Immunogenicity and Safety of Human Papilloma Virus Vaccine in Solid Organ Transplant Recipients

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.