Immunogenicity and Safety of Human Papilloma Virus Vaccine in Solid Organ Transplant Recipients
Condition: Late Complication From Kidney Transplant; Complication of Transplanted Liver; Human Papillomavirus-Related Carcinoma
MeSH terms: Papilloma
Study type: Interventional
Phase: Phase 4

Summary: 
      The human papilloma virus (HPV) is known to be an important cause of cervical and anal
      cancers. Studies on patients who have received a solid organ transplant (such as a liver or
      kidney transplant) have suggested the risk of HPV-related cancers may be higher in this
      population. The HPV vaccine, Gardasil®, has been approved for use in males and females by
      Health Canada. In studies on healthy subjects this vaccine is nearly 100% effective at
      preventing infections from HPV serotypes that are in the vaccine. These serotypes,
      representing different viral strains, are known to cause 70% of cervical cancers and 90% of
      genital warts. The vaccine was also shown to be very safe and well tolerated in healthy
      subjects. Transplant patients are at higher risk of HPV related complications and cancers. As
      a result transplant experts have recommended this vaccine for use in their patients; however
      there have been no studies looking at the response to vaccination or safety of this vaccine
      in solid organ transplant recipients. Our objective is to study the immune response and side
      effects of Gardasil® in children who have received kidney or liver transplants. We will study
      this by comparing immune responses to the vaccine in healthy adolescent females compared to
      female liver and kidney transplant recipients. We will be recruiting females ages 12-19, as
      the province of Ontario funds the vaccine for this group. We will evaluate the transplant
      subjects for side effects after they receive the vaccine. Our hypothesis is that transplant
      recipients will have lower immunogenicity than healthy controls.
    

Detailed description: 
      1. Hypothesis The Human papillomavirus (HPV) vaccine, Gardasil®, will likely provide
           protection in solid organ transplant patients against the vaccinated strains with lower
           immunogenicity rates compared to healthy controls. We expect higher levels of immune
           suppression to influence immunogenic response.

        2. Objective Primary: To evaluate the immunogenicity of the recombinant HPV vaccine,
           Gardasil®, in pediatric solid organ transplant recipients compared to controls, as well
           evaluate for clinical risk factors associated with lower responses in transplant
           recipients. Immunogenicity will be assessed through geometric mean titres (GMT) as well
           as seroconversion.

           Secondary: To evaluate the safety of Gardasil® in transplant recipients.

        3. Background

           3.1 Disease HPV is known to predispose to cervical, anal, and a variety of head and neck
           cancers in both healthy adults and in those who are immunocompromised, including those
           who have received solid organ transplants. An estimated 3 million women in Canada are
           infected with HPV. Peak incidence occurs within 5-10 years of first sexual experience
           and adolescent females represent the largest cohort affected by HPV.

           3.2 Vaccine In 2006 the Food and Drug Administration approved the quadravalent
           recombinant HPV vaccine, Gardasil®, which targets strains 16 and 18 as well as 6 and 11,
           which are responsible for 70% of cervical cancer cases and 90% of genital warts,
           respectively. Health Canada has recently approved Gardasil® for use in females' aged
           9-45 years and males 9-26 years. Gardasil® has been shown in numerous clinical trials to
           be effective in the management of HPV by preventing vaccine sub-type related infections
           and precancerous lesions. Gardasil® is regarded as generally safe and well tolerated
           based on reported adverse events through government databases in the United States, as
           well as analyses by independent researches. The bivalent HPV vaccine, Cervarix®, also
           appears safe and effective in preventing cervical cancer, however the data are less
           robust and there would be no protection against genital wart strains. Long term benefits
           of HPV vaccination are unknown, however models have predicted both a significant
           mortality benefit by preventing cases of cervical cancer7 and overall
           cost-effectiveness; particularly if the vaccine is administered to girls under the age
           of twelve.

           3.3 HPV in Transplant Patients Due to the prominent role of cell-mediated immunity in
           HPV, transplant recipients are felt to be at increased risk of infection leading to
           extensive or frequent warts, and increased incidence of skin and anogenital
           malignancies. Skin cancers are the most common malignancy affecting patients post
           transplantation. Anogenital cancer incidence is estimated to be 30-100 times greater in
           transplant patients compared to the general population. HPV is a preventable cause of a
           large number of these malignancies, suggesting that a vaccine could potentially thwart
           some of the morbidity and mortality experienced by transplant recipients. Furthermore,
           studies have suggested that organ transplant patients are more likely to be infected
           with HPV as well as develop secondary neoplasias. For these reasons vaccinating this
           population against HPV has the potential for significant long-term benefits.

        4. Methods 4.1 Design We are proposing a prospective observational study by evaluating the
           serological response for the vaccine covered HPV serotypes; 6, 11, 16, and 18. This
           study will take advantage of routine, provincially funded population based vaccination
           program, and patients will receive the vaccine in the study that healthy adolescents
           receive at school in grades 7 or 8. Study subjects will be identified using the liver
           and kidney transplant clinical database and control subjects will be identified through
           the Hospital for Sick Children adolescent medicine clinic. A letter of introduction will
           be sent to the families. Consent will be obtained by the transplant nurse or physician
           known to the patient. Transplant subjects will undergo baseline and post-immunization
           serology to evaluate both GMT as well as to document seroconversion response to the
           vaccine. Gardasil® will be funded through the province of Ontario. Controls will receive
           their vaccine through the adolescent clinic, schools, or Toronto Public Health clinics
           in the community as per the recommended schedule. At recruitment attempt will be made to
           draw baseline serology status, vaccinate, and then collect post-immunization serology to
           document seroconversion. However, to facilitate recruitment for controls that have
           documented receipt of three doses of the vaccine these children will be recruited for
           post-vaccination serology only to compare GMTs. Control vaccines will also be funded by
           the province of Ontario and administered in accordance with Health Canada standards.

      4.2 Investigational Agent

      4.2.1 Vaccine storage and characteristics Gardasil® (Merck Canada Inc), the Quadravalent
      Human papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine, was selected for this study
      for its efficacy and safety data in healthy subjects, being publically funded by the province
      of Ontario, and it provides protection for 4 HPV serotypes. Gardasil® should be stored
      refrigerated 2-8 degrees Celsius, should not be frozen and remain protected from light. The
      total time outside of refrigerator should not to exceed 72 hours. Vaccines will be stored
      compliant with the division 5 Canadian regulations.

      4.2.2 Administration of vaccine Gardasil® vaccine is recommended to be administered
      intramuscularly in deltoid or thigh at a dose of 0.5ml at 0, 2, and 6 months. While every
      effort will be made to keep the aforementioned schedule, studies support some flexibility in
      the schedule. The 2nd dose will be administered at least 1 month after the 1st, but not more
      than 9 months. The 3rd dose can be administered 3 months following the second dose, but not
      more than 1 year following the first dose. All 3 doses must be administered within a 1 year
      period to be included in analysis. Subjects will be monitored for 15 min post-vaccination for
      any adverse effects.

      4.3 Sample Size The study will be powered based on GMT immunogenicity. Based on this primary
      outcome, we wish to compare serum titres in transplant patients compared with controls. The
      sample size calculation is based on 90% power and 95% confidence and the assumption that a
      HPV vaccination will result in protective titres in 80% of transplant patients compared to
      100% of controls. A sample size of approximately 75 transplant recipients and 75 controls
      will therefore be preferred to detect a significant difference, however recruitment of at
      least 50 participants in each group is acceptable. Recruitment will take place over a 6 month
      period, resulting in a total study duration of approximately 12 months, up to a maximum of 18
      months accounting for possible delays in vaccine administration up to 1 year from end of
      recruitment.

      4.4. Analysis In the primary analysis of immunogenicity, the GMTs will be summarized for
      transplant recipients and compared with controls. The proportions of subjects achieving
      protective GMTs, as defined previously, will be compared using Chi-square or Fishers' exact
      test as appropriate. Means will be compared using Students t-test or a non-parametric
      procedure will be used to compare medians, as appropriate. Subjects and controls will be
      evaluated as a head-to-head comparison. For controls serology will be interpreted relative to
      time from last dose given. The investigators will use a multivariate analytic procedure to
      examine the effects of several independent variables with immunogenicity as the dependent
      variable. These independent variables are ones that could be potentially associated with
      differences in immune responsiveness (e.g., the interval between transplantation and vaccine
      administration). Other variables include the following: age; type of organ transplanted;
      presence or absence of graft rejection; type of immune suppression (e.g., use of anti-T
      lymphocyte therapy); immune globulin therapy; cytomegalovirus infection and disease;
      Epstein-Barr virus infection and disease; presence of bacterial opportunistic infections,
      concurrent diseases, steroid doses, and total lymphocyte count.

      The secondary analysis will capture and describe the adverse effects among transplant
      recipients through telephone calls at 48 hours and 7 days utilizing the Public Health Ontario
      adverse event reporting form

      4.5 Data Safety Monitoring Board and Research Ethics The study will be done with the approval
      of the institution's Research Ethics Board. In addition, although we have no reasons to
      anticipate problems with this vaccines in transplant patients, we will establish a Data
      Safety Monitoring Board that will review emerging data that relate to any major or
      catastrophic events that are temporally associated with the vaccine (even in the absence of
      obvious causality).

      4.5.1 Early Termination or Withdrawal Subjects and/or parents/legal guardians have the right
      to withdraw from the study at any time for any reason. The investigator also has the right to
      withdraw subjects from the study if it is in the best interest of the subject.

      Subject withdrawal criteria are as follows:

        -  Withdrawal of informed consent (subject's decision to withdraw for any reason)

        -  Serious adverse event which, in the opinion of the investigator, indicates that
           continued participation in the study is not in the best interest of the subject

        -  Any clinical adverse event or inter-current illness which, in the opinion of the
           investigator, indicates that continued participation in the study is not in the best
           interest of the subject (ex. Participants who develop symptoms of hypersensitivity after
           receiving the first or second dose of Gardasil® will be withdrawn from the study and
           will not receive further doses of Gardasil®)

        -  Pregnancy

        -  Subject non-adherence with the vaccine administration schedule defined above In the
           event a subject is withdrawn due to an Adverse Event, this will be recorded and subjects
           will continue to be followed until these events are resolved or stabilized, if possible.

      4.5.2 Adverse Events All adverse events will be reported to the Hospital for Sick Children
      Research Ethics Board according to the Hospital for Sick Children's adverse event reporting
      requirements. All serious, unexpected adverse drug reactions to the study medication will be
      reported to Health Canada within 15 calendar days or for death or life-threatening events,
      within 7 calendar days. In the latter case, a follow-up report must be filed within 8
      additional calendar days. Adverse reactions will be managed according to the Hospital for
      Sick Children's standard clinical management practices.
    

Intervention name(s): Quadravalent human papillomavirus vaccine
Intervention type(s): Drug
Intervention description(s): Vaccine will be administered to all transplant recipients. Controls will be recruited based on previous documented receipt of vaccine
Other intervention name(s): Gardasil
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention