Clinical trial NCT05073003: A Study on the Safety and Immune Responses to the GVGH altSonflex1-2-3 Vaccine Against Shigellosis in Adults, Children, and Infants
Official title: A Staged Phase I/II Observer-blind, Randomised, Controlled, Multi-country Study to Evaluate the Safety, Reactogenicity, and Immune Responses to the GVGH altSonflex1-2-3 Vaccine Against S. Sonnei and S. Flexneri, Serotypes 1b, 2a, and 3a, in Adults in Europe (Stage 1) Followed by Age De-escalation From Adults to Children and Infants, and Dose-finding in Infants in Africa (Stage 2)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Diarrhoea
Keywords: Shigella infection
Shigellosis
Diarrhoea
S. sonnei
S. flexneri
Low and middle income countries
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2021-10-11
Enrollment: 552
Sex: ALL
Minimum age (years): 9
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

Brief summary: The aim of the current clinical study is to evaluate, for the first time in humans (FTIH), the safety and immunogenicity of the altSonflex1-2-3 candidate vaccine against S. sonnei and S. flexneri serotypes 1b, 2a, and 3a. The vaccine will be first administered in adults 18 to 50 years of age in Europe. Subsequently, the vaccine will be administered to a shigellosis-endemic population in Africa, first in adults 18 to 50 years of age, then in children 24 to 59 months of age, finally in infants 9 months of age. Infants will also receive a third vaccination. Three different doses of the vaccine \[low (Dose A), medium (Dose B), and high (Dose C) amounts of antigen\] will be evaluated using an age de-escalation approach (from least vulnerable adult population to most vulnerable paediatric population). The results of this study will allow the selection of the most appropriate dose for further vaccine development in infants 9 months of age, which is the main target age group for this vaccine.


Eligibility criteria: Inclusion Criteria:

All participants:

* Participants and/or participants' parent(s)/legally acceptable representative(s) LAR(s), 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 assessment.
* Participants satisfying all screening requirements.
* Participants seronegative for hepatitis B, and hepatitis C.
* Participants negative for human leukocyte antigen B27 (HLA-B27).

Adults 18 to 50 years of age:

* 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.
* Participants seronegative for human immunodeficiency virus (HIV).

Children 24 to 59 months of age:

* A male or female between, and including, 24 and 59 months of age at the time of first vaccination.
* Normal nutritional Z score (-2 standard deviation or greater).
* Previously completed routine childhood vaccinations to the best knowledge of the participant's parent(s)/LAR(s).
* Born after gestation period of ≥37 weeks.
* Participants seronegative for HIV.

Infants 9 months of age:

* A male or female 9 months of age at the time of first vaccination.
* Normal nutritional Z score (-2 standard deviations or greater).
* 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.
* Participants negative for HIV as confirmed by deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) testing.

Exclusion Criteria:

All participants:

* Known exposure to Shigella during lifetime of the participant as confirmed during interview with the participant or documented by patient records (e.g., history of microbiologically-confirmed Shigella infection), recent travel\* (within 2 years) to a country where Shigella or other enteric infections are endemic, or recent occupation\* (within 3 years) involving Shigella species.

  \*Exclusion due to travel or occupation is applicable only to Adults 18 to 50 years of age in Europe (Stage 1).
* Progressive, unstable or uncontrolled clinical conditions.
* History (known or suspected) of any reaction or hypersensitivity likely to be exacerbated by any component of the study vaccine.
* Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
* Hypersensitivity, including allergy, to medicinal products or medical equipment whose use is foreseen in this study.
* Clinical conditions representing a contraindication to IM vaccination and blood draws.
* 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 disease and/or fever (defined as temperature ≥38.0°C) at the time of enrolment\*.

  * The participant can still be enrolled into the study at a time when the acute disease and/or fever has resolved.
* Any clinically significant haematological and/or biochemical laboratory abnormality.
* Confirmed positive COVID-19 test during the period starting 30 days before the first administration of study vaccines (Day -30 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.
* Administration of long-acting immune-modifying drugs at any time during the study period (e.g. infliximab).
* Prior receipt of an experimental Shigella vaccine or live Shigella challenge.
* Use of any investigational or non-registered product (drug, vaccine or medical device)\* other than the study vaccine during the period starting 30 days before the first dose of study intervention (Day -30 to Day 1), or planned use during the study period.

  \*Use of herbs and traditional treatments is not considered an exclusion criterion
* A vaccine not foreseen\* by the Study Protocol administered during the period starting at -21 days before the first dose (-28 days in the case of live vaccines) and ending after the last dose of study intervention administration\*\*.

  \*Vaccines allowed by the Protocol include flu and COVID-19 vaccines in all participants and EPI vaccines in children and infants.

  \*\*In case of emergency mass vaccination, the time period above can be reduced.
* 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 (drug or invasive medical device).
* Any study personnel or immediate dependents, family, or household member.

Adults 18 to 50 years of age:

* Acute or chronic illness, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests.
* 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 vaccine study intervention. For corticosteroids, this will mean prednisone equivalent ≥20 mg/day for adult participants. Inhaled and topical steroids are allowed.
* Pregnant or lactating female.
* Female planning to become pregnant or planning to discontinue contraceptive precautions.
* History of or current chronic alcohol consumption and/or drug abuse.

Adults 18 to 50 years of age and Children 24 to 59 months age:

• Administration of immunoglobulins and/or any blood products or plasma derivatives, or bone marrow transplantation, during the period starting 3 months before the first dose of study vaccine or planned administration during the study period.

Children 24 to 59 months of age and infants 9 months of age:

* Acute or chronic clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests.
* 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 vaccine dose. For corticosteroids, this will mean prednisone ≥0.5 mg/kg/day or 20 mg/day whichever is the maximum dose for paediatric participants. Inhaled and topical steroids are allowed.
* Child in care.

Infants 9 months of age:

• Administration of immunoglobulins and/or any blood products or plasma derivatives, or bone marrow transplantation, from birth or planned administration during the study period.

Primary outcomes:
measure: Anti-serotype specific Shigella lipopolysaccharide (LPS)/O-Antigen (OAg) serum immunoglobulin G (IgG) geometric mean concentrations (GMCs) in infants 9 months of age in Africa
timeFrame: At Day 281 (28 days after the third study intervention administration)
measure: Number of adults 18 to 50 years of age in Europe with solicited administration site events
timeFrame: During 7 days after each study intervention administration (study interventions administered at Day 1 and Day 85/Day 169)
measure: Number of adults 18 to 50 years of age in Europe with solicited systemic events
timeFrame: During 7 days after each study intervention administration (study interventions administered at Day 1 and Day 85/Day 169)
measure: Number of adults 18 to 50 years of age in Europe with unsolicited adverse events (AEs)
timeFrame: During 28 days after each study intervention administration (study interventions administered at Day 1 and Day 85/Day 169)
measure: Number of adults 18 to 50 years of age in Europe with serious adverse events (SAEs)
timeFrame: During the entire study participation period [Day 1 to Day 113 (for ST1_Adults_Placebo_GR1 and ST1_Adults_Dose C_GR1 groups)/Day 197 (for ST1_Adults_Placebo_GR2 and ST1_Adults_Dose C_GR2 groups)
measure: Number of adults 18 to 50 years of age in Europe with deviations from normal values of haematological, renal, and hepatic panel test results at Day 8 (7 days after the first study intervention administration)
timeFrame: At Day 8 (7 days after the first study intervention administration)
measure: Number of adults 18 to 50 years of age in Europe with deviations from normal values of haematological, renal, and hepatic panel test results at Day 92/Day 176 (7 days after the second study intervention administration)
timeFrame: At Day 92 (for ST1_Adults_Placebo_GR1 and ST1_Adults_Dose C_GR1 groups)/Day 176 (for ST1_Adults_Placebo_GR2 and ST1_Adults_Dose C_GR2 groups) (7 days after the second study intervention administration)
measure: Number of adults 18 to 50 years of age in Africa with solicited administration site events
timeFrame: During 7 days after each study intervention administration (study interventions administered at Day 1 and Day 85)
measure: Number of adults 18 to 50 years of age in Africa with solicited systemic events
timeFrame: During 7 days after each study intervention administration (study interventions administered at Day 1 and Day 85)
measure: Number of adults 18 to 50 years of age in Africa with unsolicited AEs
timeFrame: During 28 days after each study intervention administration (study interventions administered at Day 1 and Day 85)
measure: Number of adults 18 to 50 years of age in Africa with SAEs
timeFrame: During the entire study participation (Day 1 to Day 113)
measure: Number of adults 18 to 50 years of age in Africa with deviations from normal values of haematological, renal, and hepatic panel test results at Day 8 (7 days after the first study intervention administration)
timeFrame: At Day 8 (7 days after the first study intervention administration)
measure: Number of adults 18 to 50 years of age in Africa with deviations from normal values of haematological, renal, and hepatic panel test results at Day 92 (7 days after the second study intervention administration)
timeFrame: At Day 92 (7 days after the second study intervention administration)
measure: Number of children 24 to 59 months of age in Africa with solicited administration site events
timeFrame: During 7 days after each study intervention administration (study interventions administered at Day 1 and Day 85)
measure: Number of children 24 to 59 months of age in Africa with solicited systemic events
timeFrame: During 7 days after each study intervention administration (study interventions administered at Day 1 and Day 85)
measure: Number of children 24 to 59 months of age in Africa with unsolicited AEs
timeFrame: During 28 days after each study intervention administration (study interventions administered on Day 1 and Day 85)
measure: Number of children 24 to 59 months of age in Africa with SAEs
timeFrame: During the entire study participation period (Day 1 to Day 113)
measure: Number of children 24 to 59 months of age in Africa with deviations from normal values of haematological, renal, and hepatic panel test results at Day 8 (7 days after the first study intervention administration)
timeFrame: At Day 8 (7 days after the first study intervention administration)
measure: Number of children 24 to 59 months of age in Africa with deviations from normal values of haematological, renal, and hepatic panel test results at Day 92 (7 days after the second study intervention administration)
timeFrame: At Day 92 (7 days after the second study intervention administration)
measure: Number of infants 9 months of age in Africa with solicited administration site events
timeFrame: During 7 days after each study intervention administration (study interventions administered at Day 1, Day 85 and Day 253)
measure: Number of infants 9 months of age in Africa with solicited systemic events
timeFrame: During 7 days after each study intervention administration (study interventions administered at Day 1, Day 85 and Day 253)
measure: Number of infants 9 months of age in Africa with unsolicited AEs
timeFrame: During 28 days after each study intervention administration (study intervention administered at Day 1, Day 85 and Day 253)
measure: Number of infants 9 months of age in Africa with SAEs
timeFrame: During the entire study participation period (Day 1 to Day 281)
measure: Number of infants 9 months of age in Africa with deviations from normal values of haematological, renal, and hepatic panel test results at Day 8 (7 days after the first study intervention administration)
timeFrame: At Day 8 (7 days after the first study intervention administration)
measure: Number of infants 9 months of age in Africa with deviations from normal values of haematological, renal, and hepatic panel test results at Day 92 (7 days after the second study intervention administration)
timeFrame: At Day 92 (7 days after the second study intervention administration)
measure: Number of infants 9 months of age in Africa with deviations from normal values of haematological, renal, and hepatic panel test results at Day 260 (7 days after the third study intervention administration)
timeFrame: At Day 260 (7 days after the third study intervention administration)
Secondary outcomes:
measure: Anti-serotype specific Shigella LPS/OAg serum IgG GMCs in adults 18 to 50 years of age in Europe
timeFrame: At Day 1 and Day 85/Day 169 (before each study intervention administration), at Day 15 (14 days after the first study intervention administration) and at Day 29 and Day 113/Day197 (28 days after each study intervention administration)
measure: Anti-serotype specific Shigella LPS/OAg serum IgG GMCs in adults 18 to 50 years of age in Africa
timeFrame: At Day 1 and Day 85 (before each study intervention administration) and at Day 29 and Day 113 (28 days after each study intervention administration)
measure: Anti-serotype specific Shigella LPS/OAg serum IgG GMCs in children 24 to 59 months of age in Africa
timeFrame: At Day 1 and Day 85 (before each study intervention administration) and at Day 29 and Day 113 (28 days after each study intervention administration)
measure: Anti-serotype specific Shigella LPS/OAg serum IgG GMCs in infants 9 months of age in Africa
timeFrame: At Day 1, Day 85 and Day 253 (before each study intervention administration) and at Day 29, Day 113 and Day 281 (28 days after each study intervention administration)
measure: Number of adults 18 to 50 years of age in Europe achieving a GVGH ELISA level equivalent to ≥1:800 titer against S. sonnei LPS/OAg
timeFrame: At Day 1 and Day 85/Day 169 (before each study intervention administration), at Day 15 (14 days after the first study intervention administration) and at Day 29 and Day 113/Day 197 (28 days after each study intervention administration)
measure: Number of adults 18 to 50 years of age in Africa achieving a GVGH ELISA level equivalent to ≥1:800 titer against S. sonnei LPS/OAg
timeFrame: At Day 1 and Day 85 (before each study intervention administration) and at Day 29 and Day 113 (28 days after each study intervention administration)
measure: Number of children 24 to 59 months of age in Africa achieving a GVGH ELISA level equivalent to ≥1:800 titer against S. sonnei LPS/OAg
timeFrame: At Day 1 and Day 85 (before each study intervention administration) and at Day 29 and Day 113 (28 days after each study intervention administration)
measure: Number of infants 9 months of age in Africa achieving a GVGH ELISA level equivalent to ≥1:800 titer against S. sonnei LPS/OAg
timeFrame: At Day 1, Day 85 and Day 253 (before each study intervention administration) and at Day 29, Day 113 and Day 281 (28 days after each study intervention administration)
measure: Number of adults 18 to 50 years of age in Europe achieving a GVGH ELISA level equivalent to ≥1:1600 titer against S. sonnei LPS/OAg
timeFrame: At Day 1 and Day 85/Day 169 (before each study intervention administration), at Day 15 (14 days after the first study intervention administration) and at Day 29 and Day 113/Day 197 (28 days after each study intervention administration)
measure: Number of adults 18 to 50 years of age in Africa achieving a GVGH ELISA level equivalent to ≥1:1600 titer against S. sonnei LPS/OAg
timeFrame: At Day 1 and Day 85 (before each study intervention administration) and at Day 29 and Day 113 (28 days after each study intervention administration)
measure: Number of children 24 to 59 months of age in Africa achieving a GVGH ELISA level equivalent to ≥1:1600 titer against S. sonnei LPS/OAg
timeFrame: At Day 1 and Day 85 (before each study intervention administration) and at Day 29 and Day 113 (28 days after each study intervention administration)
measure: Number of infants 9 months of age in Africa achieving a GVGH ELISA level equivalent to ≥1:1600 titer against S. sonnei LPS/OAg
timeFrame: At Day 1, Day 85 and Day 253 (before each study intervention administration) and at Day 29, Day 113 and Day 281 (28 days after each study intervention administration)
measure: Number of adults 18 to 50 years of age in Europe showing at least a 4-fold increase in anti-serotype specific Shigella LPS/OAg serum IgG concentrations, as measured by GVGH ELISA
timeFrame: At Day 15 (14 days after first study intervention administration) and at Day 29 and Day 113/197 (28 days after each study intervention administration) compared to Day 1 and Day 85/Day 169 (baseline)
measure: Number of adults 18 to 50 years of age in Africa showing at least a 4-fold increase in anti-serotype specific Shigella LPS/OAg serum IgG concentrations, as measured by GVGH ELISA
timeFrame: At Day 29 and Day 113 (28 days after each study intervention administration) compared to Day 1 and Day 85 (baseline)
measure: Number of children 24 to 59 months of age in Africa showing at least a 4-fold increase in anti-serotype specific Shigella LPS/OAg serum IgG concentrations, as measured by GVGH ELISA
timeFrame: At Day 29 and Day 113 (28 days after each study intervention administration) compared to Day 1 and Day 85 (baseline)
measure: Number of infants 9 months of age in Africa showing at least a 4-fold increase in anti-serotype specific Shigella LPS/OAg serum IgG concentrations, as measured by GVGH ELISA
timeFrame: At Day 29, Day 113 and Day 281 (28 days after each study intervention administration) compared to Day 1, Day 85 and Day 253 (baseline)
measure: Anti-measles IgG concentrations in infants 9 months of age in the dose-finding groups in Africa
timeFrame: At Day 1 (before the first MR-VAC dose administration) and Day 281 (28 days after the second MR-VAC dose administration)
measure: Anti-rubella IgG concentrations in infants 9 months of age in the dose-finding groups in Africa
timeFrame: At Day 1 (before the first MR-VAC dose administration) and Day 281 (28 days after the second MR-VAC dose administration)
measure: Number of infants 9 months of age in the dose-finding groups in Africa achieving anti-measles IgG concentrations of ≥150 mIU/mL and ≥200 mIU/mL
timeFrame: At Day 281 (28 days after the second MR-VAC dose administration)
measure: Number of infants 9 months of age in the dose-finding groups in Africa achieving anti-rubella IgG concentrations of ≥4 IU/mL and ≥10 IU/mL
timeFrame: At Day 281 (28 days after the second MR-VAC dose administration)
Other outcomes:
Locations:
city: Gent
country: Belgium
facility: GSK Investigational Site
city: Kericho
country: Kenya
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: