Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
In the Netherlands, the human Papillomavirus (HPV) vaccination will be added to the National
 Vaccination Program for girls to protect against the development of cervical cancer. The
 vaccine protects against HPV type 16 & 18, which cause about 75% of cervical cancer. Studies
 have shown that the vaccine is effective in healthy subjects in preventing infection by HPV
 16 & 18. However, no evidence exists on the immunogenicity and safety of HPV vaccination in
 patients with an immune system disorder, such as primary humoral immunodeficiency (i.e.
 hypogammaglobulinemia) or autoimmune diseases. Concerns exist that vaccination may cause an
 aggravation of the underlying disease. In addition, the immune response to vaccination may be
 diminished due to immunosuppressive therapy or the underlying disease.

 Objective: The primary goal of the current study is to study the immunogenicity of HPV
 vaccination in patients with an autoimmune disease and a primary humoral immunodeficiency.

 Based on retrospective analysis with other vaccines we hypothesize that patients with
 autoimmune diseases who are under immunosuppressive medication and patients with a immune
 system disorder have a decreased serological response to HPV vaccination, and that the
 produced HPV antibodies titers decrease more rapidly than in healthy individuals.

 The secondary objective is to explore safety of HPV vaccination and immune regulatory
 mechanisms induced by vaccination in a subset of patients. The investigators hypothesize that
 HPV vaccination is safe and that HPV-induced regulatory T cells are able to prevent an
 increase in the activity of an autoimmune disease.
Study design: prospective observational cohort study.

 Study population: Females aged 12 - 18 years with one of the autoimmune diseases Juvenile
 Idiopathic Arthritis (JIA), Systemic Lupus Erythematosus (SLE) and Juvenile Dermatomyositis
 (JDM) are included. Included females are treated at the rheumatology unit from the University
 Medical Center Utrecht. A small control group of healthy girls aged 13 -17 years will also be
 included to compare the kinetics of HPV serology with healthy individuals.

 Intervention: Starting from September 2009 all girls aged 12 years will be offered a HPV
 vaccination via the National Vaccination Program. Prior to this, a national campaign will be
 started in March 2009 to vaccinate all girls aged 13-17 years at once.We will use this
 national vaccination campaign as an opportunity to analyze the serological response and
 safety of this vaccine in a large group of with an immune system disorder. The vaccines are
 administered by our national health organisation. The effects are monitored in our clinics.

 Main study parameters/endpoints:

 -  Primary outcome immunogenicity is measured by antibody levels against HPV serotype 16 &
 18 over time. We consider HPV vaccination to be immunogenic at antibody titers above the
 cutoffs 20 and 24 mMU/ml for HPV 16 and 18, respectively; or at a ≥2 fold increase in
 antibody levels against both serotypes. The antibody levels will be measured prior to
 vaccination, and after 3,7 and 12 months.

 -  The secondary outcome is safety of vaccination, measured as activity of the underlying
 autoimmune disease. In addition, frequency of common adverse effects, and immunological
 changes induced by HPV vaccination, such as number and function of cytotoxic T cells and
 Tregs will be described.

 Nature and extent of the burden and risks associated with participation, benefit and group
 relatedness:

 Burden: included patients will be asked to visit the hospital 4 times in a period of 12
 months. During these visits, physical examination will be performed and blood will be
 obtained for serological and immunological analysis. Most of these visits are combined with
 routine follow-up and venous punctures of the patients. However, one extra visit to the
 hospital and vena puncture is expected. 5 ml (extra) blood is obtained four times from all
 patients for serological analysis. Included healthy controls will be asked to visit one
 plenary information meeting in the evening. Controls will have a venous punctures four times
 during the study, during which 5 ml of blood is obtained. These samples will be obtained at
 the hospital during evening clinics or at school. In a subset of patients (n=50) and healthy
 controls (n=10), an additional 15 ml is obtained for immunological analysis.

 Risks: participants may experience adverse events of the HPV vaccination. Benefits:
 Protection against human Papillomavirus infection and therefore reduced risk of cervix
 carcinoma, certainty about protection against HPV 16 & 18 and about safety of HPV
 vaccination.

 Group relatedness: This study can only be done in patients who need this vaccination (i.e.
 females in the age group 12-24 years) and have an immune system disorder, such as JIA, SLE or
 JDM. Appropriate comparison with healthy controls must be performed in age-matched healthy
 females who are also recruited for the National HPV vaccination campaign, in this case girls
 in the age group 13-17 years.
Inclusion Criteria:

 -  Females

 -  Clinical diagnosis of JIA, SLE or JDM

 -  And who are in the following age groups:

 -  12 years (these girls are vaccinated via the National Vaccination Program from
 September 2009)

 -  13-18 years (these girls are vaccinated during a national vaccination campaign
 from March-May 2009)

 -  Current co-medication: all co-medication prescribed may be continued

 -  And in the control group: healthy girls aged 13-17 years (these girls are vaccinated
 during a national vaccination campaign from March-May 2009)

 Exclusion Criteria:

 -  No HPV vaccination

 -  Refusal to allow venous puncture

 -  Proven or suspected cervical carcinoma