Rotavirus is the leading cause of severe diarrhea in infants and young children, accounting for 45% of severe diarrhea disease in both developed and developing countries. Annually, rotavirus causes approximately 111 million episodes of gastroenteritis requiring home care, 25 million clinic visits, 2 million hospitalizations, and approximately 440,000 deaths in children less than 5 years of age, of which approximately 90% of hospitalizations and 99% of deaths occur in developing countries. Although rotavirus infection is not more common in HIV-infected children, it complicates their care and interferes with their nutrition. Chances of death by these infections can be greater in HIV-infected children when they also suffer from wasting, malnutrition, and/or opportunistic infections. The primary purpose of this study was to evaluate the safety and immunogenicity of the Rotavirus vaccine candidate, RotaTeq, in HIV-infected and uninfected children born to HIV-infected mothers.

International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1072 was an international Phase II randomized double-blind study to assess the safety and immunogenicity of a live, attenuated rotavirus vaccine (RotaTeq) in HIV-1 infected (n=160) and uninfected (n=160) children born to HIV-1 infected mothers. Infants between 2 and <15 weeks of age at screening were assigned to one of four strata, based on HIV-1 status and in the HIV-1 infected, by Cluster of Differentiation percentage (CD4%) [≥ 20% (n=80), 15% ≤ CD4% < 20% (n=60) and < 15% (n=20)]. Screening had to be completed such that the first dose of study vaccine was administered when the participant was 4 to < 15 weeks of age. Within each stratum infants were randomized to receive either active RotaTeq vaccine (three doses of 2.0 mL each at intervals of 4 to 10 weeks with the third dose administered by 32 weeks of age) or placebo on the same schedule.

Participants were followed until six weeks after the last dose of vaccine, with visits at 7, 14, 21 and 42 days after each dose. The day 42 visit after the first two study doses was only required if the next study vaccination was done more than 42 days after the previous dose. At each visit, data were recorded on adverse events observed by the caretaker and investigator, including signs/symptoms ≥ grade 1 and new clinically significant diagnoses. No hematology or chemistry testing was required by the protocol, but sites could record laboratory results in the database if the results were pertinent. Stool samples for fecal shedding were collected at entry, days 7, 14, 21 and 42 after the first vaccination, 7 and 21 days after the second and third vaccinations, and at any unplanned visits for gastroenteritis. Serum for immunogenicity testing was collected at entry and 14 days (or 42 days if not collected at 14 days) after the third vaccination.

In January 2012, rotavirus vaccine (Rotarix) became available as standard of care at the Lusaka study site in Zambia, so enrollment ceased at that site. Infants already enrolled and within the age range where they could receive the Rotarix series were unblinded. Those on placebo were given Rotarix. Those in the active vaccine arm continued receiving the study vaccine. All infants continued to attend study visits. A similar procedure was followed after July 2012, when Rotarix became available as standard of care in Botswana.

During 2013, Zimbabwe was the only site enrolling participants, most of whom were HIV-1 uninfected. The team decided to close the study to enrollment prematurely at the end of September 2013 with a total of 126 HIV-1 uninfected (79% of the target of 160) and 76 HIV-1 infected (48% of the target: 81% of those with CD4% ≥ 20% and 14% of those with CD4% < 20%). Because of the low enrollment of HIV-1 infected infants with lower CD4%, results in the HIV-1 infected stratum were reported combined across CD4% strata.

Baseline characteristics are presented 'as-randomized'. Safety data are presented 'as-randomized' and include all follow-up on study up to 42 days after the third vaccination. Immunogenicity results are presented for the 'per-protocol' population which includes participants who received the 'as-randomized' vaccine and completed the three vaccinations within the required windows (first vaccination between 4 and < 15 weeks of age, subsequent vaccinations at least 28 days after previous vaccination, and third dose by 32 weeks of age).

Inclusion Criteria for All Vaccinations:

• Participant was born to an HIV-1-infected mother whose HIV-1 diagnosis was determined by two different tests performed on the same or separate maternal samples obtained before or during pregnancy or during the post-partum period. Acceptable tests are antibodies in serum or saliva, HIV RNA or DNA, or antigen in the blood.
• Presence or absence of HIV RNA or DNA in the blood of the infant
• CD4% documented at screening
• Parent or legal guardian agreed to give written informed consent and was willing to comply with study requirements
• Parents/guardians of each participant stated their willingness to have the child follow the country-specific childhood Expanded Programme on Immunization ("EPI") schedule for concomitant childhood vaccines recommended during the study period
• HIV-infected participants had initiated antiretroviral therapy (ART) before or at the time of administration of the first dose of study vaccine/placebo. Note: It was not acceptable for participants to take a prescription home with them to start ART on the day of vaccination.

Inclusion Criteria for second and third vaccinations:

• Successful administration of first vaccine (for second vaccination) and second vaccine (for third vaccination)
• Participants were less than 32 weeks of age at the time of the third vaccine/placebo dose

Exclusion Criteria for All Vaccinations:

• Concurrent participation in any study of an investigational drug or vaccine, except for studies for prevention of perinatal HIV-1 transmission
• Known allergy to any component of the study vaccine
• Active gastrointestinal illness or fever. Fever was defined as greater than or equal to 38.5º C in accordance with WHO guidelines for administration of childhood vaccines.
• Could not be enrolled from any site at which rotavirus vaccine was available and was being administered
• Any condition, which would, in the opinion of the site investigator, place the participant at an unacceptable risk of injury or render the participant unable to meet the requirements of the protocol
• Any other condition, situation, or clinically significant finding (other than HIV infection) that, in the investigator's opinion, would interfere with study participation, or interpretation
• Participants with a known history of Severe Combined Immunodeficiency (SCID) or intussusception

Exclusion Criteria for second and third vaccinations:

- Any Grade 4 adverse events believed to be possibly/probably/definitely related to vaccine would disqualify subjects from receiving additional doses. Grade 3 adverse events believed to be possibly/probably related to vaccine had to be demonstrated to have improved to less than Grade 2 prior to receiving the next scheduled dose.

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