Safety and Immunogenicity of a Novel Conjugate Vaccine Against Salmonella Typhi and Salmonella Paratyphi A in Healthy Adults

A Phase 1, Observer-blind, Randomised, Controlled, Single-centre Study to Evaluate the Safety, Reactogenicity, and Immune Responses to an Adjuvanted and Non-adjuvanted Conjugate Vaccine Against Salmonella Typhi and Salmonella Paratyphi A in Healthy Adults 18 to 50 Years of Age in Europe

A bivalent Typhoid and Paratyphoid A conjugate investigational vaccine aimed to prevent both typhoid and paratyphoid enteric fever in infants and older age groups has been developed by GlaxoSmithKline (GSK).

The purpose of this first-time-in-human study is to evaluate the safety and immunogenicity profile of a low and a full dose of the investigational vaccine, formulated with or without adjuvant, administered in 2 doses, 24 weeks apart, in healthy adults 18 to 50 years of age in Europe.

Study Overview

• Status: Completed
• Conditions: Typhoid Fever
• Intervention / Treatment: Biological: TYP04A Low Dose without Alum investigational vaccine; Biological: TYP03A Low Dose with Alum investigational vaccine; Biological: TYP04B Full Dose without Alum investigational vaccine; Biological: TYP03B Full Dose with Alum investigational vaccine; Biological: Sanofi Pasteur's Typhoid Vi polysaccharide vaccine; Biological: GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Edegem, Belgium, 2610
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Participants who, in the opinion of the Investigator, can and will comply with the requirements of the Protocol (e.g., completion of the diary cards, return for follow-up visits).
• Written informed consent obtained from the participant prior to performance of any study specific procedure.
• Healthy participants as established by medical history, clinical examination, and screening laboratory investigations.
• Participant satisfying screening requirements.
• Participant seronegative for human immunodeficiency virus, hepatitis B, and hepatitis C at Screening.
• A male or female participant between, and including, 18 and 50 years of age at the time of the first study intervention administration.
• Female participants of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current bilateral tubal ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause.

• Female participants of childbearing potential may be enrolled in the study if the participant:

  • has practiced adequate contraception for 1 month prior to study intervention administration, and
  • has a negative pregnancy test on the day of study intervention administration, and
  • has agreed to continue adequate contraception during the entire treatment period and for 1 month after completion of the study intervention administration series.

Exclusion Criteria:

Medical conditions

• Progressive, unstable or uncontrolled clinical conditions.
• History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine.
• Hypersensitivity, including allergy, to medicinal products or medical equipment whose use is foreseen in this study.
• Clinical conditions representing a contraindication to intramuscular vaccination and blood draws.
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
• Any behavioural or cognitive impairment or psychiatric disease that, in the opinion of the Investigator, may interfere with the participant's ability to participate in the study.

• Acute* or chronic illness, clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by physical examination or laboratory screening tests.

  *Participants with a minor illness (such as mild diarrhoea or mild upper respiratory infection) without fever may be enrolled at the discretion of the Investigator.

• Any clinically significant* haematological and/or biochemical laboratory abnormality.

  *The Investigator should use his/her clinical judgement to decide which abnormalities are clinically significant.

• Confirmed positive COVID-19 test during the period starting 14 days before the first administration of study vaccines (Day -14 to Day 1).
• Any other clinical condition that, in the opinion of the Investigator, might pose additional risk to the participant due to participation in the study.
• Confirmed or suspected autoimmune diseases (e.g., vitiligo, autoimmune thyroiditis).

Prior/Concomitant therapy

• Previous administration of any type of Typhoid vaccine (Ty21a, Vi-PS, or Typhoid conjugate vaccine).
• Use of any investigational or non-registered product (drug, vaccine, or medical device) other than the study interventions during the period starting 30 days before the first administration of study vaccines (Day -30 to Day 1), or planned use during the study period.

• A vaccine not foreseen by the study protocol administered during the period starting at -14 days before the first dose (-21 days in the case of live vaccines) and ending 28 days after the last dose of study intervention administration*, with the exception of flu and COVID-19 vaccines, administered during the period starting at 7 days before and 7 days after each dose (14 days before and 14 days after in case of live vaccines).

  *In case emergency mass vaccination for an unforeseen public health threat (e.g., a pandemic) is recommended and/or organised by public health authorities outside the routine immunisation programme, the time period described above can be reduced if, necessary for that vaccine, provided it is used according to the local governmental recommendations and that the Sponsor is notified accordingly. When regulations allow, the recommended time intervals for administration of these vaccines are at least 7 days before or 7 days after (at least 14 days before or 14 days after in case of live vaccines) each dose of study intervention administration.

• Administration of long-acting immune-modifying drugs at any time during the study period (e.g., infliximab).
• Administration of immunoglobulins and/or any blood products or plasma derivatives during the period starting 3 months before the administration of the first dose of study intervention or planned administration during the study period.
• Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting 3 months prior to the first study intervention dose. For corticosteroids, this will mean prednisone equivalent ≥20 mg/day for adult participants. Inhaled and topical steroids are allowed.

Prior/Concurrent clinical study experience • Concurrently participating in another clinical study, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational vaccine/product (drug/invasive medical device).

Other exclusions

• History of travel to countries of Asia that are considered endemic* for enteric fever in the last 3 years.

  *this also includes travel during study duration.

• Pregnant or lactating female.
• Female participants planning to become pregnant or planning to discontinue contraceptive precautions.
• History of or current chronic alcohol consumption and/or drug abuse.
• Any study personnel or immediate dependents, family, or household member.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Step 1a: Low dose TYP04A vaccine without Alum; Participants received low dose of the TYP04A vaccine without Alum intramuscularly on Day 1 and Day 169.	Biological: TYP04A Low Dose without Alum investigational vaccine; 2 doses of TYP04A Low Dose without Alum investigational vaccine administered intramuscularly as a priming dose on Day 1 and a booster dose on Day 169.; Other Names: Typhoid and Paratyphoid A conjugate low dose without adjuvant vaccine
Experimental: Step 1b: Low dose TYP03A vaccine with Alum; Participants received low dose of the TYP03A vaccine with Alum intramuscularly on Day 1 and Day 169.	Biological: TYP03A Low Dose with Alum investigational vaccine; 2 doses of TYP03A Low Dose with Alum investigational vaccine administered intramuscularly as a priming dose on Day 1 and a booster dose on Day 169.; Other Names: Adjuvanted Typhoid and Paratyphoid A conjugate low dose vaccine
Experimental: Step 2: Full dose TYP04B vaccine without Alum; Participants received full dose of the TYP04B vaccine without Alum intramuscularly on Day 1 and day 169.	Biological: TYP04B Full Dose without Alum investigational vaccine; 2 doses of TYP04B Full Dose without Alum investigational vaccine administered intramuscularly as a priming dose on Day 1 and a booster dose on Day 169.; Other Names: Typhoid and Paratyphoid A conjugate full dose without adjuvant vaccine
Experimental: Step 2: Full dose TYP03B vaccine with Alum; Participants received full dose of the TYP03B vaccine with Alum intramuscularly on Day 1 and day 169.	Biological: TYP03B Full Dose with Alum investigational vaccine; 2 doses of TYP03B Full Dose with Alum investigational vaccine administered intramuscularly as a priming dose on Day 1 and a booster dose on Day 169.; Other Names: Adjuvanted Typhoid and Paratyphoid A conjugate full dose vaccine
Active Comparator: Control: TYPHIM VI and BOOSTRIX vaccine; Participants received TYPHIM VI as comparator intramuscularly on Day 1, and BOOSTRIX as comparator on Day 169.	Biological: Sanofi Pasteur's Typhoid Vi polysaccharide vaccine; 1 dose of Sanofi Pasteur's Typhoid Vi polysaccharide vaccine administered intramuscularly, at Day 1, to participants in the control group.; Other Names: TYPHIM VI; Biological: GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine; 1 dose of GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine administered intramuscularly, at Day 169, to participants in the control group.; Other Names: BOOSTRIX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Solicited Administration-site Events After the First Vaccination	Solicited administration site events included pain, redness, and swelling.	From Day 1 to Day 7
Number of Participants With Solicited Administration-site Events After the Second Vaccination	Solicited administration site events included pain, redness, and swelling.	From Day 169 to Day 175
Number of Participants With Solicited Systemic Events After the First Vaccination	The solicited systemic events included arthralgia (joint pain), fatigue (tiredness), fever, headache, and myalgia (muscle pain). Fever is defined as body temperature more than or equal to (>=) 38.0 degrees Celsius (°C).	From Day 1 to Day 7
Number of Participants With Solicited Systemic Events After the Second Vaccination	The solicited systemic events included arthralgia (joint pain), fatigue (tiredness), fever, headache, and myalgia (muscle pain).	From Day 169 to Day 175
Number of Participants With Unsolicited Adverse Events (AEs) After the First Vaccination	An unsolicited AE is defined as an AE that was either not included in the list of solicited events or could be included in the list of solicited events but with an onset outside the specified period of follow-up for solicited events.	From Day 1 to Day 28
Number of Participants With Unsolicited Adverse Events After the Second Vaccination	An unsolicited adverse event is defined as an adverse event that was either not included in the list of solicited events or could be included in the list of solicited events but with an onset outside the specified period of follow-up for solicited events.	From Day 169 to Day 196
Number of Participants With Any Serious Adverse Events (SAEs)	An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study participant, results in abnormal pregnancy outcomes or any other situation based on appropriate medical or scientific judgement.	From Day 1 to Day 197
Number of Participants With AEs/SAEs Leading to Withdrawal From the Study	Any AEs including SAEs that lead to withdrawal from the study are considered under this outcome measure. A participant is considered to have withdrawn from the study if no new study procedure has been performed or no new information has been collected for him/her since the date of withdrawal/last contact.	From Day 1 to Day 197
Number of Participants With SAEs Leading to Withholding Further Study Intervention Administration	An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study participant, results in abnormal pregnancy outcomes or any other situation based on appropriate medical or scientific judgement. SAEs that lead to withholding of the study intervention administration were considered under this outcome measure.	From Day 1 to Day 197
Number of Participants With AEs Leading to Withholding Further Study Intervention Administration	An AE is any untoward medical occurrence (an unfavourable/unintended sign - including an abnormal laboratory finding), symptom, or disease (new or exacerbated) in a clinical study participant that is temporally associated with the study intervention. AEs that lead to withholding of the study intervention administration were considered under this outcome measure.	From Day 1 to Day 197
Number of Participants With Deviations From Normal or Baseline Values of Haematological, Renal, and Hepatic Panel Test Results at Day 8	Assessed hematological laboratory parameters include basophils, eosinophils, erythrocytes, hemoglobin, hematocrit, lymphocytes, monocytes, neutrophils, platelets, leukocytes. Hepatic laboratory parameters include alanine aminotransferase [ALT], aspartate aminotransferase [AST] and renal laboratory parameters include creatinine and blood urea. Categories reported when comparing Day 1 (baseline) and Day 8 hematological, renal and hepatic laboratory results are defined as follows: <parameter>-<range at baseline>-<range at timing> (e.g. ALT-Within-Within). Range level being classified as below, within or above the normal range.	At Day 8 compared to Day 1 (Baseline)
Number of Participants With Deviations From Normal or Baseline Values of Haematological, Renal, and Hepatic Panel Test Results at Day 176	Assessed hematological laboratory parameters include basophils, eosinophils, erythrocytes, hemoglobin, hematocrit, lymphocytes, monocytes, neutrophils, platelets, leukocytes. Hepatic laboratory parameters include alanine aminotransferase [ALT], aspartate aminotransferase [AST] and renal laboratory parameters include creatinine and blood urea. Categories reported when comparing Day 169 (baseline) and Day 176 hematological, renal and hepatic laboratory results are defined as follows: <parameter>-<range at baseline>-<range at timing> (e.g. ALT-Within-Within). Range level being classified as below, within or above the normal range.	At Day 176 compared to Day 169 (Baseline)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Any SAE	An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study participant, results in abnormal pregnancy outcomes or any other situation based on appropriate medical or scientific judgement.	From Day 197 to Day 337
Number of Participants With AEs/SAEs Leading to Withdrawal From the Study	Any AEs including SAEs that lead to withdrawal from the study are considered under this outcome measure. A participant is considered to have withdrawn from the study if no new study procedure has been performed or no new information has been collected for him/her since the date of withdrawal/last contact.	From Day 197 to Day 337
Geometric Mean Concentrations (GMCs) of Anti-Vi Antigen Immunoglobulin G (IgG) Antibody Concentrations	Anti-Vi specific IgG antibodies were measured by an anti-Vi IgG Enzyme-Linked Immunosorbent Assay (ELISA) kit. Blood samples were collected at specified timepoints.	At Day 1 (pre-dose 1), Day 29, Day 169 (pre-Dose 2), Day 176 and Day 197
Geometric Mean Ratio (GMR) for Anti-Vi Antigen IgG Antibody Concentrations	Anti-Vi specific IgG antibodies were measured by an anti-Vi IgG ELISA kit. Blood samples were collected at specified timepoints. Within participant GMRs were calculated as ratio of concentration in the post-vaccination timepoint to the pre-vaccination timepoint.	At Day 29, Day 169, Day 176, and Day 197 compared to Day 1 (baseline)
GMR for Anti-Vi Antigen IgG Antibody Concentrations	Anti-Vi specific IgG antibodies were measured by an anti-Vi IgG ELISA kit. Blood samples were collected at specified timepoints. Within participant GMRs were calculated as ratio of concentration in the post-vaccination timepoint to the pre-vaccination timepoint.	At Day 176 and Day 197 compared to Day 169 (baseline)
GMC of Anti-O:2 IgG Antibody Concentrations	Anti-O:2 IgG antibodies in serum were measured by an ELISA assay. Blood samples were collected at specified timepoints.	At Day 1 (pre-dose 1), Day 29, Day 169 (pre-dose 2), Day 176 and Day 197
GMR for Anti-O:2 IgG Antibody Concentrations	Anti-O:2 IgG antibodies in serum were measured by an ELISA assay. Blood samples were collected at specified timepoints. Within participant GMRs were calculated as ratio of concentration in the post-vaccination timepoint to the pre-vaccination timepoint.	At Day 29, Day 169, Day 176, and Day 197 compared to Day 1 (baseline)
GMR for Anti-O:2 IgG Antibody Concentrations	Anti-O:2 IgG antibodies in serum were measured by an ELISA assay. Blood samples were collected at specified timepoint. Within participant GMRs were calculated as ratio of concentration in the post-vaccination timepoint to the pre-vaccination timepoint.	At Day 176 and Day 197 compared to Day 169 (baseline)
Number of Participants With Anti-Vi Antigen IgG Antibody Concentrations Greater Than or Equal to (>=) 4.3 Micrograms Per Milliliter (µg/mL)	Blood samples were collected at specified timepoint for each component as measured by ELISA.	At Day 1, Day 29, Day 169, Day 176 and Day 197
Number of Participants With Anti-Vi Antigen IgG Antibody Concentrations >= 2.0 µg/mL	Blood samples were collected at specified timepoint for each component as measured by ELISA.	At Day 1, Day 29, Day 169, Day 176 and Day 197
Number of Participants With at Least 4-fold Increase in Anti-O:2 IgG Antibody Concentrations	Blood samples were collected at specified timepoint for each component as measured by ELISA. 4-fold increase was defined as 4 times the baseline value of anti-O:2 IgG antibody concentrations.	At Day 29, Day 169, Day 176 and Day 197 compared to Day 1 (baseline)

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Collaborators: Biological E. Limited
• Investigators: Study Director: GSK Clinical Trials, GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2022
• Primary Completion (Actual): December 6, 2023
• Study Completion (Actual): April 2, 2024

Study Registration Dates

• First Submitted: November 4, 2022
• First Submitted That Met QC Criteria: November 4, 2022
• First Posted (Actual): November 14, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 4, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: First-time-in-human; Conjugate vaccine; Typhoid fever; Enteric fever; Salmonella Typhi; Salmonella Paratyphi A; Paratyphoid fever
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Negative Bacterial Infections; Enterobacteriaceae Infections; Salmonella Infections; Typhoid Fever; Immunologic Factors; Physiological Effects of Drugs; Adjuvants, Immunologic; Adjuvants, Vaccine; Vaccines; Aluminum sulfate
• Other Study ID Numbers: 205480; 2021-002029-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, a key secondary endpoints and safety data of the study.
• IPD Sharing Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No