Human Challenge Model With ST-only Enterotoxigenic Escherichia Coli
Human Challenge Model With ST-only Enterotoxigenic Escherichia Coli
Heat stable toxin (ST) producing ETEC strains are important causes of childhood diarrhea in
 many countries. Vaccine candidates targeting ST are in development. A human challenge model
 using an epidemiologically relevant enterotoxigenic E.coli (ETEC) strain expressing ST, but
 not other diarrhea inducing toxins like heat labile toxin (LT), is necessary to perform an
 early and efficient evaluation of an ST-toxoid based vaccine.

 In this controlled human infection study the investigators will assess the safety of a
 ST-only producing ETEC strain and the dose needed to achieve an attack rate of 70% in healthy
 human volunteers.
The investigators have evaluated the ST-only ETEC strain TW10722 in volunteers previously,
 and will also evaluate the ETEC strain TW11681, an ETEC family 8, serotype O19:H45,
 expressing STh, CFA/I, and CS21. These strains have been selected because it is a good
 representative of one of the most important ETEC families commonly associated with childhood
 ETEC diarrhea. The TW10722 will also be evaluated at higher dose if TW11681 does not work
 well.

 After screening including routine blood sampling, intestinal lavage and pre-challenge
 sampling will be done. Volunteers will then be admitted three at a time to Haukeland
 University Hospital and isolated before receiving the oral bacterial inoculum doses, starting
 with 10^6 and increasing one log per round until a safe dose that elicits diarrhoea is found.
 Fine adjustment of the dose needed for a diarrhea attack rate of 70% will then be done in the
 remaining volunteers. Volunteers will be monitored for a range of symptoms, stool output and
 adverse events.

 Antibiotic treatment will be administered at certain predetermined severities of diarrheal
 disease, or after 5 days to eradicate the ETEC infection in all volunteers before leaving the
 hospital. Volunteers will be monitored and sampled again at day 10, 28 and 365 after
 infection. Serum, plasma, stool, intestinal lavage and PBMC samples will be obtained before,
 during and after the ETEC infection to evaluate immune responses and potential correlates of
 protection.
Inclusion Criteria:

 -  Provide written informed consent before initiation of any study procedures.

 -  Healthy as judged by the Principal Investigator (PI) and determined by medical
 history, physical examination, and medication history.

 -  Within 15 days of vaccination, have normal screening laboratories for white blood
 cells (WBC), hemoglobin (Hgb), platelets, absolute neutrophil count (ANC), sodium,
 potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, alanine
 aminotransferase (ALT), C-reactive protein (CRP).

 -  Demonstrate comprehension of the protocol procedures and knowledge of study by passing
 a written examination (passing grade is at least 80 percent).

 -  Capable of understanding, consenting and complying with the entire study protocol.

 -  Female subjects must be of non-childbearing potential, (as defined as surgically
 sterile or postmenopausal for more than 1 year), or if of childbearing potential must
 be practicing abstinence or using an effective licensed method of birth control (e.g.,
 history of hysterectomy or tubal ligation; use hormonal or barrier birth control such
 as implants, injectables, combined oral contraceptives, some intrauterine devices
 (IUDs), cervical sponges, diaphragms, condoms with spermicidal agents, or must have a
 vasectomized partner) within 2 months of infection and must agree to continue such
 precautions during the study and for 30 days after the Day 56 study visit. Male
 subjects must agree not to father a child for 90 days after the Day 28 study visit. A
 woman is eligible if she is monogamous with a vasectomized male.

 -  Agrees not to participate in another clinical trial during the study period.

 Exclusion Criteria:

 -  Women who are pregnant or lactating or have a positive serum pregnancy test at
 screening or positive urine pregnancy test upon admission to inpatient facility.

 -  Abnormal Vital signs, defined as:

 -  Hypertension (systolic blood pressure >140 mm Hg or diastolic blood pressure >90
 mm Hg) at rest on 2 separate days; or (heart rate <55 at rest on 2 separate days)

 -  Respiratory rate >17

 -  Temperature >/= 38.0 C (100.4 F) or symptoms of an acute self-limited illness
 such as an upper respiratory infection or gastroenteritis within 7 days of
 inoculum.

 -  Active positive Hepatitis B, C, and Human Immunodeficiency Virus (HIV) serologies.

 -  History of antimicrobial treatment in the 2 weeks before bacterial inoculum

 -  Received previous experimental E. coli, LT, or cholera vaccines or live E. coli or
 Vibrio cholerae challenges; or previous infection with cholera or diarrheagenic E.
 coli.

 -  Abnormal bowel habits as defined by fewer than 3 stools per week or more than 2 stools
 per day in the past 6 months.

 -  History of chronic gastrointestinal illness, including severe dyspepsia (mild or
 moderate heartburn or epigastric pain occurring no more than 3 times per week is
 permitted), lactose intolerance, or other significant gastrointestinal tract disease.

 -  Regular use (weekly or more often) of laxatives, anti-diarrheal, anti-constipation, or
 antacid therapy.

 -  History of major gastrointestinal surgery, excluding uncomplicated appendectomy or
 cholecystectomy.

 -  Long-term use of oral steroids, parenteral steroids, or high-dose inhaled steroids
 (>800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6
 months (Nasal and topical steroids are allowed).

 -  Have a diagnosis of schizophrenia or other major psychiatric diagnosis.

 -  Receiving the following psychiatric drugs: aripiprazole, clozapine, ziprasidone,
 haloperidol, molindone, loxapine, thioridazine, molindone, thiothixene, pimozide,
 fluphenazine, risperidone, mesoridazine, quetiapine, trifluoperazine, chlorprothixene,
 chlorpromazine, perphenazine, trifluopromazine, olanzapine, carbamazepine, divalproex
 sodium, lithium carbonate or lithium citrate

 -  History of receiving immunoglobulin or other blood product within the 3 months before
 enrollment in this study.

 -  Traveled to Enterotoxigenic Escherichia coli (ETEC) endemic areas within the past 2
 years, ever having used Cholera/ETEC vaccine (Dukoral) or having been raised in a
 cholera or ETEC endemic area.

 -  Received any licensed vaccine within 2 weeks (for inactivated vaccines) or 4 weeks
 (for live vaccines) before enrollment in this study.

 -  An acute or chronic medical condition that, in the opinion of the investigator, would
 render ETEC infection unsafe or would interfere with the evaluation of responses. This
 includes, but is not limited to: known or suspected immunodeficiency, known chronic
 liver disease, significant renal disease, unstable or progressive neurological
 disorders, history of diabetes, cancer (other than a healed skin lesion), heart
 disease (in the hospital for a heart attack, history of irregular heart beat or
 fainting caused by an irregular heart beat), unconsciousness (other than a single
 brief "concussion"), seizures (other than with fever when subject was a child <5 years
 old), asthma requiring treatment with inhaler or medication in the prior 2 years,
 autoimmune disease or eating disorder, and transplant recipients.

 -  Received an experimental agent (vaccine, drug, biologic, device, blood product or
 medication) within 1 month before enrollment in this study or expects to receive an
 experimental agent during the study.

 -  History of alcohol or drug abuse in the last 5 years.

 -  Planned to travel abroad in the time between vaccination and 30 days following the
 ETEC inoculum dose.

 -  Any condition that would, in the opinion of the Site Investigator, place the subject
 at an unacceptable risk of injury or render the subject unable to meet the
 requirements of the protocol.

 -  Use of prescription and over-the-counter (OTC) medications that contain acetaminophen,
 aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs within 48 hours
 prior to receiving the investigational product.

 -  Use of prescription acid suppression medication or OTC antacids within 72 hours of
 investigational product administration.

 -  Subjects with autoimmune disorders, chronic inflammatory disorders or neurological
 disorders with a potential autoimmune correlation.