A Phase I Study of Quadrivalent Human Papilloma Virus (HPV) (Types 6, 11, 16, 18) Recombinant Vaccine in HIV-Infected and HIV-Negative Pre-Adolescents, Adolescents, and Young Adults

Background:

Human papilloma virus (HPV) is one of the most common sexually transmitted diseases and a
significant cause of cutaneous genital warts and anogenital cancer.

Infection with high-risk, oncogenic HPV types, most commonly types 16 and 18, is associated
with low and high-grade cervical cellular abnormalities that are precursors to invasive
cervical cancer, as well as vulvar and anal cancer, while HPV types 6 and 11 are associated
with genital warts.

Persistence of HPV infection is more common in individuals with or at risk for chronic
immunosuppression and HIV-infected individuals have a higher prevalence of HPV infection and
HPV-associated anogential disease compared to age-matched HIV-negative controls.

Study Objectives:

To assess the safety and immunogenicity of quadrivalent human papillomavirus (types 6, 11,
16, 18) recombinant vaccine in HIV-infected preadolescents, adolescents and young adults
12-26 years of age.

To determine whether there are differences in HPV vaccine immunogenicity between HIV-infected
and HIV negative age-matched controls.

To determine whether there are differences in HPV vaccine immunogenicity between HIV-infected
patients receiving highly active antiretroviral therapy (HAART) and those not receiving HAART
with similar CD4 and viral load parameters at entry.

To determine whether HPV vaccination alters HIV-1 RNA levels.

To investigate the impact of CD4 count and HIV-1 RNA levels on HPV vaccine immunogenicity.

To characterize HPV DNA positivity in the study cohort populations through oral/buccal and
anogenital sampling at baseline.

To characterize HPV and HIV knowledge and risk and sexual behaviors in the study cohort
populations.

Eligibility:

Individual Cohorts

Cohort 1: HIV-positive, CD4 cell count greater than or equal to 350 cells/mm3, HIV-1 RNA
level by RT PCR less than or equal to 20,000 copies/ml, on stable HAART regimen for greater
than or equal to 6 months.

Cohort 2: HIV-infected, CD4 cell count greater than or equal to 500 cells/mm3, HIV-1 RNA
level by RT PCR less than or equal to 20,000 copies/ml, on no antiretroviral treatment.

Cohort 3: healthy, HIV-negative controls All Cohorts

Females and males age 12 to 26 years

Patients must have a hemoglobin greater than or equal to 10.0 gm/dL, neutrophil count (ANC)
greater than or equal to 1500/mm3, platelet count greater than or equal to 75,000/mm3 and PT
or PTT less than or equal to 1.5x ULN (with the exception of patients with known clotting
disorders or lupus anticoagulant); SGPT/SGOT < 2/5x ULN, total bilirubin less than or equal
to 1.5x ULN unless attributable to protease inhibitor therapy.

Patients must test negative for hepatitis B virus and hepatitis C virus, unless the result is
consistent with prior vaccination or prior infection with full recovery.

No use of investigational agents within 4 weeks of study enrollment or use of
immunosuppressive or immunomodulating agents within 8 weeks of study entry.

Study Design:

This is a non-randomized, prospective, phase I study of quadrivalent human papillomavirus
(types 6, 11, 16, 18) recombinant vaccine.

The study includes 3 cohorts of pre-adolescents, adolescents and young adults 12-26 years of
age as outlined under Eligibility Criteria. Each cohort will enroll 35 patients.

All study subjects will receive three doses of HPV vaccine at 0, 2 and 6 months administered
IM.

Study participants will be monitored at months 0, 1, 2, 3, 6, 7, and 12 (+/- 2 weeks for each
visit, and every 6 months (+/- 30 days) thereafter for 48 months total.

- ELIGIBILITY CRITERIA:

Cohort 1 Inclusion and Exclusion Eligibility Criteria:

INCLUSION CRITERIA:

2.1.1.1 Age 12 to 26 years

2.1.1.2 Females and males

2.1.1.3 HIV-positive

2.1.1.4 CD4 cell count and HIV-1 RNA level parameters

- CD4 cell count greater than or equal to 350 cells/mm(3)

- HIV-1 RNA level by RT PCR less than or equal to 20,000 copies/ml

2.1.1.5 On stable HAART regimen for greater than or equal to 6 months with CD4 and viral
load parameters as outlined in 2.1.1.4

2.1.1.6 Patients greater than or equal to 18 years willing to provide informed consent or
parent/guardian willing to provide informed consent for minor children less than 18 years
of age.

2.1.1.7 Informed assent for patients 12-17 years of age (Optional at the discretion of the
Principal Investigator and Parent/Guardian based on maturity level of minor)

2.1.1.8 Willing to use acceptable forms of contraception, if applicable, or abstinence to
prevent pregnancy.

EXCLUSION CRITERIA:

2.1.1.9 Any of the following hematologic abnormalities

- Hemoglobin less than 10.0 g/dL

- Neutrophil count less than 1500/mm(3)

- Platelet count less than 75,000/mm(3)

- PT or PTT greater than or equal to 1.5 times ULN (with the exception of patients with
known clotting disorders or known lupus anticoagulant).

2.1.1.10 Any of the following hepatic abnormalities

- ALT/SGPT and/or AST/SGOT greater than 2.5 times ULN

- Total bilirubin greater than 1.5 times ULN unless attributable to protease inhibitor
therapy.

2.1.1.11 Positive tests (antibody and/or antigen) for hepatitis B and hepatitis C viruses,
unless the result is consistent with prior vaccination or prior infection with full
recovery.

2.1.1.12 Acute infection requiring therapy at time of enrollment. Participants may be
eligible for study after being on stable and appropriate anti-infective therapy.

2.1.1.13 Chemotherapy for active cancer.

2.1.1.14 Documented history of non-adherence to antiretroviral treatment regimen within 12
months of study entry.

2.1.1.15 Pregnancy or breastfeeding.

2.1.1.16 Use of immunosuppressive or immunomodulating agents within 8 weeks of study
enrollment. Note: patients receiving oral corticosteroids for management of asthma or
contact hypersensitivity for less than or equal to 14 days in duration will be allowed to
enroll as long as it has been greater than or equal to 30 days since oral corticosteroid
administration.

2.1.1.17 Known immediate hypersensitivity to yeast or any of the vaccine components.

2.1.1.18 Use of investigational agents within 4 weeks prior to study enrollment.

2.1.1.19 Active external genital warts requiring treatment or CIN2/3

2.1.1.20 Any clinically significant diseases (other than HIV infection) or findings during
study screening that, in the opinion of the Principal Investigator or Lead Associate
Investigator, may interfere with the study.

Cohort 2 Inclusion and Exclusion Eligibility Criteria:

Inclusion Criteria

2.1.2.1 Age 12 to 26 years

2.1.2.2 Females and males

2.1.2.3 HIV-positive

2.1.2.4 CD4 cell count and HIV-1 RNA level parameters

- CD4 cell count greater than or equal to 500 cells/mm(3)

- HIV-1 RNA level by RT PCR less than or equal to 20,000 copies/ml.

2.1.2.5 Not receiving antiretroviral treatment with CD4 and viral load parameters as
outlined in 2.1.2.4.

2.1.2.6 Patients greater than or equal to 18 years willing to provide informed consent or
parent/guardian willing to provide informed consent for minor children less than 18 years
of age.

2.1.2.7 Informed assent for patients 12-17 years of age (Optional at the discretion of the
Principal Investigator and Parent/Guardian based on maturity level of minor)

2.1.2.8 Willing to use acceptable forms of contraception, if applicable, or abstinence to
prevent pregnancy.

EXCLUSION CRITERIA:

2.1.2.9 Any of the following hematologic abnormalities:

- Hemoglobin less than 10.0 g/dL

- Neutrophil count less than 1500/mm(3)

- Platelet count less than 75,000/mm(3)

- PT or PTT greater than or equal to 1.5 times ULN (with the exception of patients with
known clotting disorders or known lupus anticoagulant).

2.1.2.10 Any of the following hepatic abnormalities

- ALT/SGPT and/or AST/SGOT greater than 2.5 times ULN

- Total bilirubin greater than 1.5 times ULN unless attributable to protease inhibitor
therapy.

2.1.2.11 Positive tests (antibody and/or antigen) for hepatitis B and hepatitis C viruses,
unless the result is consistent with prior vaccination or prior infection with full
recovery.

2.1.2.12 Acute infection requiring therapy at time of enrollment. Participants may be
eligible for study after being on stable and appropriate anti-infective therapy.

2.1.2.13 Chemotherapy for active cancer.

2.1.2.14 Pregnancy or breastfeeding.

2.1.2.15 Use of immunosuppressive or immunomodulating agents within 8 weeks prior to study
enrollment. Note: patients receiving oral corticosteroids for management of asthma or
contact hypersensitivity for less than or equal to 14 days in duration will be allowed to
enroll as long as it has been greater than or equal to 30 days since oral corticosteroid
administration.

2.1.2.16 Known immediate hypersensitivity to yeast or any of the vaccine components.

2.1.2.17 Use of investigational agents within 4 weeks prior to study enrollment.

2.1.2.18 Active external genital warts requiring treatment or CIN2/3

2.1.2.19 Any clinically significant diseases (other than HIV infection) or findings during
study screening that, in the opinion of the Principal Investigator or Lead Associate
Investigator may interfere with the study.

Cohort 3 Inclusion and Exclusion Eligibility Criteria:

INCLUSION CRITERIA:

2.1.3.1 Age 12 to 26 years

2.1.3.2 Females and males

2.1.3.3 HIV-negative

2.1.3.4 Patients greater than or equal to 18 years willing to provide informed consent or
parent/guardian willing to provide informed consent for minor children less than 18 years
of age.

2.1.3.5 Informed assent for patients 12-17 years of age (Optional at the discretion of the
Principal Investigator and Parent/Guardian based on maturity level of minor)

2.1.3.6 Willing to use acceptable forms of contraception, if applicable, or abstinence to
prevent pregnancy.

EXCLUSION CRITERIA:

2.1.3.7 Any of the following hematologic abnormalities:

- Hemoglobin less than 10.0 g/dL

- Neutrophil count less than 1500/mm(3)

- Platelet count less than 75,000/mm(3)

- PT or PTT greater than or equal to 1.5 times ULN (with the exception of patients with
known clotting disorders or known lupus anticoagulant).

2.1.3.8 Any of the following hepatic abnormalities

- ALT/SGPT and/or AST/SGOT greater than 2.5 times ULN

- Total Bilirubin greater than 1.5 times ULN unless attributable to protease inhibitor
therapy.

2.1.3.9 Positive tests (antibody and/or antigen) for HIV, hepatitis B and hepatitis C
viruses, unless the result is consistent with prior vaccination or prior infection with
full recovery.

2.1.3.10 Acute infection requiring therapy at time of enrollment. Participants may be
eligible for study after being on stable and appropriate anti-infective therapy.

2.1.3.11 Chemotherapy for active cancer.

2.1.3.12 Pregnancy or breastfeeding

2.1.3.13 Use of immunosuppressive or immunomodulating agents within 8 weeks prior to study
enrollment. Note: patients receiving oral corticosteroids for management of asthma or
contact hypersensitivity for less than or equal to 14 days in duration will be allowed to
enroll as long as it has been greater than or equal to 30 days since oral corticosteroid
administration.

2.1.3.14 Known immediate hypersensitivity to yeast or any of the vaccine components.

2.1.3.15 Use of investigational agents within 4 weeks prior to study enrollment.

2.1.3.16 Active external genital warts requiring treatment or CIN2/3

2.1.3.17 Any clinically significant diseases or findings during study screening that, in
the opinion of the Principal Investigator or Lead Associate Investigator may interfere with
the study.