Safety and Efficacy Challenge Study of CVD 1208S, a Live, Attenuated Oral Vaccine to Prevent Shigella: Phase IIb

Safety, Immunogenicity, and Efficacy Following Experimental Challenge of CVD 1208S, a Delta guaBA, Delta Sen, Delta Set Shigella Flexneri 2a Live, Oral Vaccine: Phase IIb Challenge Study

The purpose of this study is to determine whether CVD 1208S (a live, attenuated, oral vaccine) is safe and effective in the prevention of Shigella infection.

The study comprises a Phase 2 vaccination study and a Phase 2b challenge study. The primary objectives of the Phase 2 vaccination study are: 1. To evaluate, in healthy volunteers, the safety and clinical acceptability of three spaced doses (one month apart) of an investigational, live, oral, attenuated vaccine called CVD 1208S, with particular attention to the occurence of diarrhea, dysentery, and fever, and 2. To characterize immune responses following ingestion of this vaccine. The primary objective of the Phase 2b challenge study is to measure the protective efficacy of 3 spaced doses of vaccine after ingestion of an oral challenge strain called Shigella flexneri 2a strain 2457T.

Shigella is a leading cause of disease and death among children younger than 5 years living in developing countries. The difficulty controlling this infection has led experts to believe that prevention with the use of a vaccine is a promising strategy. At the CVD, we have pursued an approach of developing an oral, attenuated Shigella vaccine that prevents infection with the Shigella types of greatest clinical and epidemiologic importance. One of the strains to be included in the vaccine is called Shigella flexneri 2a. Investigators at the CVD have created a vaccine from Shigella flexneri 2a, designated CVD 1208S, using molecular biology techniques. To date, nearly 40 subjects have received varying doses of this vaccine with good clinical tolerance and modest immunogenicity. Previously a single dose of vaccine was used. In the current study, we will administer doses of vaccine on days 0, 28, and 56 to attempt to maximize immunogenicity. Approximately one month after the 3rd dose, a group of ~15-20 vaccinated volunteers along with a similar number of unvaccinated control subjects will be admitted to the CVD Research Isolation Ward at SNBL and challenged with wild type Shigella flexneri 2a. By comparing the attack rate of illness in vaccinated vs. unvaccinated subjects, we will determine the vaccine's ability to confer protective immunity.

Inclusion Criteria:

• Age 18 to 45 years, inclusive

• Good general health as determined by a screening evaluation within 45 days before inoculation

• Expressed interest and availability to fulfill study requirements

• Informed, written consent

• Agrees to indefinite storage of unused clinical specimens at the CVD for use in future research, which may require separate IRB approval

• Agrees not to participate in another investigational vaccine or drug trial during the 6-month study

• Has no childbearing potential, i.e., either surgically sterilized or 1 year postmenopausal, or agrees to abstain from becoming pregnant from the day of screening (at least 14 days before vaccination) through Day 42 of the trial by using one of the following methods of birth control:

  • Abstinence
  • Intrauterine contraceptive device
  • Oral contraceptives or equivalent hormonal contraception, e.g., progestogen-only implantable, cutaneous hormonal patch, injectable contraceptives, or Nuvaring (vaginal hormonal ring)
  • Diaphragm in combination with contraceptive jelly, cream, or foam
  • Condoms with spermicide

Exclusion Criteria:

• An acute or chronic medical condition that, in the opinion of the investigator, would render vaccination unsafe or would interfere with the evaluation of responses. This includes, but is not limited to:

  • Chronic liver disease, renal insufficiency, unstable or progressive neurological disorders, diabetes mellitus, collagen vascular disease (such as lupus), active neoplastic disease (not cured or in remission), or previous hematological malignancy
  • Repeated (two or more) seizures occurring after 5 years of age, and not related to a concussion
  • Any of the following in the past 10 years: Crohn's disease, ulcerative colitis, irritable bowel disease, celiac disease, stomach or intestinal ulcers, or 2 or more episodes of arthritis (joint pain and swelling);
  • Recurrent infections (more than 1 hospitalization for invasive bacterial infections, e.g., pneumonia, meningitis)
  • G6PD deficiency
  • Any current illness requiring daily medication (vitamins, birth control pills, nasal or topical medications, allowed)
  • Blood in stool on more than 2 occasions (other than small amounts from straining) in past 12 months
  • Recurrent diarrhea (more than 5 episodes in past 6 months, each lasting 3 days or more)

• Immunosuppression as a result of an underlying illness or treatment within the preceding 36 months,

• long term use of steroids, or high-dose inhaled steroids (greater than 800 micrograms/day of beclomethasone dipropionate or equivalent) within the preceding 6 months (Nasal and topical steroids are allowed)

• History of the following types of abdominal surgery:

  • Any major gastrointestinal surgery (e.g., intestinal resection or splenectomy)
  • A laparotomy for any reason (e.g., hysterectomy, Caesarian section, appendectomy, or herniorrhaphy) within the last 3 years
  • Laparoscopic abdominal surgery within the past year
  • A large abdominal scar of unclear origin

• Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months

• Known allergy or intolerance to ciprofloxacin, trimethoprim/sulfamethoxazole (or other sulfa antibiotic) or ampicillin (for women)

• History of shigellosis or Shigella vaccination (except as a participant in Part A of this study) or challenge or a laboratory worker with known exposure to Shigella

• During the past 3 years, developed diarrhea during travel to a developing country, or within 1 week of returning home

• Anticipates any of the following during 30 days after discharge from the Isolation Ward:

  • Shares a household with a child less than 3 years of age, a pregnant woman, or a woman who plans to become pregnant during this time period
  • Household or sexual contact with someone who has weakened immunity (such as someone with HIV infection, someone receiving treatment for cancer, or an elderly person greater than 70 years)
  • Occupation as a food-handler, childcare (for children less than 3 years), or health care worker with direct patient contact

• Poor peripheral access for placement of an intravenous line

• A clinically significant abnormality on physical examination, including, but not limited to:

  • A pathologic heart murmur
  • Lymphadenopathy
  • Hypertension (either systolic blood pressure greater than 150 or diastolic blood pressure greater than 90 on 2 separate days)
  • A large abdominal scar of unclear origin

• Any of the following laboratory abnormalities detected during medical screening:

  • WBC less than 3.0 x 103/mm3
  • Neutrophils less than 1500/mm3
  • Hemoglobin less than 12.5 g/dL (men) or less than 11.5 g/dL (women)
  • Platelets less than 130,000/mm3
  • Serum sodium less than 130 or greater than 150
  • Creatinine greater than 1.5 mg/dL
  • Fasting glucose greater than 99 mg/dl (if screening >99 mg/dl)
  • SGPT greater than 82 U/L (men) or greater than 60 U/L (women)
  • HLA B27 positive
  • Positive serology for syphilis, hepatitis C or HIV antibody or hepatitis B surface antigen
  • Stool culture positive for Salmonella, Shigella, Campylobacter, Yersinia, V. cholera, or pathogenic protozoa or lacking normal flora
  • EKG showing pathologic Q waves and significant STT wave changes; left ventricular hypertrophy; any nonsinus rhythm excluding isolated premature atrial contractions; right or left bundle branch block; or advanced (secondary or tertiary) A-V heart block.

• Positive serum pregnancy test during medical screening or within 24 hours of challenge, or current breast feeding (women)

• A psychological condition, including a personality, anxiety, or affective disorder, and schizophrenia, which in the opinion of a clinical psychologist compromises the ability of the volunteer to tolerate an inpatient trial

• Receipt of any of the following (does not include the CVD 1208S vaccine):

  • Any vaccine or investigational drug within 30 days of challenge
  • A live, attenuated vaccine within the 30 days of the challenge
  • A subunit or killed vaccine within the 14 days of the challenge
  • A blood product, including immunoglobulin, in the 90 days before the challenge

• Receipt of antibiotics within 7 days of inoculation (or within 21 days if the antibiotic was azithromycin)

• Loose stools (grade 3-5) or any other acute illness such as fever greater than or equal to 100.4 degrees F during the 48 hour acclimation on the inpatient ward that continues until time of challenge

• Other condition that in the opinion of the investigator would jeopardize the safety or rights of a study participant or render the subject unable to comply with the protocol.