Clinical trial NCT06213506: A Study on the Safety, Reactogenicity, and Immune Response to the GVGH iNTS-GMMA Vaccine Against Invasive Nontyphoidal Salmonella in Adults, Children, and Infants
Official title: A Phase IIa Observer-blind, Randomized, Controlled, Age-de-escalation, Single Center Interventional Study to Evaluate the Safety, Reactogenicity, and Immune Response of the GVGH iNTS Vaccine Against S. Typhimurium and S. Enteritidis, in Adults, Children and Infants, Including Dose-finding in Infants, in Africa
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Salmonella Infections
Keywords: GVGH iNTS-GMMA vaccine
Safety
Reactogenicity
Immunogenicity
sub-Saharan Africa
African adults, children and infants
Age de-escalation
Dose escalation
Invasive nontyphoidal Salmonella
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: European & Developing Countries Clinical Trials Partnership
name: Kwame Nkrumah University of Science and Technology
name: Pedvac iNTS consortium
First posted: 2024-01-19
Enrollment: 516
Sex: ALL
Minimum age (years): 6
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Data will be collected in an observer-blind manner.
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to evaluate the safety, reactogenicity, and immune response of the GlaxoSmithKline (GSK) Vaccines Institute for Global Health (GVGH) invasive nontyphoidal Salmonella-generalized modules for membrane antigens (iNTS-GMMA) candidate vaccine against S. Typhimurium and S. Enteritidis with an age de-escalation and dose escalation approach in African population, starting with adults (18-50 years of age), then on children (24-59 months of age) and finally to infants (9 months and 6 weeks of age). Infants are the target for primary vaccination from 6 weeks of age.

Detailed description: The study will be conducted in two stages:

Stage 1: Age De-escalation from Adults to Children and Infants

* Adult participants will receive either iNTS-GMMA Dose C (high) or a control vaccine intramuscularly on Day 1 and Day 57.
* Child participants will receive either Dose B (medium) or Dose C (high) of the candidate vaccine or the control on Day 1 and Day 57.
* Infant participants (9 months of age) will receive either Dose A (low), Dose B (medium), or Dose C (high) of the candidate vaccine or the control on Day 1, Day 85, and Day 169.
* Infant participants (6 weeks of age) will receive either Dose A (low), Dose B (medium), or Dose C (high) of the candidate vaccine or the control on Day 1, Day 85 (Priming phase), and Day 232 (Booster phase).

Stage 2: Dose-finding in Infants of 6 weeks of age

-Infants (6 weeks of age) will receive one of the three dose levels (Dose A \[low\], Dose B \[medium\], or Dose C \[high\]) of the candidate vaccine or the control on Day 1, Day 85 (Priming phase), and Day 232 (Booster phase).

Eligibility criteria: Inclusion criteria:

All participants (adults, children, infants at 9 months of age and infants at 6 weeks of age) will be enrolled in the clinical site in Ghana and must satisfy ALL the following criteria at study entry:

* Participants and/or participants' parent(s)/Legally Acceptable Representative(s) (LAR), 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 or witnessed/thumb printed informed consent obtained from the participant/parent(s)/LAR(s) of the participant prior to performance of any study-specific procedure.
* Healthy participants as established by medical history, clinical examination, and laboratory investigations.
* Participants satisfying screening requirements.
* Participants negative for human immunodeficiency virus (HIV), hepatitis B, and hepatitis C.

Adult participants must satisfy ALL the following criteria at study entry:

* A male or female 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.

The Ghana card will be used as source document to verify the ages for the adults.

Child participants must satisfy ALL the following criteria at study entry:

* A male or female between and including 24 and 59 months of age at the time of the first study intervention administration.
* Previously completed routine childhood vaccinations to the best knowledge of the participant's parent(s)/LAR's.
* Born after a gestation period of ≥37 weeks.

Infant participants must satisfy ALL the following criteria at study entry:

* A male or female 6 weeks or 9 months of age at the time of the first study intervention administration.
* Born after a gestation period of ≥37 weeks.
* Born to a mother seronegative for HIV, hepatitis B virus and hepatitis C virus.

The Road to Health Chart will be used as source document to confirm the ages for the children and infants.

Exclusion criteria:

Medical conditions

* Known exposure to S. Typhimurium or S. Enteritidis during the period starting at birth for infants and children, and at 3 years for adults, as documented by patient records
* History of any reaction or hypersensitivity likely to be exacerbated by any component of the study interventions.
* Hypersensitivity, including allergy, to medicinal products or medical equipment whose use is foreseen in this study.
* Progressive, unstable, or uncontrolled clinical conditions.
* Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination
* Major congenital defects, as assessed by the investigator.
* Acute or chronic clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by physical examination or laboratory screening tests.
* Acute disease and/or fever at the time of enrollment (fever is defined as temperature ≥ 38.0°C).
* Recurrent history or uncontrolled neurological disorders or seizures.
* Any clinically significant hematological and/or biochemical laboratory abnormality.
* Undernutrition defined as WHO Z-score less than -2 SD.
* Malaria infection defined as the presence of asexual parasites in the blood.
* Clinical conditions representing a contraindication to intramuscular vaccination and blood draws.
* Any behavioral 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.
* Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the participant due to participation in the study.

Prior/Concomitant therapy

* History of receiving any investigational iNTS or GMMA vaccines in the participant's life.
* Use of any investigational or non-registered product other than the study interventions during the period beginning 30 days before the first dose of study interventions, or their planned use during the study period.
* Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 14 days before each dose and ending 28 days after the last dose of study interventions administration, with the exception of flu vaccines and vaccines administered as part of a public health vaccination campaign.
* A vaccine not foreseen by the study protocol administered during the period starting at 14 days before the first dose and ending 14 days after the last dose of study interventions administration for live vaccines or 7 days in case of inactivated vaccines\*, with the exception of flu vaccines or COVID-19 vaccine which may be considered on a case-by-case basis.

  * If emergency mass vaccination for an unforeseen public health threat (e.g., a pandemic) is organized by public health authorities outside the routine immunization program, the time period described above can be reduced if, provided it is used according to the local governmental recommendations and Sponsor is notified.

Under such circumstances, a participant may be considered eligible for study enrollment and/or study intervention administration after the appropriate window for delay has passed and inclusion/exclusion criteria have been re-checked, and if the participant is confirmed to be eligible.

* Administration of long-acting immune-modifying drugs at any time during the study period.
* Administration of immunoglobulins and/or any blood products or plasma derivatives from birth (for infant 6 weeks of age) or during the period starting 3 months before the administration of the first dose of study intervention(s) 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(s) up to the end of the study. For corticosteroids, this will mean prednisone equivalent greater than or equal to (\>=) 20 mg/day for adult participants/ \>= 0.5 mg/kg/day with maximum of 20 mg/day for pediatric participants (infants and children). 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 intervention (vaccine, drug and device).

Other exclusions

* Pregnant or lactating female.
* Female planning to become pregnant or planning to discontinue contraceptive precautions.
* History of/current chronic alcohol consumption and/or drug abuse. This will be decided at the discretion of the investigator.
* Any study personnel or their immediate dependents, family, or household members.
* Child in care.

Primary outcomes:
measure: Anti-invasive nontyphoidal Salmonella (iNTS) serotype specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) in infants 6 weeks of age part of the dose-finding cohort
timeFrame: At Day 85 (28 days after the second study intervention administration)
measure: Percentage of adult participants 18-50 years of age with solicited administration site events
timeFrame: During 7 days after the first study intervention administration occurring at Day 1
measure: Percentage of adult participants 18-50 years of age with solicited administration site events
timeFrame: During 7 days after the second study intervention administration occurring at Day 57
measure: Percentage of adult participants 18-50 years of age with solicited systemic events
timeFrame: During 7 days after the first study intervention administration occurring at Day 1
measure: Percentage of adult participants 18-50 years of age with solicited systemic events
timeFrame: During 7 days after the second study intervention administration occurring at Day 57
measure: Percentage of adult participants 18-50 years of age with unsolicited adverse events (AEs)
timeFrame: During 28 days after the first study intervention administration occurring at Day 1
measure: Percentage of adult participants 18-50 years of age with unsolicited adverse events (AEs)
timeFrame: During 28 days after the second study intervention administration occurring at Day 57
measure: Percentage of adult participants 18-50 years of age with serious adverse events (SAEs)
timeFrame: From first study intervention administration (Day 1) up to the end of study participation (Day 85)
measure: Percentage of adult participants 18-50 years of age with adverse events (AEs) leading to withdrawal from the study or discontinuation of study intervention
timeFrame: From first study intervention administration (Day 1) up to the end of study participation (Day 85)
measure: Percentage of adult participants 18-50 years of age with deviations from reference ranges l or baseline values for hematological, renal and hepatic panel test results
timeFrame: At Day 8 (7 days after the first study intervention administration)
measure: Percentage of adult participants 18-50 years of age with deviations from reference ranges or baseline values for hematological, renal and hepatic panel test results
timeFrame: At Day 64 (7 days after the second study intervention administration)
measure: Percentage of child participants 24-59 months of age with solicited administration site events
timeFrame: During 7 days after the first study intervention administration occurring at Day 1
measure: Percentage of child participants 24-59 months of age with solicited administration site events
timeFrame: During 7 days after the second study intervention administration occurring at Day 57
measure: Percentage of child participants 24-59 months of age with solicited systemic events
timeFrame: During 7 days after the first study intervention administration occurring at Day 1
measure: Percentage of child participants 24-59 months of age with solicited systemic events
timeFrame: During 7 days after the second study intervention administration occurring at Day 57
measure: Percentage of child participants 24-59 months of age with unsolicited AEs
timeFrame: During 28 days after the first study intervention administration occurring at Day 1
measure: Percentage of child participants 24-59 months of age with unsolicited AEs
timeFrame: During 28 days after the second study intervention administration occurring at Day 57
measure: Percentage of child participants 24-59 months of age with serious adverse events (SAEs)
timeFrame: From first study intervention administration (Day 1) up to the end of study participation (Day 85)
measure: Percentage of child participants 24-59 months of age with AEs leading to withdrawal from the study or discontinuation of study intervention
timeFrame: From first study intervention administration (Day 1) up to the end of study participation (Day 85)
measure: Percentage of child participants 24-59 months of age with deviations from reference ranges or baseline values for hematological, renal and hepatic panel test results
timeFrame: At Day 8 (7 days after the first study intervention administration)
measure: Percentage of child participants 24-59 months of age with deviations from reference ranges or baseline values for hematological, renal and hepatic panel test results
timeFrame: At Day 64 (7 days after the second study intervention administration)
measure: Percentage of infant participants 9 months of age with solicited administration site events
timeFrame: During 7 days after the first study intervention administration occurring at Day 1
measure: Percentage of infant participants 9 months of age with solicited administration site events
timeFrame: During 7 days after the second study intervention administration occurring at Day 85
measure: Percentage of infant participants 9 months of age with solicited administration site events
timeFrame: During 7 days after the third study intervention administration occurring at Day 169
measure: Percentage of infant participants 9 months of age with solicited systemic events
timeFrame: During 7 days after the first study intervention administration occurring at Day 1
measure: Percentage of infant participants 9 months of age with solicited systemic events
timeFrame: During 7 days after the second study intervention administration occurring at Day 85
measure: Percentage of infant participants 9 months of age with solicited systemic events
timeFrame: During 7 days after the third study intervention administration occurring at Day 169
measure: Percentage of infant participants 9 months of age with unsolicited adverse events (AEs)
timeFrame: During 28 days after the first study intervention administration occurring at Day 1
measure: Percentage of infant participants 9 months of age with unsolicited adverse events (AEs)
timeFrame: During 28 days after the second study intervention administration occurring at Day 85
measure: Percentage of infant participants 9 months of age with unsolicited adverse events (AEs)
timeFrame: During 28 days after the third study intervention administration occurring at Day 169
measure: Percentage of infant participants 9 months of age with serious adverse events (SAEs)
timeFrame: From first study intervention administration (Day 1) up to the end of study participation (Day 337)
measure: Percentage of infant participants 9 months of age with adverse events (AEs) leading to withdrawal from the study or discontinuation of study intervention
timeFrame: From first study intervention administration (Day 1) up to the end of study participation (Day 337)
measure: Percentage of infant participants 9 months of age with deviations from reference range or baseline values for hematological, renal and hepatic panel test results
timeFrame: At Day 8 (7 days after the first study intervention administration)
measure: Percentage of infant participants 9 months of age with deviations from reference range or baseline values for hematological, renal and hepatic panel test results
timeFrame: At Day 92 (7 days after the second study intervention administration)
measure: Percentage of infant participants 9 months of age with deviations from reference range or baseline values for hematological, renal and hepatic panel test results
timeFrame: At Day 176 (7 days after the third study intervention administration)
measure: Percentage of infant participants 6 weeks of age with solicited administration site events
timeFrame: During 7 days after the first study intervention administration occurring at Day 1 in the Priming phase
measure: Percentage of infant participants 6 weeks of age with solicited administration site events
timeFrame: During 7 days after the second study intervention administration occurring at Day 57 in the Priming phase
measure: Percentage of infant participants 6 weeks of age with solicited systemic events
timeFrame: During 7 days after the first study intervention administration occurring at Day 1 in the Priming phase
measure: Percentage of infant participants 6 weeks of age with solicited systemic events
timeFrame: During 7 days after the second study intervention administration occurring at Day 57 in the Priming phase
measure: Percentage of infant participants 6 weeks of age with unsolicited adverse events (AEs)
timeFrame: During 28 days after the first study intervention administration occurring at Day 1 in the Priming phase
measure: Percentage of infant participants 6 weeks of age with unsolicited adverse events (AEs)
timeFrame: During 28 days after the second study intervention administration occurring at Day 57 in the Priming phase
measure: Percentage of infant participants 6 weeks of age with SAEs
timeFrame: From first study intervention administration (Day 1) up to 28 days after second study intervention (Day 85)
measure: Percentage of infant participants 6 weeks of age with adverse events (AEs) leading to MR-VAC administration withdrawal from the study or discontinuation of study intervention
timeFrame: From first study intervention administration (Day 1) up to 28 days after second study intervention (Day 85)
measure: Percentage of infant participants 6 weeks of age with deviations from reference ranges or baseline values for hematological, renal, and hepatic panel test results
timeFrame: At Day 8 (7 days after the first study intervention administration) in the Priming phase
measure: Percentage of infant participants 6 weeks of age with deviations from reference ranges or baseline values for hematological, renal, and hepatic panel test results at Day 64
timeFrame: At Day 64 (7 days after the second study intervention administration) in the Priming phase
Secondary outcomes:
measure: Percentage of infant participants 6 weeks of age with solicited administration site events
timeFrame: During 7 days after the third study intervention administration occurring at Day 232 in the Booster phase
measure: Percentage of infant participants 6 weeks of age with solicited systemic events
timeFrame: During 7 days after the third study intervention administration occurring at Day 232 in the Booster phase
measure: Number of infant participants 6 weeks of age with unsolicited AEs
timeFrame: During 28 days after the third study intervention administration occurring at Day 232 in the Booster phase
measure: Percentage of infant participants 6 weeks of age with SAEs
timeFrame: From 28 days after the second study intervention administration (Day 85) up to end of study participation (Day 400)
measure: Percentage of infant participants 6 weeks of age with adverse events (AEs) leading to withdrawal from the study or discontinuation of study intervention
timeFrame: From 28 days after the second study intervention administration (Day 85) up to end of study participation (Day 400)
measure: Percentage of infant participants 6 weeks of age with deviations from reference ranges or baseline values for hematological, renal, and hepatic panel test results
timeFrame: At Day 239 (7 days after the study intervention administration) in the Booster phase
measure: Anti-invasive nontyphoidal Salmonella (iNTS) serotype specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) in infants 6 weeks of age dose finding cohort
timeFrame: At Day 260 (28 days after the booster study intervention administration)
measure: Anti-invasive nontyphoidal Salmonella (iNTS) serotype specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) in adult participants 18-50 years of age
timeFrame: At Days 1 and 57 (before each study intervention administration) and at Days 29 and 85 (28 days after each study intervention administration)
measure: Anti-invasive nontyphoidal Salmonella (iNTS) serotype specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) in child participants 24-59 months of age
timeFrame: At Days 1 and 57 (before each study intervention administration) and at Days 29 and 85 (28 days after each study intervention administration)
measure: Anti-invasive nontyphoidal Salmonella (iNTS) serotype specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) in infant participants 9 months of age
timeFrame: At Days 1, 85 and 169 (before each study intervention administration) and at Days 29, 113 and 197 (28 days after each study intervention administration)
measure: Anti-invasive nontyphoidal Salmonella (iNTS) serotype specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) in infant participants 6 weeks of age
timeFrame: At Days 1, 57 and 232 (before each study intervention administration) at Days 29, 85 and 260 (28 days after each study intervention administration) and at Day 239 (7 days after the third study intervention administration)
measure: Percentage of adult participants 18-50 years of age achieving, for each antigen (Ag), at least a 2-fold and 4-fold rise in anti-invasive nontyphoidal Salmonella (iNTS) serotype specific immunoglobulin G (IgG) antibody concentration
timeFrame: At Days 29 and 85 (28 days after each study intervention administration) compared to Day 1 (baseline, prior to first study intervention administration)
measure: Percentage of child participants 24-59 months of age achieving, for each antigen (Ag), at least a 2-fold and 4-fold rise in anti-invasive nontyphoidal Salmonella (iNTS) serotype specific immunoglobulin G (IgG) antibody concentration
timeFrame: At Days 29 and 85 (28 days after each study intervention administration) compared to Day 1 (baseline, prior to first study intervention administration)
measure: Percentage of infant participants 9 months of age achieving, for each antigen (Ag), at least a 2-fold and 4-fold rise in anti-invasive nontyphoidal Salmonella (iNTS) serotype specific immunoglobulin G (IgG) antibody concentration
timeFrame: At Days 29, 113 and 197 (28 days after each study intervention administration) compared to Day 1 (baseline, prior to first study intervention administration)
measure: Percentage of infant participants 6 weeks of age achieving, for each antigen (Ag), at least a 2-fold and 4-fold rise in anti-invasive nontyphoidal Salmonella (iNTS) serotype specific immunoglobulin G (IgG) antibody concentration
timeFrame: At Days 29, 85 and 260 (28 days after each study intervention administration) and at Day 239 (7 days after the third study intervention administration) compared to Day 1 (baseline, prior to first study intervention administration)
measure: Anti-Hepatitis B surface (HBs) antigen (Ag) geometric mean concentrations (GMCs), in a subset of infant participants 6 weeks of age (dose-finding cohort)
timeFrame: At Day 1 (before the first study intervention administration) and at Day 85 (28 days after the third pentavalent vaccine administration)
measure: Anti-Hib polyribosylribitol phosphate (PRP) geometric mean concentrations (GMCs), in a subset of infant participants 6 weeks of age (dose-finding cohort)
timeFrame: At Day 1 (before the first study intervention administration) and at Day 85 (28 days after the third pentavalent vaccine administration)
measure: Anti-measles immunoglobulin G (IgG) antibody geometric mean concentrations (GMCs), in a subset of infant participants 6 weeks of age (dose-finding cohort)
timeFrame: At Day 232 (before MR-VAC administration) and at Day 260 (28 days after MR-VAC administration)
measure: Anti-rubella immunoglobulin G (IgG) antibody geometric mean concentrations (GMCs), in a subset of infant participants 6 weeks of age (dose-finding cohort)
timeFrame: At Day 232 (before MR-VAC administration) and at Day 260 (28 days after MR-VAC administration)
measure: Percentage of a subset of infant participants 6 weeks of age (dose-finding cohort) achieving an anti-measles IgG antibody concentration of equal to or above (≥) 150 milli international units per milliliter (mIU/mL) and ≥ 200 mIU/mL
timeFrame: At Day 232 (before MR-VAC administration) and at Day 260 (28 days after MR-VAC administration)
measure: Percentage of a subset of infant participants 6 weeks of age (dose finding cohort) achieving an anti-rubella IgG antibody concentration of ≥ 4 international units per milliliter (IU/mL) and ≥ 10 IU/mL
timeFrame: At Day 232 (before MR-VAC administration) and at Day 260 (28 days after MR-VAC administration)
measure: Percentage of a subset of infant participants 6 weeks of age (dose finding cohort) achieving an anti-Hepatitis B IgG antibody concentration of ≥ 10 mIU/mL
timeFrame: At Day 1 (before the first study intervention administration) and at Day 85 (28 days after third pentavalent vaccine administration)
measure: Percentage of a subset of infant participants 6 weeks of age (dose-finding cohort) achieving an anti-Hib polyribosylribitol phosphate (PRP) IgG antibody concentration of ≥ 0.15 microgram per milliliter (µg/mL)
timeFrame: At Day 1 (before the first study intervention administration) and at Day 85 (28 days after third pentavalent vaccine administration)
Other outcomes:
Locations:
city: Kumasi
country: Ghana
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: