Safety of Sublingual dmLT for ETEC

Despite the public health burden of Enterotoxigenic Escherichia coli (ETEC) on travelers,
deployed soldiers and, most significantly, young children in the developing world, there is
no licensed vaccine against ETEC enteritis.This is a Phase 1 study in healthy adults to
determine the safety and immunogenicity of an ETEC candidate vaccine, attenuated recombinant
dmLT from ETEC, administered by the SL (Sublingual) or Oral Immunization. The study subject
population is 52 healthy adult male and female subjects, ages 18 to 45. Subject participation
duration is approximately 8 months with study duration of approximately 1.5-2 years,
including 6-7 months of follow-up. Potential risks include subjects could develop varying
degrees of diarrhea or other gastrointestinal symptoms (such as nausea, abdominal pain or
cramping, gas, and decreased appetite). Blood drawing may be associated with pain and
bruising at the site and rarely, with fainting or seizure. There is no direct benefit to
subjects from participating in this study but the potential benefits to children and adults
who may receive a future beneficial vaccine based on the results of this trial justify the
more than minimal risk of the subjects who will participate in this trial. The primary
objective is to assess the safety and tolerability of dmLT vaccine when administered in three
doses sublingually over a range of dosages in healthy adult subjects. The secondary
objectives are to assess long-term safety follow-up from immunization through Month 7 post
vaccination, and following three SL doses of dmLT vaccine over a range of dosages and
comparing with three doses of a comparable dosage of oral vaccine.

Inclusion Criteria:

- Male or female ages 18-45, inclusive. - Provide written informed consent before
initiation of any study procedures. - General good health, without (a) significant medical
illness, (b) clinically significant physical examination findings, including vitals, as
determined by the PI, and (c) screening laboratory values outside the site's normal limits.
- Within 46 days of vaccination, have normal screening laboratories, per Appendix B for
white blood cells (WBCs), hemoglobin (Hgb), platelets, absolute neutrophil count (ANC),
sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, alanine
aminotransferase (ALT), aspartate aminotransferase (AST). - Have normal screening
laboratories for urine protein Trace protein is acceptable. - HgbA1C <6.5% at screening. -
Demonstrate comprehension of the protocol procedures and knowledge of study by passing a
written examination (passing grade is at least 70 percent). - Agrees to complete all study
visits and procedures. - 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 using an effective method of birth control (e.g., use hormonal or
barrier birth control such as implants, injectables, combined oral contraceptives, some
intrauterine devices [IUDs], cervical sponges, diaphragms, condoms with spermicidal agents
must have a vasectomized partner) within 2 months of vaccination, or practice abstinence
and must agree to continue such precautions during the study and for 30 days after the Day
29 study visit. Male subjects must agree not to father a child for 30 days after the Day 29
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. - Agrees not to
donate blood to a blood bank for 12 months after receiving the vaccine. - Potential
subjects must be willing to adhere to the following prohibitions and restrictions during
the course of the study to be eligible for participation: - Strenuous exercise (e.g., long
distance running > 5km/day, weight lifting, or any physical activity to which the subject
is not accustomed) is to be avoided during the overnight stay and for at least 72 hours
prior to each study drug administration (and the Follow-up visit). - Subjects should not
have donated blood in the 8 weeks prior to study entry.

Exclusion Criteria:

- Women who are pregnant or lactating or have a positive serum pregnancy test at screening
or positive urine pregnancy test prior to vaccination. - 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 -- Palpated heart rate <55 or >100 beats/minute at rest on 2
separate days*; or *If heart rate between 45 and 55, subjects may be enrolled with an EKG
that demonstrates normal sinus rhythm and does not document conduction disorders.
--Temperature >/= 38.0 degrees C (100.4 degrees F) - Symptoms of an acute self-limited
illness, including a temperature >/= 38.0 degrees C (100.4 degrees F), such as an upper
respiratory infection or gastroenteritis within 7 days of administration of dmLT. -
Positive hepatitis C, or HIV serology or positive hepatitis B serology not consistent with
prior hepatitis B immunization. - Have a positive urine drug screen for opiates. - Subjects
who are unwilling or unable to cease smoking for the duration of the overnight stay. -
History of antimicrobial treatment in the 2 weeks before administration of dmLT. - Received
previous experimental E. coli, LT, or cholera vaccines or live E. coli or Vibrio cholera
challenges; or previous infection with cholera or diarrheagenic E. coli. - Abnormal routine
bowel habits as defined by fewer than three stools per week or more than two 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 three times
per week is permitted), 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, defined as longer than 14 days, 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. - Are
receiving the following psychiatric drugs: aripiprazole, clozapine, ziprasidone,
haloperidol, molindone, loxapine, thioridazine, thiothixene, pimozide, fluphenazine,
risperidone, mesoridazine, quetiapine, trifluoperazine, chlorprothixene, chlorpromazine,
perphenazine, trifluopromazine, olanzapine, carbamazepine, divalproex sodium, lithium
carbonate, or lithium citrate. NOTE: Subjects who are receiving a single antidepressant
drug and are stable for at least 3 months before enrollment without de-compensating
symptoms are allowed to be enrolled in the study. - History of receiving Ig or other blood
product within the 3 months before enrollment in this study. - Traveled to ETEC-endemic
areas, defined as Africa, Middle East, South Asia, or Central or South America within the
past 3 years or 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 or plans to receive any licensed vaccine within 2 weeks (for inactivated
vaccines) or 4 weeks (for live vaccines) after any study vaccination. - An acute or chronic
medical condition that, in the opinion of the investigator, would render administration of
dmLT 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 pr ogressive 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 heartbeat),
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. - Plans to travel outside of the USA in the time between study vaccination
and 28 days following the final vaccination. - Unable to spend up to 48 hours at an
overnight facility following the administration of Dose 1. - 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 or over-the-counter (OTC) medications that contain acetaminophen, aspirin,
ibuprofen, and other non-steroidal 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. - Subjects who planned to travel to an ETEC-endemic area,
defined as Africa, Middle East, South Asia, or Central or South America, during the
long-term safety follow-up period (6 months) of the study. - Known allergies to study
compound. - Special populations, e.g., non-English speakers, children, illiterate or
non-writing individuals, vulnerable populations. - Any abnormality of the palate.