| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of invasive nontyphoidal Salmonella disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Infection caused by Salmonella typhimurium (S. typhimurium) and Salmonella enteritidis (S. enteritidis) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To identify the preferred dose of each component of the iNTS-GMMA vaccine (Dose A [low], Dose B [medium], or Dose C [high]) for infant participants 6 weeks of age after Priming phase
• To evaluate the safety and reactogenicity of the iNTS-GMMA vaccine in all participants |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate safety and reactogenicity of the iNTS-GMMA vaccine in infant participants 6 weeks of age after booster vaccination
• To compare different doses of each component of the iNTS-GMMA vaccine (Dose A [low], Dose B [medium], or Dose C [high]) for infant participants 6 weeks of age after booster phase
• To evaluate the immunogenicity profile of the iNTS-GMMA vaccine in all participants
• To evaluate the seroresponse to the iNTS-GMMA vaccine after each administration in all participants
• To evaluate the immunogenicity of coadministered Hepatitis B and Hib vaccines, and Measles and Rubella Vaccine (MR-VAC) in a subset of infant participants 6 weeks of age
• To evaluate the seroresponse of the coadministered Hepatitis B and Hib vaccines, and MR-VAC in a subset of infant participants 6 weeks of age |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
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. |
|
| E.4 | Principal 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Anti-iNTS serotype specific IgG(Anti-S. Typhimurium O Ag and anti-S. Enteritidis O Ag total IgG)* GMCs, as measured by ELISA, in infant 6 weeks of age dose finding cohort, 28 days after the second administration (Day 85).
2. Percentage of adult participants 18–50 years of age with solicited administration site and systemic events during 7 days after each study intervention administration by study intervention group
3. Percentage of adult participants 18–50 years of age with unsolicited AEs during 28 days after each study intervention administration by study intervention group.
4. Percentage of adult participants 18–50 years of age with SAEs from first study intervention administration up to study end, by study intervention group.
5. Percentage of adult participants 18–50 years of age with AEs leading to withdrawal from the study or discontinuation of study intervention, from first study intervention administration up to study end, by study intervention group.
6. 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 at 7 days after each study intervention administration, by study intervention group.
7. Percentage of child participants 24–59 months of age with solicited administration site and systemic events during 7 days after each study intervention administration, by study intervention group.
8. Percentage of child participants 24–59 months of age with unsolicited AEs during 28 days after each study intervention administration, by study intervention group.
9. Percentage of child participants 24–59 months of age with SAEs from first study intervention administration up to study end, by study intervention group.
10. Percentage of child participants 24–59 months of age with AEs leading to withdrawal from the study or discontinuation of study intervention from first study intervention administration up to study end, by study intervention group.
11. 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 at 7 days after each study intervention administration, by study intervention group.
12. Percentage of infant participants 9 months of age with solicited administration site and systemic events during 7 days after each study intervention administration, by study intervention group.
13. Percentage of infant participants 9 months of age with unsolicited AEs during 28 days after each study intervention administration, by study intervention group.
14.Percentage of infant participants 9 months of age with SAEs from first study intervention administration up to study end.
15. Percentage of infant participants 9 months of age with AEs leading to withdrawal from the study or discontinuation of study intervention, from first study intervention administration up to study end, by study intervention group.
16. Percentage of infant participants 9 months of age with deviations from reference ranges or baseline values for hematological, renal and hepatic panel test results at 7 days after each study intervention administration, by study intervention group.
17. Percentage of infant participants 6 weeks of age with solicited administration site and systemic events during 7 days after Priming administration, by study intervention group.
18. Number of infant participants 6 weeks of age with unsolicited AEs during 28 days after Priming administration, by study intervention group.
19. Percentage of infant participants 6 weeks of age with SAEs from first study intervention administration up to 28 days after second study intervention, by study intervention group.
20. Percentage of infant participants 6 weeks of age with AEs leading to withdrawal from the study or discontinuation of study intervention, from first study intervention administration up to 28 days after second study intervention, by study intervention group.
21. 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 7 days after Priming administration, by study intervention group (in the dose finding cohort, safety blood draws will be restricted to only the first 105 infants at Day 8, post first study intervention administration). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
(1) at Day 85
(2, 7, 17) on the day of study intervention administration, at Day 1 and Day 57, and the 6 subsequent days
(3, 8, 18) on the day of study intervention administration, at 1 and Day 57, and the 27 subsequent days
(4, 5, 9, 10, 19, 20) from Day 1 to Day 85
(6, 11) at Day 8 and Day 64
(12) on the day of study intervention administration, at Day 1, Day 57 and Day 169, and the 6 subsequent days
(13) on the day of study intervention administration, at Day 1, Day 57 and Day 169, and the 27 subsequent days
(14, 15) from Day 1 to Day 337
(16) at Day 8, Day 92, and Day 176
(21) at Day 8 and Day 64 for infant 6 weeks of age safety cohort and at Day 8 for the first 105 infant 6 weeks of age dose finding cohort |
|
| E.5.2 | Secondary end point(s) |
1. Percentage of infant 6 weeks of age with solicited administration site and systemic events during 7 days after booster administration, by study intervention group.
2. Number of infant 6 weeks of age with unsolicited AEs during 28 days after booster administration, by study intervention group.
3. Percentage of infant 6 weeks of age with SAEs from 28 days after second study intervention administration up to study end, by study intervention group.
4. Percentage of infant 6 weeks of age with AEs leading to withdrawal from the study or discontinuation of study intervention from 28 days after second study intervention up to study end, by study intervention group.
5. Percentage of infant 6 weeks of age with deviations from reference ranges or baseline values for hematological, renal and hepatic panel test results at 7 days after booster administration, by study intervention group.
6. Anti-iNTS serotype specific IgG GMCs, in infant 6 weeks of age dose finding cohort, 28 days after the third administration.
7. Anti-iNTS serotype specific IgG GMCs, in adult participants 18–50 years of age, before each study intervention administration and 28 days after each study intervention administration, for each study intervention group.
8. Anti-iNTS serotype specific IgG GMCs, in child participants 24–59 months of age, before each study intervention administration and 28 days after each study intervention administration, for each study intervention group.
9. Anti-iNTS serotype specific IgG GMCs, in infant 9 months of age, before each study intervention administration and 28 days after each study intervention administration, for each study intervention group.
10. Anti-iNTS serotype specific IgG GMCs, in infant 6 weeks of age, before each study intervention administration, 28 days after each study intervention administration, and 7 days after the third study intervention administration, for each study intervention group.
11. Percentage of adult 18–50 years of age achieving, for each Ag, at least a 2-fold and 4-fold rise in anti-iNTS serotype specific IgG antibody concentration 28 days after each study intervention administration compared to baseline at Day 1, by study intervention group.
12. Percentage of child 24–59 months of age achieving, for each Ag, at least a 2-fold and 4-fold rise in anti-iNTS serotype specific IgG antibody concentration 28 days after each study intervention administration compared to baseline at Day 1, by study intervention group.
13. Percentage of infant 9 months of age achieving, for each Ag, at least a 2-fold and 4-fold rise in anti-iNTS serotype specific IgG antibody concentration 28 days after each study intervention administration compared to baseline at Day 1, by study intervention group.
14. Percentage of infant 6 weeks of age achieving, for each Ag, at least a 2-fold and 4-fold rise in anti-iNTS serotype specific IgG antibody concentration 28 days after each study intervention administration and 7 days after the third study intervention administration, compared to baseline at Day 1, by study intervention group.
15. Anti- HBs Ag GMCs, in a subset of infant 6 weeks of age (dose finding cohort) randomly selected from each arm, before the first study intervention and 28 days after the third pentavalent vaccine administration.
16. Anti-Hib PRP GMCs, in a subset of infant 6 weeks of age (dose finding cohort) randomly selected from each arm, before the first study intervention and 28 days after the third pentavalent vaccine administration.
17. Anti-measles IgG antibody GMCs, in a subset of infant 6 weeks of age (dose finding cohort) randomly selected from each arm, before and 28 days after MR-VAC administration.
18. Anti-rubella IgG antibody GMCs, in subset of infant 6 weeks of age (dose finding cohort) randomly selected from each arm, before and 28 days after MR-VAC administration.
19. Percentage of a subset of infant 6 weeks of age (dose-finding cohort) randomly selected from each arm, achieving an anti-measles IgG antibody concentration of ≥150 mIU/mL and ≥ 200 mIU/mL, before and 28 days after MR-VAC administration.
20. Percentage of a subset of infant 6 weeks of age (dose finding cohort) randomly selected from each arm, achieving an anti-rubella IgG antibody concentration of ≥4 IU/mL and ≥10 IU/mL, before and 28 days after MR-VAC administration.
21. Percentage of a subset of infant 6 weeks of age (dose-finding cohort) randomly selected from each arm, achieving an anti-Hepatitis B IgG antibody concentration of ≥10 mIU/mL, before the first study intervention and 28 days after third pentavalent vaccine administration.
22. Percentage of a subset of infant 6 weeks of age (dose-finding cohort) randomly selected from each arm, achieving an anti-Hib PRP antibody concentration of ≥0.15 µg/mL before the first study intervention and 28 days after third pentavalent vaccine administration. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1) at Day 232 and the subsequent 6 days
(2) at Day 232 and the subsequent 27 days
(3, 4) from Day 85 to Day 400
(5) at Day 239 for infant 6 weeks of age safety cohort and at Day 8 for the first 105 infant 6 weeks of age dose finding cohort
(6) at Day 260
(7, 8) at Day 1, Day 57, Day 29 and Day 85
(9) at Day 1, Day 85, Day 169, Day 29, Day 113 and Day 197
(10) at Day 1, Day 57, Day 232, Day 29, Day 85, Day 260, and at Day 239
(11, 12) at Day 29 and Day 85 compared to baseline at Day 1
(13) at Day 29, Day 113 and Day 197 compared to baseline at Day 1
(14) at Day 29, Day 85, Day 260, and Day 239 compared to baseline at Day 1
(15, 16, 21, 22) at Day 1 and Day 85
(17, 18, 19, 20) at Day 232 and Day 260 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Reactogenicity and Immunogenicity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| age de-escalation and dose-escalation approach in endemic country |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Observer-blind (a type of double blinding) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 22 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| Yes |
| E.8.4 | Will this trial be conducted at multiple sites globally? | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study (EoS) is defined as the date of the last testing/reading released of the Human Biological Samples or imaging data, related to primary and secondary endpoints. EoS must be achieved no later than 8 months after last subject last visit (LSLV). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 22 |
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