A Phase I Study to Evaluate the Safety and Immunogenicity of Recombinant HIV-1 Envelope Antigen in Children Born to HIV-Infected Mothers

• Development of adverse clinical, laboratory, or immunological responses to any of the recombinant vaccines [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Changes in viral load in infants found to be HIV infected [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Changes in the slope of absolute CD4 counts in all immunized children [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

PRIMARY: To determine the safety of envelope recombinant proteins rgp120/HIV-1MN (Genentech) and rgp120/HIV-1SF2 (Chiron/Biocine) in infants who are of indeterminate HIV status born to HIV-infected women. To evaluate changes in viral load in infants proven to be infected and absolute CD4 counts in all immunized infants.

SECONDARY: To evaluate the immunogenicity of these envelope recombinant proteins in infants of indeterminate HIV status born to HIV-infected women.

Only 30-50 percent of HIV-infected infants have detectable virus at birth. Successful early sensitization to HIV envelope epitopes may help prevent infection or, alternatively, may enhance HIV-specific immune function to alter HIV replication and disease progression.

Only 30-50 percent of HIV-infected infants have detectable virus at birth. Successful early sensitization to HIV envelope epitopes may help prevent infection or, alternatively, may enhance HIV-specific immune function to alter HIV replication and disease progression.

Newborns are randomized to one of three different doses of either rgp120/HIV-1MN or rgp120/HIV-1SF2 or their matching placebos. At each dose level, 12 patients receive vaccine and three patients receive placebo. Immunizations are performed at 0, 4, 12, and 20 weeks, and patients are followed until 2 years of age. Three of four patients treated at a given dose level must have received two immunizations without evidence of grade 3 or 4 clinical or laboratory toxicity before dose escalation occurs. Twelve additional patients are treated with the optimal dose of each vaccine at weeks 0, 2, 8, and 20 (An accelerated schedule PER AMENDMENT 3/20/96. Changed from - 0, 4, 8, and 20) accompanied by three additional placebo patients per vaccine. PER AMENDMENT 3/20/96: The optimal dose of rgp120/HIV-1MN is 100 mcg and will be given to the 12 patients and the placebo will be given to 3. The optimal dose of rgp120/HIV-1SF2 is 5 mcg and will be given to the 12 patients and the placebo will be given to 3.

PER 2/3/95 AMENDMENT: After the initial patients are enrolled, 18 additional newborns will be randomized to one of the three dose levels of rgp120/HIV-1MN (with no placebos). PER AMENDMENT 6/5/95: Another group of 18 newborns will be randomized to one of three treatments representing 3 different doses of the Chiron/Biocine vaccine (with no placebos).

• HIV Infections
• HIV Seronegativity

• Biological: rgp120/HIV-1MN
  Administered at weeks 0, 4, 8, 12, and 20. Individual group assignment will determine specific dosage and schedule.
• Biological: rgp120/HIV-1 SF-2
  Administered at weeks 0, 4, 8, 12, and 20. Individual group assignment will determine specific dosage and schedule.
• Biological: Placebo version of rgp120/HIV-1MN
  Administered at weeks 0, 4, 8, 12, and 20. Individual group assignment will determine specific dosage and schedule.
• Biological: Placebo version of rgp120/HIV-1SF2
  Administered at weeks 0, 4, 8, 12, and 20. Individual group assignment will determine specific dosage and schedule.

• Experimental: 1
  Patients who will receive rgp120/HIV-1MN
  Intervention: Biological: rgp120/HIV-1MN
• Experimental: 2
  Patients who will receive rgp120/HIV-1SF2
  Intervention: Biological: rgp120/HIV-1 SF-2
• Placebo Comparator: 3
  Patients who will receive the placebo counterpart of 120/HIV-1MN
  Intervention: Biological: Placebo version of rgp120/HIV-1MN
• Placebo Comparator: 4
  Patients who will receive the placebo counterpart of rgp120/HIV-1SF2
  Intervention: Biological: Placebo version of rgp120/HIV-1SF2

• Rogers MF, Mofenson LM, Moseley RR. Reducing the risk of perinatal HIV transmission through zidovudine therapy: treatment recommendations and implications. J Am Med Womens Assoc. 1995 May-Aug;50(3-4):78-82, 93. Review.
• Cunningham CK, Wara DW, Kang M, Fenton T, Hawkins E, McNamara J, Mofenson L, Duliege AM, Francis D, McFarland EJ, Borkowsky W; Pediatric AIDS Clinical Trials Group 230 Collaborators. Safety of 2 recombinant human immunodeficiency virus type 1 (HIV-1) envelope vaccines in neonates born to HIV-1-infected women. Clin Infect Dis. 2001 Mar 1;32(5):801-7. Epub 2001 Feb 28.
• Cunningham CK, Wara DW, Fenton T, Kang M, Hawkins E, McNamara J, Mofenson L, Duliege AM, Francis D, McFarland E, Borkowsky W. Safety of recombinant HIV-1 envelope vaccines in neonates born to HIV-1 infected women. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:93 (abstract no 81)
• Borkowsky W, Wara D, Fenton T, McNamara J, Kang M, Mofenson L, McFarland E, Cunningham C, Duliege AM, Francis D, Bryson Y, Burchett S, Spector SA, Frenkel LM, Starr S, Van Dyke R, Jimenez E. Lymphoproliferative responses to recombinant HIV-1 envelope antigens in neonates and infants receiving gp120 vaccines. AIDS Clinical Trial Group 230 Collaborators. J Infect Dis. 2000 Mar;181(3):890-6.

Inclusion Criteria

Concurrent Medication:

Allowed:

• Antiretroviral therapy.
• Coenrollment in a therapeutic protocol if begun at least 30 days following the week 20 immunization.
• Routine immunizations if given more than 1 week before or after study vaccine.

Patients must be:

• > 37 weeks gestation and < 72 hours of age born to HIV-infected women.
• NOT born to women who received either passive or active immunotherapy during pregnancy.
• NOT breast-fed.
• NOT born to women who are hepatitis B surface antigen positive.
• Receiving AZT at study entry (except infants enrolled in ACTG 076).

NOTE:

• Parent or guardian must provide informed consent and be willing to comply with study requirements.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Documented or suspected serious bacterial infection, metabolic illness, or other immediate life-threatening conditions.

Concurrent Medication:

Excluded:

• Passive or active HIV-specific immunotherapy other than the study candidate vaccines.
• Investigational medications.

• Genentech
• Biocine