Immunogenicity of Off-Schedule Dosing of HPV Vaccine

The immune response to the quadrivalent human papillomavirus (HPV) vaccine in the
non-clinical trial settings is unknown. In addition, the immune response following
administration of vaccine at substantially prolonged intervals is unknown. Early indications
suggest that many girls will be receiving the vaccine at prolonged intervals and that this
timing may affect immunogenicity. The lack of knowledge about the immunogenicity of prolonged
intervals between vaccine doses precludes evidence based recommendations for patients who are
substantially late for their second or third dose. Some clinicians currently restart the
series while others give the doses at the incorrect interval (unpublished observation)
without the ability to counsel their patients as to their expected level of immune response
or protection. Examining the immune response prior to the third dose and at one and six
months after the third dose will allow a better understanding of the immunogenicity of this
vaccine and immune response to booster doses. Furthermore, determining factors related to
non-adherence in the adolescent age group is important and timely. As an increasing number of
vaccines are being recommended to the adolescent age group, elucidating factors involved with
non-adherence to the recommended dosing schedule is now critical. This information can guide
interventions that aim to increase adolescent adherence to the recommended schedules.
Eligible girls 9 - 17 years old receiving the quadrivalent HPV vaccine from their primary
care provider will be enrolled into this study on the day of, but prior to, receiving their
third HPV vaccine dose or at approximately 28 days after the third HPV dose . Blood for
immunogenicity testing will be obtained up to three times throughout the study: one month
(Study Day 28) and six months (Study Day 180) after the third dose (Study Day 0) for all
subjects and just prior to the third dose for subjects on time for their third dose
(regardless of the time interval between the first and second dose). The primary analysis
will be based on comparing the geometric mean titer (GMTs) and sero-response rate of subjects
receiving the vaccine doses at substantially prolonged intervals to GMTs and sero-response
rate of subjects receiving the second and third dose on time. In addition, on Study Day 0,
patient and parent related factors known to impact health care utilization may be measured
using a questionnaire given to parents/legal guardians and 14 to 17 year old subjects.
Analysis based on a health care utilization model will be used to determine factors
associated with non-adherence to the vaccine schedule. Initially, all subjects meeting
eligibility criteria will be enrolled regardless of timing of the second and third vaccine
doses. When a study arm reaches the accrual target, it will be closed to enrollment.
Enrollment for the entire study will remain open until the control and three primary
experimental arms have completed enrollment One or more experimental arms may be dropped from
the study after monitoring of accrual rates indicates that it/they cannot be fully enrolled
in a timely fashion. Monitoring will occur monthly. Assessment of accrual rates will occur
semi-annually. The primary objective is to compare the GMT one month after completing the
three dose vaccination series in 9 to 17 year old subjects who received the second and/or
third dose at substantially prolonged intervals to subjects who receive both the second and
third dose on time after adjusting for age.

Inclusion Criteria:

Girls will be eligible if they are: -9 to 17 years of age (defined as between 9 years 0
days and younger than 18 years of age) at time of receipt of third HPV dose; -Receiving the
third human papillomavirus (HPV) vaccine as part of routine health care; -Able and willing
to complete all study visits and evaluations; -Able and willing to participate in the study
by providing written informed assent/consent (as applicable); -Parent or legal guardian
provides permission (as applicable). Parent/legal guardian inclusion criteria: At sites
administering the survey and health literacy assessment, parent or legal guardian providing
permission for their daughter to participate in the study will be eligible to participate
in the parental questionnaire if they are able to provide informed consent for themselves.

Exclusion Criteria:

Girls meeting any of the following exclusion criteria at baseline will be excluded from
study participation. -Unable to comply with the study protocol. -Receipt of more than 3
doses of human papillomavirus (HPV) vaccine. -Receipt of blood and or blood products
(including immunoglobulin) in the past 3 months or anticipated receipt during the study
period. -History of any physical, mental, or developmental disorder that study personnel
believe may hinder a participant's ability to comply with the study requirements. -History
of malignancy or confirmed or suspected immunodeficient condition, such as human
immunodeficiency virus infection. -Receipt of or history of receipt of any medications or
treatments that affect the immune system, such as immune globulin, interferon,
immunomodulators, cytotoxic drugs or other drugs known to be frequently associated with
significant major organ toxicity since six months prior to the first HPV vaccine dose.
-Receipt of long-term (greater than or equal to 2 weeks) potentially immunosuppressive
corticosteroid use within six months or anticipated receipt during the study period.
Specifically, potentially immunosuppressive corticosteroids or any parenteral
corticosteroid, high dose (>800 mcg/day) beclomethasone dipropionate or equivalent
medication; nasal and topical steroids are allowed. -Current or former participation in HPV
vaccine related research. -Receipt of an investigational or alternate (Cervarix) HPV
vaccine. -Receipt of a live virus vaccine (varicella virus vaccine, any measles, mumps, or
rubella virus vaccine, or yellow fever vaccine but not including live attenuated influenza
virus vaccine) within 4 weeks before or after the 3rd dose of HPV vaccine or anticipated
receipt of a live virus vaccine within 4 weeks after the 3rd dose of HPV vaccine. However,
subjects may receive any vaccine on the same day as the third dose of HPV. Parent/legal
guardian exclusion criteria: If the site is actively recruiting adolescents from a clinic
population, the survey and health literacy assessments are not available for the
parents/legal guardians from that clinic population. Therefore they will not be asked to
participate in the study. -At sites administering the survey and health literacy
assessment, parents/legal guardians meeting any of the following exclusion criteria at
baseline will be excluded from filling out the study questionnaire examining factors
associated with adherence: -History of any physical, mental or developmental disorder that
study personnel believe may hinder a participant's ability to comply with study
requirements.