing immunological memory. | ||
Actual start date of recruitment |
18 Aug 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 112
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Worldwide total number of subjects |
112
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
112
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Healthy adults aged between 18 and 60 years were recruited via several methods including poster, media and website advertising, direct mail-out, email campaign, Oxford Vaccine Centre database and exhibitions. | ||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
For Group A 1486 participants were assessed for eligibility between Aug 18, 2015 and Nov 4, 2016. Of the 207 volunteers who were screened, 73 failed to meet the eligibility criteria and 22 declined further study participation. 112 were enrolled, randomised and vaccinated. | ||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Group A (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||
Blinding implementation details |
Participants were randomised 1:1:1 to receive Vi-TCV, Vi-PS or meningococcal ACWY vaccines.
The randomisation schedule was generated by an independent statistician using a fixed block size of six and stratified according to baseline anti-Vi IgG titre to ensure participants with pre-existing detectable antibodies were equally distributed between vaccine groups. The allocation sequence was implemented using a randomisation system to ensure allocation concealment.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Vi-TCV (IMP) | ||||||||||||||||||||||||||||
Arm description |
Single dose intramuscular vaccine; 28 days pre-challenge | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Vi polysaccharide-tetanus toxoid conjugate vaccine (Vi-TCV)
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Investigational medicinal product code |
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Other name |
Typbar-TCV®, Bharat Biotech
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Each 0.5mL vaccine dose contains 25μg of purified Vi capsular polysaccharide (S. Typhi Ty2 strain) conjugated to non-toxic tetanus toxoid.
The vaccine is supplied in a prefilled syringe containing sodium chloride solution and water for injection.
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Arm title
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Vi-PS | ||||||||||||||||||||||||||||
Arm description |
Single dose intramuscular vaccine; 28 days pre-challenge | ||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Plain Vi capsular polysaccharide vaccine (Vi-PS)
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Investigational medicinal product code |
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Other name |
TYPHIM Vi®, Sanofi Pasteur
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Each 0.5 mL vaccine dose contains 25 μg of purified Vi capsular polysaccharide (S. Typhi Ty2 strain).
The vaccine is supplied in a prefilled syringe containing phosphate buffer and sodium chloride solution and 0.25% phenol preservative.
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Arm title
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Control group | ||||||||||||||||||||||||||||
Arm description |
Single dose intramuscular vaccine; 28 days pre-challenge | ||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Quadrivalent Meningococcal ACWY oligosaccharide Diphtheria CRM197 conjugate vaccine
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Investigational medicinal product code |
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Other name |
MENVEO®, Novartis Vaccines and Diagnostics
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
A single vaccine dose after reconstitution is 0.5 mL.
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 is supplied as a lyophilised MenA conjugate vaccine component to be reconstituted with the accompanying Men CYW-135 liquid conjugate vaccine component.
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Baseline characteristics reporting groups
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Reporting group title |
Vi-TCV (IMP)
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Reporting group description |
Single dose intramuscular vaccine; 28 days pre-challenge | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Vi-PS
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Reporting group description |
Single dose intramuscular vaccine; 28 days pre-challenge | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control group
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Reporting group description |
Single dose intramuscular vaccine; 28 days pre-challenge | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Vi-TCV (IMP)
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Reporting group description |
Single dose intramuscular vaccine; 28 days pre-challenge | ||
Reporting group title |
Vi-PS
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Reporting group description |
Single dose intramuscular vaccine; 28 days pre-challenge | ||
Reporting group title |
Control group
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Reporting group description |
Single dose intramuscular vaccine; 28 days pre-challenge | ||
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End point title |
Typhoid Diagnosis | ||||||||||||||||
End point description |
To determine the relative protective effect of Vi-TCV compared to control vaccine, and the relative protective effect of Vi-PS compared to control vaccine, in a healthy adult typhoid challenge model
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End point type |
Primary
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End point timeframe |
During the 14-day challenge period
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Statistical analysis title |
Vaccine Efficacy Vi TCV (IMP) vs Control group | ||||||||||||||||
Comparison groups |
Vi-TCV (IMP) v Control group
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Number of subjects included in analysis |
68
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0005 | ||||||||||||||||
Method |
Chi-squared | ||||||||||||||||
Parameter type |
Vaccine Efficacy | ||||||||||||||||
Point estimate |
54.6
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
26.8 | ||||||||||||||||
upper limit |
71.8 | ||||||||||||||||
Statistical analysis title |
Vaccine Efficacy Vi PS vs Control group | ||||||||||||||||
Comparison groups |
Vi-PS v Control group
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.001 | ||||||||||||||||
Method |
Chi-squared | ||||||||||||||||
Parameter type |
Vaccine Efficacy | ||||||||||||||||
Point estimate |
52
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
23.2 | ||||||||||||||||
upper limit |
70 | ||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Serious adverse Event were reported during the whole trial.
Solicited symptoms were reported for 7 days following vaccination and for 21 days following challenge.
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Adverse event reporting additional description |
The frequency of solicited adverse events during the 21 days after challenge, according to vaccine group allocation are reported in the following publication:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32149-9/fulltext#supplementaryMaterial
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
Protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
10.0
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Reporting groups
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Reporting group title |
Vi TCV (IMP)
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Reporting group description |
Single dose intramuscular vaccine; 28 days pre-challenge | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Vi PS
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Reporting group description |
Single dose intramuscular vaccine; 28 days pre-challenge | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control group
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Reporting group description |
Single dose intramuscular vaccine; 28 days pre-challenge | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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27 Feb 2015 |
Changes to the Study Protocol:
1. Use of contraception changed for consistency across the protocol (as requested by MHRA)
2. Clarification of safety reporting
3. Amendment to sample collection
4. Amendment to Secondary Objective
5. Amendment to Section 10 – Laboratory
Changes to the Study Information Booklet and the Study Card:
Changes in sample collection.
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17 Jun 2015 |
Changes to the Study Protocol:
1. Administrative amendment to sample collection
2. Administrative amendment to Section 10.8 Other laboratory investigations
3. Substantial amendment to Section 8.5 Randomisation, blinding and code-breaking
4. Substantial amendment to Section 6.2 (Sample collection)
The volume of blood collected at screening has been increased from 11ml to 14ml. The additional 3ml will be used to screen for baseline anti-Vi capsular polysaccharide antibody.
Changes to the Study Information Booklet:
Changes in total blood volume and the time of unblinding.
Changes to the Diary Card Backup:
Administrative amendment to the diary card backup
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09 Oct 2015 |
Changes to the Study Protocol
1. Substantial Amendment for Sample Collection Chart (Table 2 of Section 6.2)
2. Substantial Amendment for Recruitment methods (Section 8.1)
GP Eligibility Letter
Simplification of the letter to the GP and eligibility form
Screening Invitation Text (administrative amendment)
Addition of the following sentence:
“Your Abdominal Ultrasound appointment is on [date at time] in the Radiology Department at the Churchill Hospital. Please do not have anything to eat for 6 hours prior to this appointment. You may drink clear fluids.”
Additional change in the wording of the text to remind participants to bring bank account details for reimbursement purposes.
Participant Invitation Letter (administrative amendment)
Change from “Recruiting 2015” to “Recruiting Now”
Addition of the following:
“We are inviting healthy adults aged 18 to 60 years to take part in this study. We use various ways to contact anyone who may be interested in this study, including via the Electoral Roll or the National Health Applications and Infrastructure Services (NHAIS). As a result of this, you may have previously received this invitation. We apologise for any inconvenience caused.”
“If you are aged 18 to 60 yrs old, in good health and have never previously received a typhoid vaccine, you may be eligible to take part in the study”
D-28 Visit reminder (administrative amendment)
Addition of the following sentence:
“Please remember to bring your signed 24-hour contact letter to this visit.”
Removal of the following sentence:
“We require you to bring a stool sample to the vaccination appointment. The stool specimen collection procedure is attached to this email”
Study Information Booklet, page 13 (administrative amendment)
The total blood volume taken over the 13-month study duration has been changed from 1,398ml to 1,399ml.
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26 Jan 2016 |
Changes to the Study Protocol
The sections of the protocol that have been changed include:
• Synopsis – Addition of tertiary objective
• Section 4.5 (Aim of project) - Explanation of rationale behind creating an anti-Vi IgG serum standard
• Objectives and Endpoints – Addition of tertiary objective
• Section 6.3 (Study Design) – Explanation of Group B participants study timeline and sample collection
• Section 7 (Participants) – Highlighting differences in inclusion/exclusion criteria for Group B participants compared to Group A participants
• Section 8.1-8.8 (Trial procedures) - Explanation of trial procedures for Group B participants
• 10.2 (Laboratory) – Serum processing and manufacture of serum standard
• Section 11 (Safety reporting) – Minor wording changes
• Section 16.6 (Participant Reimbursement) – Inclusion of participant reimbursement for Group B participants
New documentation for submission relating to Group B participants:
1. Group B Informed Consent Form
2. Group B Study Information Booklet
3. Group B GP enrolment letter
4. Group B GP study completion letter
5. Group B Diary Card Backup
New documentation for submission relating to both Group A and Group B participants:
Vaccine Alert Card
This vaccine alert card will be given to participants at the vaccination visit for use in case of medical emergency to notify medical staff that the participant is taking part in a study and has received a vaccine (potentially an investigational vaccine). Group A participants will also receive a Medic Alert Card (previously reviewed and approved by REC) to be used from the time of challenge until completion of antibiotics.
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11 Jul 2016 |
Study Protocol
1. Substantial Amendment to Number of Participants (Section 2, Section 6.1, Section 12.2)
2. Substantial Amendment for Sample Collection (Table 1 and 2 of Section 6.2, Section 7.11)
3. Amendment to S. Typhi clearance stool culture requirements (Section 8.15 and Section 7.8)
4. Amendment to Section 8.5 Group A Randomisation, Blinding and Code Breaking
5. Substantial Amendment to Section 6.2 Group A visit structure
Study Information Booklet
Page 4 – change to the number of participants enrolled in the study from 99 participants to “a minimum of 105 participants”.
Page 5 – addition of the word “approximately” to explain that challenge will occur around one month after vaccination, in keeping with the window period changes described in the protocol.
Page 13 – the total blood volume collected (maximum) has been changed from 1,399ml to 1,324ml.
Page 16 – clarification of payment processing; now stating that payments may take up to 6 weeks to be processed after being requested.
Pages 15 and 17 – clarification of clearance stool requirements for all participants as three negative clearance stool samples collected 48 hours apart one week after completion of antibiotics.
Consent Quiz
Change to question 12. “After completing a course of antibiotics, to ensure you are clear of infection we will: A. Require three stool samples, 48 hours apart”
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08 Sep 2016 |
Changes to the Study Protocol
1. Substantial Amendment To Randomisation Process (Section 8)
2. Substantial Amendment to Statistical Analysis (Section 12)
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24 Nov 2017 |
Changes to the Study Protocol
1. Synopsis – Addition of tertiary objective (ii)
2. Section 4.5 (Aim of project) - Explanation of rationale behind boosting Vi-TCV participants with Vi-PS vaccine to investigate the B cell receptor repertoire
3. Objectives and Endpoints – Addition of tertiary objective (ii)
4. Section 6.4 (Study Design) – Explanation of Group C participants study timeline and sample collection
5. Section 7 (Participants) – Highlighting differences in inclusion/exclusion criteria for Group C participants compared with Group A and B participants. Page 2 of 2
6. Section 7.13 – Updates regarding total blood volume collected. • Section 8.1-8.8 (Trial procedures) - Explanation of trial procedures for Group C participants including recruitment.
7. Section 10.3 (Laboratory) – Serum and PBMC processing and generation of Vi-specific monoclonal antibodies
8. Section 11 (Safety reporting) – Participants in Group C will not complete an eDiary. AEs and SAEs will be collected for participants continuing into Group C up until and including their Day 28 post-vaccination.
9. Section 16.6 (Participant Reimbursement) – Inclusion of participant reimbursement for Group C participants
In addition to the protocol, new documents have been created for Group C participants due to the difference in study involvement from Groups A or B.
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24 May 2018 |
Changes to the Study Protocol
1. Synopsis – Group C sample size changed to 10-15
2. Section 6.1 (Summary of the study design) – sample size changed to 10-15, deletion of the exclusion criteria (re: taken part in two challenge studies)
3. Section 7.7 (Group C – Exclusion criteria) – deletion of the exclusion criteria (re: taken part in two challenge studies)
4. Section 16.6 (Participant reimbursement) – Group C participants will be reimbursed at the end of their study participation. Wording changed to reflect information in SIB
In addition, the Participant Invitation Letter, Participant Email Invitation Text, and SIB-ICF have been changed to reflect these adjustments.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Full report of the primary, the secondary end point and the safety reporting are included in the publications. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/28965718 http://www.ncbi.nlm.nih.gov/pubmed/34203328 http://www.ncbi.nlm.nih.gov/pubmed/33424833 http://www.ncbi.nlm.nih.gov/pubmed/31781100 http://www.ncbi.nlm.nih.gov/pubmed/33180929 http://www.ncbi.nlm.nih.gov/pubmed/35254093 http://www.ncbi.nlm.nih.gov/pubmed/30252031 http://www.ncbi.nlm.nih.gov/pubmed/31877141 http://www.ncbi.nlm.nih.gov/pubmed/30201529 http://www.ncbi.nlm.nih.gov/pubmed/34714686 |
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