Safety of and Immune Response to a Novel Human Papillomavirus Vaccine in HIV Infected Children

Genital HPV infection is the most common sexually transmitted infection in the world and may
lead to genital warts, anogenital dysplasias, and invasive cancers. HIV infected people and
others with compromised immunity are at greater risk for HPV-related complications. In
particular, researchers are concerned about the risk of HPV infection to women, who may be
infected by their male partners, especially if these partners engage in anal intercourse. HIV
infected women tend to have multiple types of HPV (associated with a greater risk of
HPV-related disease), are less likely to clear HPV-related conditions, and are more likely to
progress to HPV-related disease. The quadrivalent HPV (types 6, 11, 16, 18) L1 virus-like
particle (VLP) vaccine to be tested in this study was safe and generally well tolerated in
previous studies conducted in healthy and HPV-exposed adolescents, young adults, and older
women. However, it is still unclear if the vaccine will be safe and will elicit a similar
immune response in younger children. The purpose of this study is to evaluate the safety and
immunogenicity of the novel quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine in HIV
infected children 7 to 12 years of age.

This study had two stages and lasted at least 108 weeks. In Stage I, participants were
stratified by CD4 percentage (CD4%) nadir and CD4% at study screening (Stratum A: CD4% Nadir
< 15 and CD4% ≥ 15 at screening, Stratum B: CD4% Nadir ≥ 15 and < 25 and CD4% ≥ 15 at
screening, Stratum C: CD4% Nadir ≥ 25 and CD4% ≥ 25 at screening). Within each stratification
group, they were randomly assigned to one of two arms. During Stage I, Arm A
(QHPV:Quadrivalent human papillomavirus vaccine) participants received 3 doses of vaccine,
while Arm B (Placebo/QHPV) participants received 3 doses of placebo. Participants did not
know whether they were receiving vaccine or placebo. Participants received their assigned
intervention at study entry and Weeks 8 and 24. At Week 96, Stage II began, and all study
participants were told if they received vaccine or placebo in Stage I. Arm A participants
received an additional dose of vaccine at Week 96; Arm B participants received doses of
vaccine at Weeks 96, 104, and 120. Over the course of the study, there were at least 12 study
visits. A physical exam and blood collection occurred at most visits; medical history
occurred at selected visits.

After each vaccination, participants were observed for at least 30 minutes to monitor for any
allergic reactions possibly resulting from the vaccination. For 15 days following
vaccination, parents or guardians were asked to complete a "report card" with details of each
child's signs and symptoms. Three days after each vaccination, parents or guardians of study
participants were contacted by telephone and asked about any adverse events that a child may
have experienced.

Inclusion Criteria

Children ages ≥ 7 to < 12 years of age.

A confirmed diagnosis of HIV infection, defined as two positive assays from two different
samples. The two results may be in any combination of the following:

- at any age: Deoxyribonucleic acid (DNA) polymerase chain reaction (PCR), Ribonucleic
acid (RNA) PCR

- age > 4 weeks: p24 antigen detection

- age >18 months: licensed ELISA (Enzyme-linked immunosorbent assay) with confirmatory
Western Blot

CD4% ≥ 15 at the time of screening is required (Note that this is a minimum requirement,
and that for Stratum C the CD4% needs to be ≥ 25).

For Strata A and B: Currently stable (≥ 3 months) on highly active antiretroviral therapy
(HAART) regimen, defined as three or more antiretrovirals from at least two different
therapeutic classes, or therapy with the combination of azidothymidine, lamivudine, and
abacavir.

For stratum C no antiretroviral therapy is required.

Parent or legal guardian able and willing to provide signed informed consent.

Negative urine pregnancy test sensitive to 25 International Unit (IU) beta-human chorionic
gonadotropin (HCG) for girls who are menstruating (child bearing potential).

Female study volunteers who are participating in sexual activity that could lead to
pregnancy must agree to use two reliable methods of contraception, one of which must be a
barrier method. A barrier method of contraception (condoms or cervical cap) together with
another reliable form of contraception (condoms a , with a spermicidal agent; a diaphragm
or cervical cap with spermicide; an intrauterine device [IUD]; or hormonal-based
contraception) must be used while on this study. Condoms are recommended because their
appropriate use is the only contraception method effective for preventing HIV-1
transmission

Males participating in the study must not attempt to impregnate a woman, or participate in
sperm donation programs. Males engaging in sexual activity that could lead to pregnancy
must use a condom.

Exclusion Criteria

Body temperature ≥ 101 F or ≥ 38.3 C, orally determined, within 72 hours prior to the first
and each subsequent injection. Subjects may be vaccinated any time in the next seven days
thereafter, provided that the site investigator is satisfied that the febrile illness has
ended.

Total bilirubin ≥ 5 x Upper Limit of Normal (ULN) at screening.

Alanine transaminase (ALT) or serum glutamic pyruvic transaminase (SGPT) ≥ 5 x ULN at
screening in the absence of other explained causes (as determined by the site investigator)
at screening.

Serum creatinine ≥ 1.5 mg/dL at screening.

Absolute neutrophil count ≤ 750 cells/mm3 at screening.

Hemoglobin ≤ 9.9 g/dL at screening.

Platelet count ≤ 75,000 cells/mm³ at screening.

Presence of an acute opportunistic non-bacterial or bacterial infection requiring therapy
at the time of enrollment; the subject may be entered once he/she is stable on appropriate
anti-infective therapy.

Chemotherapy for active malignancy.

Other known or suspected disease of the immune system, or immunosuppressive therapy.

Prior treatment with immunosuppressive or immunomodulation therapy within 60 days of
screening.

Prior treatment with three or more week-long courses of corticosteroids (≥ 2.0 mg/kg or ≥
20 mg total of prednisone-equivalent) within one year of screening; or any systemic (oral
or parenteral) steroids (≥ 2.0 mg/kg or ≥ 20 mg total of prednisone-equivalent for ≥ 3
days) within 30 days of study entry.

Prior vaccinations with inactivated vaccines received within two weeks of any dose of study
vaccine, and no other vaccinations may be planned for two weeks after each dose of study
vaccine.

Prior vaccinations with live vaccines received within three weeks before any dose of study
vaccine, and no other vaccinations may be planned for two weeks after each dose of study
vaccine.

Prior diagnosis of sexually transmitted infections (STIs), genital warts, or juvenile
recurrent papillomatosis.

History of any severe allergic reaction (e.g., swelling of the mouth and throat, difficulty
breathing, hypotension, or shock) that required medical intervention.

Known allergies to any vaccine component, including aluminum, yeast, or BENZONASE™
(nuclease, Nycomed [used to remove residual nucleic acids from this and other vaccines]).

Previous treatment with any immune globulin preparation or blood-derived products within
the six months prior to the first injection and none may be planned during the study.

Known coagulation disorder that would contraindicate Intramuscular (IM) injections.

Any clinically significant diseases (other than HIV infection) or clinically significant
findings during the screening medical history or physical examination that, in the
investigator's opinion, would compromise the outcome of this study.

Breastfeeding.