Safety and Immune Response of a Rotavirus Vaccine in HIV-infected and Uninfected Children Born to HIV-infected Mothers

• Safety as assessed by all laboratory values (hematologic and chemistry) or signs or symptoms (adverse events) at least Grade 3 not present before the administration of the first vaccination and occurring until the subject goes off study [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Immunogenicity of of RotaTeq as measured by serum anti-rotavirus IgA ELISA SNA responses to type-specific outer surface proteins of the vaccine virus [ Time Frame: At least 14 days after third vaccination ] [ Designated as safety issue: No ]

• Safety of any dose of RotaTeq given to HIV-infected children born to HIV-infected mothers [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Immunogenicity of 3-dose regimen of RotaTeq in HIV-infected and uninfected children born to HIV-infected mothers [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

• Fecal shedding of RotaTeq strains [ Time Frame: At entry and on days 7, 14, 21 and 42 days after the first dose, and at days 7 and 21 after the next two doses ] [ Designated as safety issue: No ]
• Presence of rotavirus in stool samples resulting from acute gastroenteritis as assessed by EIA, testing for infectious virus and RT-PCR [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• HIV RNA or DNA [ Time Frame: At entry and the last determination at the end of the study ] [ Designated as safety issue: No ]
• CD4 count and CD4% [ Time Frame: At entry and the last determination at the end of the study ] [ Designated as safety issue: No ]
• Safety for HIV-1 uninfected participants [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Acquisition of HIV-1 infection by participants classified at screening or entry as HIV-1 uninfected [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

• Fecal shedding of RotaTeq strains after each dose [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Relationship between anti-rotavirus serologic immune responses to CD4 count and/or CD4%, plasma RNA or DNA, and antiretroviral therapy after a 3-dose regimen of RotaTeq given to HIV-infected children born to HIV-infected mothers [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Incidence of HIV infection [ Time Frame: At Week 38 ] [ Designated as safety issue: Yes ]
• Relationship between virus shedding and rotavirus-specific SNA antibodies, copro-antibodies, and CMI against rotavirus vaccine serotypes in recipients of the rotavirus vaccine [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• IgA and IgG copro-antibodies and CMI responses against rotavirus serotypes contained in the vaccine in HIV-infected versus uninfected infants born to HIV-infected mothers [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• CD4% in HIV-infected recipients of rotavirus vaccine or placebo [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Changes in microbial translocation in response to vaccination with RotaTeq relative to placebo in HIV-infected and uninfected participants [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Relationship of mucosal and cell-mediated immune responses to CD4 counts and/or CD4%, plasma HIV RNA or DNA, and ART after 3-dose regimen of RotaTeq given to HIV-infected children [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

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. 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 is to evaluate the safety and immunogenicity of the Rotavirus vaccine candidate, RotaTeq, in HIV-infected and uninfected children born to HIV-infected mothers.

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. The primary purpose of this study is to evaluate the safety and immunogenicity of the Rotavirus vaccine candidate, RotaTeq, in HIV-infected and uninfected children born to HIV-infected mothers.

This study will last up to 18 weeks. Participants will be placed in either Group 1 or 2 and subsequently randomized to receive vaccine or placebo.

Participants in Group 1 will be HIV-uninfected. Participants in Arm 1-Vaccine will receive 3 doses of the study vaccine over a 12-week period. Participants in Arm 1-Placebo will receive 3 doses of study vaccine placebo over a 12-week period.

Participants in Group 2 will be HIV-infected. Participants in Arm 2a will have CD4 percentages of at least 20% and will receive 3 doses of the study vaccine (Arm 2a-Vaccine) or the study vaccine placebo (Arm 2a-Placebo) over a 12-week period. Participants in Arm 2b will have CD4 percentages of at least 15% and up to, but not including, 20%, and receive either 3 doses of study vaccine (Arm 2b-Vaccine) or study vaccine placebo (Arm 2b-Placebo) over a 12-week period. Participants in Arm 2c will have CD4 percentages less than 15% and receive either 3 doses of the study vaccine (Arm 2c-Vaccine) or study vaccine placebo (Arm 2c-Placebo) over a 12-week period.

There will be 16 study visits for each participant. They will occur at screening and Days 0, 7, 14, 21, 42, 49, 56, 63, 70, 91, 98, 105, 112, 119, and 140. Study vaccinations will occur on Days 0, 49, and 98. At all visits, participants will undergo a physical examination and will give a directed medical history. At most visits, stool samples will be collected, and additional testing for other potential pathogens may be conducted. Blood collection will occur at select visits. Blood and stool collected at study visits may be stored and used for future HIV-related research.

For any missed visits, study staff will contact participants' caregivers and conduct a study visit at the participant's home, if possible.

If a national recommendation for rotavirus vaccine is implemented at a study site, participants who are receiving the placebo vaccine will be discontinued from the study and will receive the rotavirus vaccine, per site procedures.

• Biological: RotaTeq vaccine
  2 mL solution of live reassortant rotaviruses, containing G1, G2, G3, G4 and P1A which contains a minimum of 2.0 - 2.8 x 106 infectious units (IU) per individual reassortant dose, depending on the serotype, and not greater than 116 x 106 IUs per aggregate dose
• Biological: RotaTeq vaccine placebo
  2 mL solution

• Experimental: 1-Vaccine
  Participants who are HIV-uninfected will receive 3 doses of the study vaccine over a 12-week period
  Intervention: Biological: RotaTeq vaccine
• Placebo Comparator: 1-Placebo
  Participants who are HIV-uninfected will receive 3 doses of the study vaccine placebo over a 12-week period
  Intervention: Biological: RotaTeq vaccine placebo
• Experimental: 2a-Vaccine
  Participants who are HIV-infected with CD4 percentages of at least 20% will receive 3 doses of the study vaccine over a 12-week period
  Intervention: Biological: RotaTeq vaccine
• Placebo Comparator: 2a-Placebo
  Participants who are HIV-infected with CD4 percentages of at least 20% will receive 3 doses of the study vaccine placebo over a 12-week period
  Intervention: Biological: RotaTeq vaccine placebo
• Experimental: 2b-Vaccine
  Participants who are HIV-infected with CD4 percentages between 15 - 20% (15% up to, but not including 20%) will receive 3 doses of the study vaccine over a 12-week period
  Intervention: Biological: RotaTeq vaccine
• Placebo Comparator: 2b-Placebo
  Participants who are HIV-infected with CD4 percentages between 15 - 20% (15% up to, but not including 20%) will receive 3 doses of the study vaccine placebo over a 12-week period
  Intervention: Biological: RotaTeq vaccine placebo
• Experimental: 2c-Vaccine
  Participants who are HIV-infected with CD4 percentages less than 15% will receive 3 doses of the study vaccine over a 12-week period
  Intervention: Biological: RotaTeq vaccine
• Placebo Comparator: 2c-Placebo
  Participants who are HIV-infected with CD4 percentages less than 15% will receive 3 doses of the study vaccine placebo over a 12-week period
  Intervention: Biological: RotaTeq vaccine placebo

• Committee on Infectious Diseases. Prevention of Rotavirus Disease: Updated Guidelines for Use of Rotavirus Vaccine. Pediatrics. 2009 Mar 30; [Epub ahead of print]
• Kiulia NM, Nyaundi JK, Peenze I, Nyachieo A, Musoke RN, Steele AD, Mwenda JM. Rotavirus Infections among HIV-Infected Children in Nairobi, Kenya. J Trop Pediatr. 2009 Mar 18; [Epub ahead of print]
• Parashar UD, Glass RI. Rotavirus vaccines--early success, remaining questions. N Engl J Med. 2009 Mar 12;360(11):1063-5. No abstract available.

Inclusion Criteria for All Steps:

• 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% is documented at screening
• Parent or legal guardian agrees to give written informed consent and is willing to comply with study requirements
• Parents/guardians of each participant must state 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 must have initiated antiretroviral therapy (ART) before or at the time of administration of the first dose of study vaccine/placebo. Note: It is not acceptable for participants to take a prescription home with them to start ART on the day of vaccination.

Inclusion Criteria for Steps 2 and 3:

• Successful administration of first vaccine (for Step 2) and second vaccine (for Step 3)
• Participants must be less than 32 weeks of age at the time of the third vaccine/placebo dose

Exclusion Criteria for All Steps:

• 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 is defined as greater than or equal to 38.5º C in accordance with WHO guidelines for administration of childhood vaccines.
• Cannot be enrolled from any site at which rotavirus vaccine is available and is 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 SCID or intussusception

Exclusion Criteria for Steps 2 and 3:

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