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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Typhoid Fever

Intervention / Treatment
-----------------
* Biological: TYP04A Low Dose without adjuvant investigational vaccine
* Biological: TYP04B Full Dose without adjuvant investigational vaccine
* Biological: TYP03A Low Dose adjuvanted investigational vaccine
* Biological: TYP03B Full Dose adjuvanted investigational vaccine
* Biological: Sanofi Pasteur's Typhoid Vi polysaccharide vaccine
* Biological: GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
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. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Step 1a low dose without adjuvant Group<br>Participants 18 to 50 years of age randomized to receive 2 doses of TYP04A Low Dose without adjuvant investigational vaccine, administered at Day 1 and Day 169. | Biological: TYP04A Low Dose without adjuvant investigational vaccine<br>* 2 doses of TYP04A Low Dose without adjuvant investigational vaccine administered intramuscularly, at Day 1 and Day 169, to participants in the Step 1a low dose without adjuvant Group.<br>* Other names: Typhoid and Paratyphoid A conjugate low dose without adjuvant vaccine;|
| Active Comparator: Step 1a control Group<br>Participants 18 to 50 years of age randomized to receive 1 dose of Sanofi Pasteur's Typhoid Vi polysaccharide vaccine at Day 1 and 1 dose of GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine at Day 169. | Biological: Sanofi Pasteur's Typhoid Vi polysaccharide vaccine<br>* 1 dose of Sanofi Pasteur's Typhoid Vi polysaccharide vaccine administered intramuscularly, at Day 1, to participants in the Step 1a control, Step 1b control, and Step 2 control groups.<br>* Other names: TYPHIM VI;Biological: GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine<br>* 1 dose of GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine administered intramuscularly, at Day 169, to participants in the Step 1a control, Step 1b control, and Step 2 control groups.<br>* Other names: BOOSTRIX;|
| Experimental: Step 1b low dose with adjuvant Group<br>Participants 18 to 50 years of age randomized to receive 2 doses of TYP03A Low Dose adjuvanted investigational vaccine, administered at Day 1 and Day 169. | Biological: TYP03A Low Dose adjuvanted investigational vaccine<br>* 2 doses of TYP03A Low Dose adjuvanted investigational vaccine administered intramuscularly, at Day 1 and Day 169, to participants in the Step 1b low dose with adjuvant Group.<br>* Other names: Adjuvanted Typhoid and Paratyphoid A conjugate low dose vaccine;|
| Active Comparator: Step 1b control Group<br>Participants 18 to 50 years of age randomized to receive 1 dose of Sanofi Pasteur's Typhoid Vi polysaccharide vaccine at Day 1 and 1 dose of GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine at Day 169. | Biological: Sanofi Pasteur's Typhoid Vi polysaccharide vaccine<br>* 1 dose of Sanofi Pasteur's Typhoid Vi polysaccharide vaccine administered intramuscularly, at Day 1, to participants in the Step 1a control, Step 1b control, and Step 2 control groups.<br>* Other names: TYPHIM VI;Biological: GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine<br>* 1 dose of GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine administered intramuscularly, at Day 169, to participants in the Step 1a control, Step 1b control, and Step 2 control groups.<br>* Other names: BOOSTRIX;|
| Experimental: Step 2 full dose without adjuvant Group<br>Participants 18 to 50 years of age randomized to receive 2 doses of TYP04B Full Dose without adjuvant investigational vaccine, administered at Day 1 and Day 169. | Biological: TYP04B Full Dose without adjuvant investigational vaccine<br>* 2 doses of TYP04B Full Dose without adjuvant investigational vaccine administered intramuscularly, at Day 1 and Day 169, to participants in the Step 2 full dose without adjuvant Group.<br>* Other names: Typhoid and Paratyphoid A conjugate full dose without adjuvant vaccine;|
| Experimental: Step 2 full dose with adjuvant Group<br>Participants 18 to 50 years of age randomized to receive 2 doses of TYP03B Full Dose adjuvanted investigational vaccine, administered at Day 1 and Day 169. | Biological: TYP03B Full Dose adjuvanted investigational vaccine<br>* 2 doses of TYP03B Full Dose adjuvanted investigational vaccine administered intramuscularly, at Day 1 and Day 169, to participants in the Step 2 full dose with adjuvant Group.<br>* Other names: Adjuvanted Typhoid and Paratyphoid A conjugate full dose vaccine;|
| Active Comparator: Step 2 control Group<br>Participants 18 to 50 years of age randomized to receive 1 dose of Sanofi Pasteur's Typhoid Vi polysaccharide vaccine at Day 1 and 1 dose of GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine at Day 169. | Biological: Sanofi Pasteur's Typhoid Vi polysaccharide vaccine<br>* 1 dose of Sanofi Pasteur's Typhoid Vi polysaccharide vaccine administered intramuscularly, at Day 1, to participants in the Step 1a control, Step 1b control, and Step 2 control groups.<br>* Other names: TYPHIM VI;Biological: GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine<br>* 1 dose of GSK's Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine administered intramuscularly, at Day 169, to participants in the Step 1a control, Step 1b control, and Step 2 control groups.<br>* Other names: BOOSTRIX;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with solicited administration-site events after the first vaccination | The solicited administration site events are pain, redness, and swelling. | During 7 days after the first vaccination occurring at Day 1 | 
| Percentage of participants with solicited administration-site events after the second vaccination | The solicited administration site events are pain, redness, and swelling. | During 7 days after the second vaccination occurring at Day 169 | 
| Percentage of participants with solicited systemic events after the first vaccination | The solicited systemic events are fever, headache, myalgia (muscle pain), arthralgia (joint pain), and fatigue (tiredness). Fever is defined as body temperature equal to or above (≥) 38.0 degrees Celsius (°C)/100.4 degrees Fahrenheit (°F). The preferred location for measuring temperature is the axilla. | During 7 days after the first vaccination occurring at Day 1 | 
| Percentage of participants with solicited systemic events after the second vaccination | The solicited systemic events are fever, headache, myalgia (muscle pain), arthralgia (joint pain), and fatigue (tiredness). Fever is defined as body temperature equal to or above (≥) 38.0 degrees Celsius (°C)/100.4 degrees Fahrenheit (°F). The preferred location for measuring temperature is the axilla. | During 7 days after the second vaccination occurring at Day 169 | 
| Percentage of participants with unsolicited adverse events after the first vaccination | Any AE reported in addition to those solicited during the clinical study. Also, any 'solicited' symptom with onset outside the specified period of follow-up for solicited symptoms will be reported as an unsolicited adverse event. | During 28 days after the first vaccination occurring at Day 1 | 
| Percentage of participants with unsolicited adverse events after the second vaccination | Any AE reported in addition to those solicited during the clinical study. Also, any 'solicited' symptom with onset outside the specified period of follow-up for solicited symptoms will be reported as an unsolicited adverse event. | During 28 days after the second vaccination occurring at Day 169 | 
| Percentage of participants with any serious adverse event (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 1 to Day 197 | 
| Percentage of participants with AEs/SAEs leading to withdrawal from the study or withholding further study intervention administration | Any AEs including SAEs that lead to discontinuation of the study intervention and/or the study are considered under this outcome measure. 'Discontinuation' of study intervention refers to any participant who has not received all planned doses of study intervention. A participant who discontinued study intervention may continue other study procedures (e.g., safety or immunogenicity), planned in the study protocol at the discretion of the Investigator. 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 | 
| Percentage of participants with deviations from normal or baseline values of haematological, renal, and hepatic panel test results at Day 8 | Panel tests include measures of leukocytes, erythrocytes, haemoglobin, haematocrit, platelets, eosinophils, basophils, neutrophils, monocytes, lymphocytes, creatinine, aspartate aminotransferase, alanine aminotransferase, and blood urea. | At Day 8 (7 days after the first vaccination) | 
| Percentage of participants with deviations from normal or baseline values of haematological, renal, and hepatic panel test results at Day 176 | Panel tests include measures of leukocytes, erythrocytes, haemoglobin, haematocrit, platelets, eosinophils, basophils, neutrophils, monocytes, lymphocytes, creatinine, aspartate aminotransferase, alanine aminotransferase, and blood urea. | At Day 176 (7 days after the second vaccination) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with any serious adverse event (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 | 
| Percentage of participants with AEs/SAEs leading to withdrawal from the study | Any AEs including SAEs that lead to discontinuation of 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 | 
| Anti-Vi antigen Immunoglobulin G (IgG) antibody concentrations | Anti-Vi antigen IgG antibody concentrations are expressed as geometric mean concentrations (GMCs), as measured by Enzyme-Linked Immunosorbent Assay (ELISA). | At Day 1 (before the first vaccination), Day 29 (28 days after the first vaccination), Day 169 (before the second vaccination), Day 176 (7 days after the second vaccination), and Day 197 (28 days after the second vaccination) | 
| Anti-O:2 Immunoglobulin G (IgG) antibody concentrations | Anti-O:2 IgG antibody concentrations are expressed as geometric mean concentrations (GMCs), as measured by Enzyme-Linked Immunosorbent Assay (ELISA). | At Day 1 (before the first vaccination), Day 29 (28 days after the first vaccination), Day 169 (before the second vaccination), Day 176 (7 days after the second vaccination), and Day 197 (28 days after the second vaccination) | 
| Percentage of participants achieving anti-Vi antigen IgG antibody concentrations equal to or above (≥) 4.3 micrograms per milliliter (µg/mL) |  | At Day 1 (before the first vaccination), Day 29 (28 days after the first vaccination), Day 169 (before the second vaccination), Day 176 (7 days after the second vaccination), and Day 197 (28 days after the second vaccination) | 
| Percentage of participants achieving anti-Vi antigen IgG antibody concentrations ≥ 2.0 µg/mL |  | At Day 1 (before the first vaccination), Day 29 (28 days after the first vaccination), Day 169 (before the second vaccination), Day 176 (7 days after the second vaccination), and Day 197 (28 days after the second vaccination) | 
| Percentage of participants achieving at least 4-fold increase in anti-O:2 IgG antibody concentrations |  | At Day 29 (28 days after the first vaccination), Day 169 (before the second vaccination), Day 176 (7 days after the second vaccination), and Day 197 (28 days after the second vaccination) compared to Day 1 (first vaccination baseline) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Salmonella Typhi, Salmonella Paratyphi A, Typhoid fever, Paratyphoid fever, Enteric fever, Conjugate vaccine, First-time-in-human