Vaccines Against Salmonella Typhi

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Brief Title

Vaccines Against Salmonella Typhi

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

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.
    

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Clinically or microbiologically proven typhoid infection

Secondary Outcome

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

Condition

Typhoid Fever

Intervention

Vi-TCV

Study Arms / Comparison Groups

 Vi-TCV
Description:  Single intramuscular injection

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

112

Start Date

September 2015

Completion Date

December 2018

Primary Completion Date

December 2, 2017

Eligibility Criteria

        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
      

Gender

All

Ages

18 Years - 60 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Andrew J Pollard, FRCPCH, PhD, , 

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT02324751

Organization ID

OVG 2014/08


Responsible Party

Sponsor

Study Sponsor

University of Oxford


Study Sponsor

Andrew J Pollard, FRCPCH, PhD, Principal Investigator, Oxford Vaccine Group, The University of Oxford


Verification Date

February 2018