Potential Mechanisms for Intussusception After Rotavirus Vaccine-Pilot Study

This is a prospective randomized clinical trial that aims to evaluate the potential effects of the first dose of rotavirus vaccines on gastrointestinal motility and anatomy and blood and stool cytokine responses. It will also assess the association between these outcomes and the pattern of the shedding of vaccine strain rotavirus in the stool. Infants will be randomized to one of four arms: monovalent rotavirus vaccine (Rotarix®, RV1) alone, RV1 with other recommended vaccines, pentavalent rotavirus vaccine (RotaTeq®, RV5) alone, or RV5 with other recommended vaccines. Data derived from the pilot study will be used to assess the feasibility of conducting a larger scale study.

Healthy infants 6-13 weeks of age will be randomized (1:1:1:1) to receive either, RV1 alone, RV1 with Advisory Committee on Immunization Practices (ACIP) routinely recommended immunizations (Diphtheria, Tetanus and Pertussis (DTaP), Haemophilus influenza type b (Hib), pneumococcal conjugate (PCV13), Hepatitis B (HBV) and inactivated polio (IPV)), RV5 alone or RV5 with ACIP routinely recommended immunizations. Imaging study personnel and parents will be blinded to the rotavirus vaccine type; parents will be informed about the rotavirus vaccine type at the completion of the study. Up to 100 infants will be enrolled.

Recruitment and enrollment will occur prior to the first clinic visit. There will be four study visits including the recruitment/enrollment visit and three clinic visits. Infants will be randomized to either RV1, RV1 plus other immunizations, RV5 alone, or RV5 plus other immunizations. Clinic Visit 1 (day 0) will include blood, saliva, stool and breast milk collection . The MRI and ultrasound will be performed prior to vaccination. Children will receive the immunizations to which they are randomized. Imaging personnel and parents will be blinded to rotavirus vaccine type; they will be informed about other vaccines administered. A second MRI and ultrasound will be performed at Clinic Visit 2 (day 5) and blood and stool samples collected. Parents will be unblinded at the completion of Clinic Visit 3 (day 14). Arrangements will be made to get remaining doses of same rotavirus vaccine. Daily stool samples will be collected at home during the 15 day study period (on vaccination day 0 and for next 14 days). A memory aid will be completed to collect reactogenicity data on days 0 and for the next 14 days. Remaining stools and reactogenicity data from parents will be collected at Visit 3.

The investigators will assess blood and stool cytokine responses and intestinal anatomy and motility after rotavirus vaccination by comparing pre-vaccination with post-vaccination responses in the study infants. Cytokines and intestinal anatomy and motility will be assessed at baseline (Visit 1, the day of vaccine receipt) and 5 days after vaccination (Visit 2). For both blood and stool, the following cytokines will be tested: IL-2, IL-6, IL-7, IL-8, IL-15, INF-γ and TNF-α. Additional biomarkers may be studied.

Eligibility Criteria:
Inclusion Criteria:

1. healthy infant 6 to 13 weeks (12 weeks and 6 days) of age at day of rotavirus vaccine administration
2. free of obvious health problems as established by medical history and confirmed with infant's primary physician prior to Visit 1
3. parent/legal guardian willing to have infant feed from a bottle for contrast
4. parent/legal guardian willing and capable of signing informed consent
5. parent/legal guardian and infant expected to be available for entire study
6. parent/legal guardian can be reached by telephone
7. parent/legal guardian expresses willingness to complete study procedures and receive 2 month immunizations, according to recommended schedule

Exclusion Criteria:

1. gestational age of \<37 weeks
2. infant unable to fast for 4 hours prior to MRI procedure
3. receipt of any vaccine except initial HBV (must have at least 28 days between HBV and Visit 1 to be included)
4. history of severe allergic reaction to HBV vaccine
5. contraindications for any of the routine vaccines

   1. Severe Combined Immune Deficiency
   2. history of intussusception
6. precautions for either RV1 or RV5 (may interfere with study outcomes)

   a. altered immunocompetence i. infants with primary and acquired immunodeficiency states, cellular immunodeficiency, hypogammaglobulinemic and dysgammaglobulinemic states ii. infants with blood dyscrasias, leukemia, lymphomas, or other malignant neoplasms affecting the bone marrow or lymphatic system iii. infants on immunosuppressive therapy (including high-dose systemic corticosteroids) iv. infants who are HIV-exposed or infected b. acute gastroenteritis c. moderate or severe acute illness with or without fever d. pre-existing chronic gastrointestinal diseases (e.g., congenital malabsorption syndromes, Hirschsprung's disease, or short-gut syndrome) e. infants with spina bifida or bladder exstrophy (latex rubber is contained in the RV1 oral applicator)
7. sensitivity to latex (latex rubber is contained in the RV1 oral applicator)
8. febrile illness within previous 14 days (axillary temperature of 100.4◦ F or higher)
9. history of vomiting (forceful expulsion of partially digested milk/food) and/or diarrhea (3 watery stools) within 14 days of Visit 1
10. receipt of any steroids, immunoglobulins, other blood products/transfusion
11. receipt of non-steroidal anti-inflammatory drugs in previous 72 hours (may affect cytokine response)
12. receipt of an antipyretic medication (acetaminophen or ibuprofen) within 72 hours prior to the first dose of rotavirus vaccine or is already planning to administer a prophylactic antipyretic medication on the day of and the day following vaccination (this exclusion does not apply if the caretaker indicates he/she might administer antipyretics after vaccination to reduce a fever)
13. is enrolled or plans to enroll in another clinical trial with an investigational product while participating in this study (observational studies are allowed)
14. any condition which, in the opinion of the investigators, may post a health risk to the subject or interfere with the MRI or vaccine evaluation
15. currently receiving medication for gastroesophageal reflux (GERD) or any other gastrointestinal condition including colic
16. infant who is a relative of any research study personnel
17. allergy to barium
18. failed newborn hearing screening

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