A Study on the Safety and Immune Responses to the GVGH altSonflex1-2-3 Vaccine Against Shigellosis in Adults, Children, and Infants

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)

The aim of the current clinical study was 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 was first administered to adults 18 to 50 years of age in Europe. Subsequently, the vaccine was administered to a shigellosis-endemic population in Africa, first to adults 18 to 50 years of age, then to children 24 to 59 months of age, and finally to infants 9 months of age. Infants also received a third vaccination. Three different doses of the vaccine [low, medium, and high amounts of antigen] were evaluated using an age de-escalation approach (from the least vulnerable adult population to the most vulnerable paediatric population). The results of this study allowed the selection of the most appropriate dose for further vaccine development in infants 9 months of age, which was the main target age group for this vaccine.

Inclusion Criteria:

All participants:

• Participants and/or participants' parent(s)/legally acceptable representative(s) (LARs), who, in the opinion of the investigator, could and would 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 was obtained from the participant/parent(s)/LAR(s) of the participant prior to the performance of any study-specific procedure.
• Healthy participants, as established by medical history, clinical examination, and laboratory assessment.
• Participants who satisfied all screening requirements.
• Participants who were seronegative for hepatitis B and hepatitis C.
• Participants who were 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.
• A normal nutritional Z score (-2 standard deviations or greater).
• Participants who had previously completed routine childhood vaccinations to the best knowledge of the participant's parent(s)/LAR(s).
• Participants who were born after a gestation period of ≥37 weeks.
• Participants who were seronegative for HIV.

Infants 9 months of age:

• A male or female 9 months of age at the time of first vaccination.
• A normal nutritional Z score (-2 standard deviations or greater).
• Participants who had previously completed routine childhood vaccinations to the best knowledge of the participant's parent(s)/LAR(s).
• Participants who were born after a gestation period of >=37 weeks.
• Participants who were negative for HIV, as confirmed by deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) testing.

Exclusion Criteria:

All participants:

• Known exposure to Shigella during the 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 was applicable only to adults 18 to 50 years of age in Europe (Stage 1).

• Progressive, unstable, or uncontrolled clinical conditions.
• A 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 was required).
• Hypersensitivity, including allergy, to medicinal products or medical equipment whose use was 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, might have interfered 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 could still be enrolled into the study at a time when the acute disease and/or fever had resolved.

• Any clinically significant haematological and/or biochemical laboratory abnormality.
• A 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 have posed 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 was not considered an exclusion criterion.

• Administration of a vaccine not foreseen* by the Study Protocol 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 included 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 could be reduced.

• Concurrent participation in another clinical study, at any time during the study period, in which the participant had been or would be exposed to an investigational or non-investigational intervention (drug or invasive medical device).
• Any study personnel or immediate dependents, family, or household members.

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 meant a prednisone equivalent ≥20 mg/day for adult participants. Inhaled and topical steroids were allowed.
• Pregnant or lactating females.
• Females planning to become pregnant or planning to discontinue contraceptive precautions.
• A history of or current chronic alcohol consumption and/or drug abuse.

Adults 18 to 50 years of age and children 24 to 59 months of 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 meant prednisone ≥0.5 mg/kg/day or 20 mg/day, whichever was the maximum dose for paediatric participants. Inhaled and topical steroids were allowed.
• A 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.