A Phase 2 Bridging Study to Assess the New Formulation of ETVAX

This is a phase 2, prospective double-blind, randomized, parallel-group study with the aim to demonstrate non-inferiority, in terms of immunogenicity, between the wet formulation and a newly developed partially dried formulation of selected components of ETVAX. A total number of 126 subjects is planned to be included in each arm of the study, i.e. 252 subjects in total. Assuming a 10% dropout rate the target number of subjects to be recruited per study arm is therefore 140, i.e. 280 subjects in total. Healthy volunteers between 18-50 years will be eligible for enrolment into the study.

Eligible subjects will be randomized on Day 1 (Visit 2) to receive either of the two oral formulations of ETVAX (1:1) and consecutively included the study. The treatment allocation (Wet formulation/Partially dried formulation) will be double-blind. The study subjects will receive two oral doses, two weeks apart (Day 1/Visit 2 and Day 15 /Visit 3).The dosing will occur at the clinic (CTC in Gothenburg, Sweden). A follow-up visit will be performed 7 days after the last (second) dose in all study subjects

The primary endpoint to be measured for each patient in the study is response (yes/no) to a vaccine. A vaccine responder will be defined by a ≥2-fold increase in IgA and/or IgG antibody levels against LTB in serum between post- compared to pre-immunization samples. The response rates (seroconversion rates) of IgA and/or IgG anti-LTB antibodies in serum will be derived and compared between the two treatment groups.

The secondary endpoint to be measured for each patient in the study is the occurrence of solicited symptoms for six days after each vaccination (day of vaccination and five subsequent days).

Exploratory analyses will be done to evaluate if ETVAX vaccination induces circulating antigen specific memory B- and/or T cells that can be assessed using recently established laboratory assays.

For the exploratory analyses, subgroups of subjects (n=20-40, evenly distributed between the two treatment arms) will participate in additional follow-up visits 5± 1, 30± 7 and 90± 14 days after the second dose. Blood samples will be collected on all exploratory visits. The extra visits and analyses for exploratory analyses may continue after the main part of the study has been completed and the database locked.

Inclusion criteria

• Male or female aged 18-50 years, inclusive at the time of signing the informed consent.
• Healthy constitution as established by medical history and physical examination.
• Willing and able to give written informed consent for participation in the study.
• Able to comply with study activities, as judged by the Investigator.
• Female Participants:
• Women of child-bearing potential (for definition see Section 9.3.6 in the protocol):
• Have to agree to use an acceptable birth control method during participation in the investigation (see Section 9.3.6).
• A negative pregnancy test (beta human chorionic gonadotropin dipstick test in urine) at Visit 2/Day 1 will be required.
• Male Participants:
• Have to agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined in Section 9.3.6

Exclusion criteria

• An acute or chronic medical condition that, in the opinion of the investigator/physician, would render ingestion of the investigational products unsafe or would interfere with the evaluation of responses. This includes, but is not limited to gastrointestinal diseases, and autoimmune diseases.
• Current malignancy or history of malignancy during the last five years, based on anamnesis.
• Gastroenteritis within two weeks prior to vaccination.
• Regular use of laxatives, antacids or other agents that lower stomach acidity.
• Any planned major surgery during the duration of the study.
• After 10 minutes supine rest, any vital signs outside the following ranges:
• Systolic BP > 160 mm Hg
• Diastolic BP > 100 mm Hg
• Heart rate < 40 or >85 beats per minute
• Antibiotic therapy within two weeks prior to the vaccination.
• Known Hepatitis A, B, C, and/or HIV infection.
• Concomitant intake of immunomodulating drugs during the study period or less than 3 months prior to the first immunization, with the following exceptions: oral anti-histamines are not allowed during the study period or less than 3 weeks prior to the first immunization. Local anti-histamine treatment is allowed during the study period.
• Any other significant medical conditions (e.g. poorly controlled psychiatric condition) judged by the Investigator to preclude entry.
• Intends to receive any other vaccine during the study period, or within two weeks prior to trial vaccination.
• Has previously received Dukoral or any type of ETEC or cholera vaccines.
• Brought up in ETEC-endemic areas (e.g., urban and rural areas of Central and South America, Caribbean, most countries in Asia, Africa, etc.).
• Has travelled to ETEC-endemic areas within the last 3 years OR spent > two months in ETEC endemic areas during the last 10 years.
• Intends to travel to ETEC endemic countries during the study period.
• Known or suspected history of drug, chemical or alcohol abuse, as deemed by the investigator/physician.
• History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to ETVAX®.
• Participation in any other clinical study that included drug treatment with the last administration within the past 3 months prior to administration of study treatment in this study. Patients consented and screened but not dosed in previous clinical studies are not excluded.
• Concomitant participation in any other clinical study.
• Females who are pregnant as determined by urine test at inclusion and prior to each vaccination.
• Females who are nursing.
• Unable to participate in all study visits.
• Any condition or circumstance which would make the subject unsuitable for participation in the study in the opinion of the investigator/physician.