Safety and Immunogenicity of Sequential Rotavirus Vaccine Schedules

Rotavirus, sometimes called the "stomach flu," is the most common cause of severe diarrhea in children. Vaccines can prevent many types of infections and work by causing the body to make proteins called antibodies that fight infection. For some vaccines, more than one vaccination is needed so that the body will make enough antibodies to fight infection. The vaccines (RotaTeq® or Rotarix® oral vaccines) given in this study are recommended for infants by the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP). These vaccines require either 2 or 3 vaccinations to be effective. Healthy infants between 6 weeks and 14 weeks, 6 days of age at Visit 1 will participate for about 10-12 months. Study procedures include reaction assessment and blood sample.

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

Each 1-mL dose of Rotarix® contains a suspension of at least 10^6 median Cell Culture Infective Dose (CCID50) of live, attenuated human G1P rotavirus after reconstitution. The lyophilized vaccine contains amino acids, dextran, Dulbecco's Modified Eagle Medium (DMEM), sorbitol, and sucrose. The liquid diluent contains calcium carbonate, sterile water, and xanthan. The diluent includes an antacid component (calcium carbonate) to protect the vaccine during passage through the acid environment of the stomach. Rotarix® contains no preservatives. Once reconstituted, the vaccine will appear white and turbid.

2-mL ready-to-use oral solution of live reassortant rotaviruses, containing G1, G2, G3, G4, and P1A, which contains a minimum of 2.0 to 2.8 x 10^6 infectious units (IU) per individual reassortant dose, depending on the serotype, and not greater than 116 x 10^6 IU per aggregate dose. The buffered stabilizer solution contains sucrose, sodium citrate, sodium phosphate monobasic monohydrate, sodium hydroxide, polysorbate 80, cell culture media, and trace amounts of fetal bovine serum. RotaTeq® contains no preservatives. RotaTeq® is a pale yellow clear liquid that may have a pink tint.

Number of Participants Developing a Serum Anti-rotavirus Immunoglobulin (Ig) A Titer of 20 or Greater in the WC3 IgA Assay

Blood was collected from all participants at the follow up visit 3-6 weeks after the last vaccination for testing in the ELISA assay to determine the anti-rotavirus IgA antibody titer. A participant met the threshold of a positive response if the post vaccination anti-rotavirus IgA antibody titer was 20 or greater.

Number of Participants Developing a Serum Anti-rotavirus Immunoglobulin (Ig) A Titer of 20 or Greater in the 89-12 IgA Assay

Blood was collected from all participants at the follow up visit 3-6 weeks after the last vaccination for testing in the ELISA 89-12 assay to determine the anti-rotavirus IgA antibody titer. A participant met the threshold of a positive response if the post vaccination anti-rotavirus IgA antibody titier was 20 or greater.

Blood was collected from all participants at the follow up visit 3-6 weeks after the last vaccination for testing in the ELISA assay to determine the anti-rotavirus IgA antibody titers. The geometric mean titers (GMT) for each group were calculated along with the 95% confidence intervals.

Blood was collected from all participants at the follow up visit 3-6 weeks after the last vaccination for testing in the neutralizing antibody assay against the most common rotavirus serotypes, G1-G4 and G9. Antigen-specific geometric mean titers (GMT) for each group were calculated along with the 95% confidence intervals.

The participants' parent/guardian was given a memory aid to record for 8 days the presence of solicited reactions of fever, diarrhea and vomiting. Fever was considered experienced if the participant was assessed with an axillary temperature of 100.4F or greater on any day in the 8-day period after any vaccination. Diarrhea was considered experienced if the participant had 3 or more looser than normal stools in a day. Vomiting was considered experienced if the participant vomited 2 or more times in a day.

Hematochezia was defined as any stools that are black and tarry; maroon in color; or frank red blood. At each visit, signs of hematochezia were assessed and the participant's parent/guardian was instructed to contact the clinical site at any time if the participant had evidence of hematochezia.

Number of Participants Developing Neutralizing Rotavirus Antibody to Rotavirus Serotypes G1, G2, G4P6 and G9

Blood was collected from all participants at the follow up visit 3-6 weeks after the last vaccination for testing in the ELISA assay to determine the antibody titers to rotavirus serotypes G1, G2, G4P6 and G9. A participant met the threshold of a positive response if the post vaccination antigen-specific antibody titer was 10 or greater.

Blood was collected from all participants prior to vaccination and at the follow up visit 3-6 weeks after the last vaccination for testing in the ELISA assay to determine the antibody titers to rotavirus serotype G3. A participant met the threshold of a positive response if the post vaccination antibody titer was 10 or greater.

Blood was collected from all participants at the follow up visit 3-6 weeks after the last vaccination for testing in the ELISA assay to determine the antibody titers to rotavirus serotype G4P8. A participant met the threshold of a positive response if the post vaccination antibody titer was 10 or greater.

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: Axillary temperature of 100.4 degrees Fahrenheit or higher, or More than 3 grossly watery stools, or 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.

Libster R, McNeal M, Walter EB, Shane AL, Winokur P, Cress G, Berry AA, Kotloff KL, Sarpong K, Turley CB, Harrison CJ, Pahud BA, Marbin J, Dunn J, El-Khorazaty J, Barrett J, Edwards KM; VTEU Rotavirus Vaccine Study Work Group. Safety and Immunogenicity of Sequential Rotavirus Vaccine Schedules. Pediatrics. 2016 Feb;137(2):e20152603. doi: 10.1542/peds.2015-2603. Epub 2016 Jan 28.