Safety and Immunogenicity of Sequential Rotavirus Vaccine Schedules

Rotavirus is the most common cause of severe gastroenteritis among children. The purpose of
the proposed study is to determine the non-inferiority and safety of the 2 licensed
rotavirus vaccines when both are administered to the same child during sequential
vaccinations. Both Rotarix® and RotaTeq® vaccines have been evaluated for safety and
efficacy in placebo-controlled trials with more than 70,000 infants each and it is likely
that both vaccines delivered in various combinations will be safe and effective. Since
RotaTeq® was licensed in the United States (US) in 2006, approximately 6 million doses have
been administered in the US. In addition, Rotarix® has been licensed in over 100 nations
worldwide and has been delivered to many children in Latin America where it has been
recommended for universal vaccination for over 2 years. Now both RotaTeq® and Rotarix® are
licensed in the US, and it is expected that health care providers will administer both
vaccines. A 3-dose regimen is recommended for RotaTeq® and a 2-dose regimen for Rotarix®.
From previous experience, it is likely that one of the vaccines may become unavailable for
some period or pediatric offices may switch from one vaccine to the other. Thus, it is
probable that mixed schedules will be administered to infants. The primary objective is to
determine if the proportion of seroresponders in the sequential mixed rotavirus vaccine
groups (RotaTeq® and Rotarix®) is non-inferior to the proportion of seroresponders in the
recommended schedule of the single vaccine alone group. Secondary Objectives are: to
determine the neutralizing rotavirus antibody responses to the most common rotavirus
serotypes (G1-G4 and G9) at 3-6 weeks after the last vaccination for both the sequential,
mixed rotavirus vaccine schedule and the single rotavirus vaccine recommended schedule; and
to determine if sequential mixed rotavirus vaccine schedules are safe with no statistically
significant increase in fever, diarrhea, vomiting, or intussusception in the mixed schedule
groups when compared with the recommended schedule of the single vaccine alone group. Normal
healthy full-term infants who are scheduled to receive their routine infant immunizations
and who are at least 6 weeks of age and no more than 14 weeks, 6 days of age at Visit 1 will
be recruited from their primary care clinic. Infants will be randomized (open label) to one
of 5 different rotavirus vaccine study groups. Two study groups will be administered the
standard RotaTeq® or Rotarix® vaccines as 3 and 2 doses, respectively, and 3 study groups
will be administered mixed sequences of RotaTeq® and Rotarix® given as 3 doses. All
rotavirus vaccines will be administered concurrently with the other routinely administered
childhood vaccines. Parents/legal guardians will be given a memory aid and a thermometer,
and asked to record any suspected fever (with measured temperature documented) or adverse
events for Days 1-8 after vaccination. At approximately 1 week after vaccination, study
personnel will contact the parents/legal guardians, review the completed memory aid, and
record the findings on the case report form. Blood for immunogenicity testing will be
obtained 3-6 weeks after the last dose of vaccine. For the four 3-dose rotavirus vaccine
study groups, blood will be obtained at approximately 7 months of age (3-6 weeks after the
last rotavirus vaccine dose). For the single Rotarix® vaccine study group, blood will be
obtained at approximately 5 months of age (3-6 weeks after the last dose of Rotarix®
vaccine). The primary analysis will be based on rates of induction of anti-rotavirus serum
immunoglobulin (Ig) A in the 5 study groups 3-6 weeks

Inclusion Criteria:

- Male or female infants who are at least 6 weeks of age and no more than 14 weeks, 6
days of age at Visit 1.

- Parent(s)/legal guardian(s) have signed informed consent documents.

- Children who will be available for the entire study period and whose parents/legal
guardians can be reached by telephone.

- Healthy infants as determined by medical history and by a baseline physical
examination with no clinically significant abnormal findings within 14 days before
the first dose.

- Parents/legal guardians able to complete all relevant study procedures during study
participation.

Exclusion Criteria:

- Any clinically significant history of gastrointestinal disease including abdominal
surgery or liver disease or other serious medical conditions as determined by the
site investigator.

- Any history of immunodeficiency in the infant (e.g., the infant is known to be human
immunodeficiency virus (HIV) positive, to have hypogammaglobulinemia, or to have an
underlying malignancy), or any infant with any unvaccinated household contact who is
immunocompromised such as:

- Any malignancies or are otherwise immunocompromised;

- Primary immunodeficiency; or

- Receiving immunosuppressive therapy.

- Known sensitivity to any vaccine components, such as latex in the Rotarix®
applicator.

- Previous receipt of a rotavirus vaccine.

- Acute illness at the time of vaccine administration, such as any of the following
within the past 48 hours:

1. Axillary temperature of 100.4 degrees Fahrenheit or higher, or

2. More than 3 grossly watery stools, or

3. Any episodes of vomiting (forceful expulsion of partially digested milk/food).
Infants with previous diagnoses of gastroesophageal reflux whose regurgitation
episodes have not changed in the 48-hour period prior to the first vaccination
may be enrolled.

If these symptoms clear within 48 hours and the subject meets the other
inclusion/exclusion criteria, then the subject may be enrolled.

- The subject is currently participating in a study that involves an experimental agent
(vaccine, drug, biologic, device, blood product, or medication) or has received an
experimental agent within 1 month prior to enrollment in this study, or expects to
receive another experimental agent during participation in this study.

- Less than 37 weeks gestation at birth.

- Receipt of blood and/or blood products (including immunoglobulin) within 4 weeks
before vaccine administration.

- Receipt of live vaccine within the past 30 days or a nonreplicating, inactivated, or
subunit vaccine within the last 14 days, although planned licensed trivalent
inactivated influenza vaccine that may be administered to children over 6 months of
age during a routine clinic visit is permitted and would not be exclusionary.

- The subject has 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.