Immunogenicity of HPV-vaccination in a reduced-dose schedule

In December 2013, the European Medicines Agency (EMA) approved a two-dose
schedule for the bivalent vaccine for girls 9 to 14 years of age. Following
this approval and the registration, the Minister of Health decided in January
2014 that the Netherlands would directly change their HPV vaccination schedule.
From that moment, girls up to 14 years of age will be vaccinated by the use of
a two-dose schedule, at month 0 and 6. The change from three- to two-dose
schedule asks for monitoring of the kinetics over time and quality of vaccine
induced immunity after a two-dose schedule. Furthermore, some girls only
received one dose of the HPV vaccine. Monitoring of the immunity in these girls
is important. From 2022 onwards, boys will also be invited for a two-dose
schedule. In addition, the age has been lowered to 9/10 years. Monitoring the
immunogenicity of the HPV vaccine after two doses among 9-10 year old boys in
the Netherlands is important to monitor the effects of HPV vaccination.

- To study the kinetics of the vaccine-induced antibody response against
HPV16/18 after a two-dose schedule by measuring these antibody responses at
approximately 7, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months following
the first dose of HPV-16/-18 vaccination in a two-dose schedule and study
whether thise levels remains above plateau up to 24 months (397.8 EU/ml for
HPV-16 and 297.3 EU/ml for HPV-18).

- To study whether HPV16/18- antibody responses are non-inferior after a
two-dose HPV 16/18-vaccination schedulecompared to a three-dose schedule at
approximately 1 *, 2 *, 3 *, 4 *, 5 *, 6 * and 7 * years after the first dose.

- To study the level and quality of antibody response at approximately 1 *, 2
*, 3 *, 4 *, 5 *, 6 * and 7 * years following one dose of HPV-16/18
vaccination.

- To study the kinetics of the antibody response against HPV types 16 and 18 at
approximately 7, 12, 24, and 36 months after the first dose of HPV vaccination
in a two-dose schedule among boys.

- To study whether the antibody response against HPV types 16 and 18 after HPV
vaccination in a two-dose schedule among boys vaccinated at 9-10 years of age
is non-inferior to a two-dose schedule among girls vaccinated at 12-13 years of
age at approximately 7, 12, 24, and 36 months after the first dose.

Avidity and quality of antibodies will be studied in a prospective cohort, also
cellulair immunity will be studied. In addition, a similar study arm is set up
among boys. To compare the antibody levels after a two-dose schedule with a
three-dose schedule, cross-sectional observational sampling will be performed.
Also cross-sectional sampling will be performed to study the cellular immunity,
the level and quality of vaccine-induced antibodies in girls who were
vaccinated by one dose. The study design and recruitment of participants is
described in detail in the study protocol starting on page 36.

A sample of boys will be obtained as a nationwide sample in the Netherlands.
Recruitment will be done by a personal letter in which the boy is invited to
participate and in which the parents/legal representative are informed about
the study and the possibility for the invited boy to participate. Selection of
eligible boys will be performed via Praeventis. The *Dienst Vaccinvoorziening
en Preventieprogramma's* (DVP) of the RIVM is responsible for managing
Praeventis. For the current study, the DVP department is responsible for
sending the personal invitation letters.
The involved researchers do not have access to the subject*s data at that time.
The subjects will receive the personal invitation letter and an informed
consent by regular mail at least four weeks before the time since first
vaccination approaches 7 months. The invitation letters will be send out around
September. A telephone number of an involded researcher and independent doctor
will be provided for questions. Parents and boys are advised to calmy read all
the information before deciding to participate in the study. If the subject
decides to participate, his parents/legal representatives fill in the informed
consent (for participation for 4 years) and send it back to the RIVM. After
returning the informed consent, the involved researcher from the RIVM will also
sign the informed consent and a copy will be sent to the parents. The
researchers will also send the research package to the participants to draw a
fingerprick blood at home. In this package a link to the online questionnaire
is also provided. The subject will fill in the questionnaire on a secured
website (url and code to log in are provided in the personal invitation letter
and research package). The finger prick blood should be sent back to the RIVM
within two weeks. When the boy reaches 12 years of age, another informed
consent will be sent by regular mail. If a subject decides to continue with the
participation in the study, the boy needs to fill in the informed consent (for
participation for another year) and send it back to the RIVM.

For girls 1997-2003 participation involves one blood sample by finger prick and
fill out one online questionnaire. For girls born in 2001 participation
involves six research moments, including an online questionnaire and vene
puncture blood sampling, the sampling moments on 72, 84, 96, 108 and 120 months
involves blood sampling by finger prick. A part of the girls born in 1997-2003
who gave a finger-prick blood sample, will participate in an additional
one-time blood collection by venepuncture. These birth cohorts are considered
because they were applicable for routine HPV vaccination. For boys born in
2012, there are four research occasions over a period of four years, consisting
of the completion of a questionnaire via the Internet and a blood collection by
means of a finger prick. The sensation of blood collection is uncomfortable to
minor extent for some participants. The risk of blood collection is generally
accepted.