| Protocol No: | ECCT/12/02/02 | Date of Protocol: | 27-06-2011 |
| Study Title: | Immunogenicity and Safety of quadrivalent human Papillomavirus Vaccine in HIV-Infected pre-adolescent girls and boys in Kenya. |
| A Longitudinal Observational Cohort Study to Assess Sustained Immunogenicity up to 48 Months to Quadrivalent Human Papillomavirus Vaccine Among HIV-infected Girls and Boys Age 9-14 Years in Kenya | |
| A longitudinal cohort study to assess effectiveness and B-memory cell response to the quadrivalent HPV vaccine 9 years post-vaccination among HIV-infected boys and girls ages 9-14 years in Kenya.
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| A longitudinal cohort study to assess effectiveness and B-memory cell response to the quadrivalent HPV vaccine 9 years post-vaccination among HIV-infected boys and girls ages 9-14 years in Kenya. | |
| A longitudinal cohort study to assess effectiveness and B-memory cell response to the quadrivalent HPV vaccine 9 years post-vaccination among HIV-infected boys and girls ages 9-14 years in Kenya.
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| Study Objectives: | Aim 1: To assess sustained efficacy for up to 48 months of the quadrivalent human papillomavirus vaccine (Gardasil®) vaccine in HIV infected girls and boys ages 9-14 in Kenya. Aim 2: To determine factors associated with sustained IgG LIA antibody after 3 doses of quadrivalent HPV vaccination such as sex, age, immune reconstitution with highly active antiretroviral therapy as determined by CD4 cell %, plasma HIV RNA and WHO disease stage classification Aim 3: To assess incidence of genital oncogenic HPV and HPV- type 6, 11 infections among sexually active HIV infected adolescent vaccinated with 3 doses of quadrivalent HPV vaccination
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| 2 | Aim 1: To evaluate the effectiveness of the quadrivalent human papillomavirus vaccine (Gardasil®), assessed by genital HPV infection and genital warts, at nine years post-vaccination among HIV-infected girls and boys vaccinated at ages 9-14 in Kenya. Hypothesis: HIV-infected adolescents are at high risk for HPV infection at sexual debut, vaccination with HPV-vaccine will provide sustained protection from HPV infection from vaccine types 6, -11, -16, and 18. Aim 2: To assess for persistence of memory B and T cell responses to QHPV nine years after vaccination among HIV-infected girls and boys as a proxy for long-term protection. Hypothesis: Three doses of QHPV will induce central memory with B-ells producing neutralizing antibodies detectable in peripheral blood nine years post-immunization |
| 3 | OBJECTIVES/AIMS Aim 1: To evaluate the effectiveness of the quadrivalent human papillomavirus vaccine (Gardasil®), assessed by genital and oral persistent HPV infection and genital warts, at nine years post-vaccination among HIV-infected girls and boys vaccinated at ages 9-14 in Kenya. Aim 2: To assess for persistence of memory B and T cell responses to QHPV nine years after vaccination among HIV-infected girls and boys as a proxy for long-term protection. |
| 4 | OBJECTIVES/AIMS Aim 1: To evaluate the effectiveness of the quadrivalent human papillomavirus vaccine (Gardasil®), assessed by genital and oral persistent HPV infection and genital warts, at nine years post-vaccination among HIV-infected girls and boys vaccinated at ages 9-14 in Kenya. Aim 2: To assess for persistence of memory B and T cell responses to QHPV nine years after vaccination among HIV-infected girls and boys as a proxy for long-term protection. |
| Laymans Summary: | HPV is a common sexually transmitted infection that affects 80% of women and 65-70% of men. The majority of HPV infections occur soon after a person becomes sexually active, typically between the ages of 14-24 years. A vaccine called GARDASIL® can protect against some types of HPV (6, 11, 16 & 18). Cervical cancer affects the mouth of the uterus (cervix), and is the second commonest cancer among women. Half a million women get this cancer each year and of those who get cervical cancer, about half die. The majority of women who get cervical cancer live in sub Saharan African countries like Kenya. This disease can be prevented if detected before it becomes cancerous using a Pap smear. Most of the time, certain types of HPV (called Type 6, Type 11, Type 16, and Type 18) are responsible for cervical cancer, cancers of the vulva or vagina, precancerous cervical, vaginal and vulva lesions, and genital warts. Studies on vaccines have already been done in children who do not have HIV, and the vaccine is already being used to protect against the above diseases. The aim of this study is to confirm the safety, usefulness and long term effectiveness of this vaccine in HIV positive children so that they can get the benefits from this vaccine and assist investigators to determine the need for booster dosing.
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| 2 | A virus called HPV, is known to be the cause of cervical, anal, vaginal and throat cancer. The HPV vaccine has been shown to protect people from vaccine specific HPV infection. A lot of research has been done for HIV-uninfected persons, to show that this vaccine provides protection for durations of over 10 years. They have also shown that children do not need three doses and two doses are enough. There is no current data to inform on the duration of protection for HIV-infected children who receive three HPV vaccine. We previously enrolled 180 HIV-infected girls and boys and vaccinated them with three doses of the QHPV vaccine in 2014. We examined the blood samples of these children to determine if their bodies responded and gave the immune response that signals the vaccine may work to protect them from HPV infection. We will ask the children to come back for enrollment, to determine if the vaccine is still effective. We shall collect blood samples at enrollment month 12 and evaluate the samples for HPV immune response. At enrollment and every 6 months we shall collect a genital swab to evaluate for HPV- infection and conduct a genital examination for genital warts. We shall also give a 4th dose to a group of approximately 30 children and collect blood to assess for memory B cells and T cells that will inform if they still have protection. The total time in the study for each participant will be 12 months. |
| 3 | A virus called HPV, is known to be the cause of cervical, anal, vaginal and throat cancer. The HPV vaccine has been shown to protect people from vaccine specific HPV infection. A lot of research has been done for HIV-uninfected persons, to show that this vaccine provides protection for durations of over 10 years. They have also shown that children do not need three doses and two doses are enough. There is no current data to inform on the duration of protection for HIV-infected children who receive three HPV vaccine. We previously enrolled 180 HIV-infected girls and boys and vaccinated them with three doses of the QHPV vaccine in 2014. We examined the blood samples of these children to determine if their bodies responded and gave the immune response that signals the vaccine may work to protect them from HPV infection. We will ask the children to come back for enrollment, to determine if the vaccine is still effective. We shall collect blood samples at enrollment month 12 and evaluate the samples for HPV immune response. At enrollment and every 6 months we shall collect both genital swab and oral rinse specimens to evaluate for persistent HPV- infection and conduct a genital examination for genital warts. We shall also give a 4th dose to a group of approximately 30 children and collect blood to assess for memory B cells and T cells that will inform if they still have protection. The total time in the study for each participant will be 12 months. |
| 4 | A virus called HPV, is known to be the cause of cervical, anal, vaginal and throat cancer. The HPV vaccine has been shown to protect people from vaccine specific HPV infection. A lot of research has been done for HIV-uninfected persons, to show that this vaccine provides protection for durations of over 10 years. They have also shown that children do not need three doses and two doses are enough. There is no current data to inform on the duration of protection for HIV-infected children who receive three HPV vaccine. We previously enrolled 180 HIV-infected girls and boys and vaccinated them with three doses of the QHPV vaccine in 2014. We examined the blood samples of these children to determine if their bodies responded and gave the immune response that signals the vaccine may work to protect them from HPV infection. We will ask the children to come back for enrollment, to determine if the vaccine is still effective. We shall collect blood samples at enrollment month 12 and evaluate the samples for HPV immune response. At enrollment and every 6 months we shall collect both genital swab and oral rinse specimens to evaluate for persistent HPV- infection and conduct a genital examination for genital warts. We shall also give a 4th dose to a group of approximately 30 children and collect blood to assess for memory B cells and T cells that will inform if they still have protection. The total time in the study for each participant will be 12 months. |
| Abstract of Study: | Design : Longitudinal Cohort Study Population: HIV-1 infected boys and girls age 9-14 years without clinical AIDS Study Size: 100 girls and 80 boys Treatment Plan: Three doses of intramuscular quadrivalent HPV vaccine 'Gardasil' administered at enrolment, month 2 and month 6. Study Duration: Each participant will be in the study for a total of 12 months. Outcome Variable: Antibody response to HPV vaccine will be tested at enrolment, month 7 and month 12. Second variable will be an assessment of safety and tolerability to the vaccine. Primary Objective: To determine the immunogenicity of quadrivalent HPV vaccine among HIV infected girls and boys age 9-14 years in Kenya. Secondary Objective:
Study Location: Partners in Prevention, Thika site, OAU Road, Off Kenyatta Avenue Section 9 |
| 1 | Design : Longitudinal observational cohort study and extension of the MISP ID: 38406 ‘immunogenicity and safety of quadrivalent human papillomavirus vaccine in HIV-infected pre-adolescent girls and boys in Kenya’. Population: HIV-1 infected boys and girls initially enrolled in the MISP 38406 Study Study Size: 100 girls and 79 boys Treatment Plan: None. This is an observational study after the initial vaccination. Study Duration: Each participant will be on an additional extended follow up study for a total of 36 months. Outcome Variable: i.) HPV type 6, 11, 16 and 18 antibodies as measured by geometric titers at re-enrollment, month 12, 24 and 36 ii.) Genital HPV infection with oncogenic and 6, 11 type specific Primary Objective: To determine sustained immunogenicity of the quadrivalent HPV vaccine, 48 months after initial vaccination, among HIV-infected girls and boys age 9-14 years Secondary Objective: 1) To determine factors associated with sustained cLIA antibody persistence after 3 doses of quadrivalent HPV vaccination such as sex, age, immune reconstitution with highly active antiretroviral therapy as determined by CD4 % and plasma HIV viral load 2) To assess incidence of genital HPV infections with oncogenic type specific and 6,11 HPV infection among HIV infected adolescent vaccinated with 3 doses of the quadrivalent HPV vaccination among sexually active girls and boys as compared to pre-sexual debut Study Location: Partners in Health, Research and Development, Thika site, OAU Road, off Kenyatta Avenue, Section 9. |
| 2 | Background: Genital Human Papilloma Virus (HPV) infections occur rapidly after sexual debut, and immunosuppressed individuals are at greater risk for incident and persistent infection. HPV vaccine contains virus-like particles (VLP), which are highly immunogenic and induce a robust humoral response that has been demonstrated to confer long term protection from HPV infection and associated disease among HIV-uninfected individuals. The magnitude of type-specific vaccine induced neutralizing HPV antibody responses are diminished among HIV-infected compared to uninfected individuals.
There is no established minimum level of antibody that predicts protection against HPV infection or associated disease, the impact of lower antibody titers among HIV infected individuals on vaccine efficacy is unknown. The risk of HPV exposure persists throughout a person’s sexual life and the duration of protection, especially when the vaccine is given in the early adolescent period is critical to vaccine effectiveness. Long lasting memory is characterized by memory B cells and long-lived plasma cells and a QHPV booster dose has demonstrated an anamnestic response among HIV-infected adolescents.
HPV efficacy and effectiveness data for HIV-uninfected individuals has informed the current World Health Organization (WHO) two-dose vaccine schedule. The field lacks data on effectiveness of three dose or two-dose for the HIV-infected adolescents. The current on-going research for single dose schedules gives urgency to the determination of long-term efficacy of three HPV vaccine doses for the HIV-infected adolescent.
We shall recall HIV-infected girls and boys who were previously vaccinated at ages 9-14 years with three doses of the quadrivalent vaccine (QHPV) in 2014 and evaluated for vaccine immunogenicity.
Method: The participants will be assessed for genital warts and genital HPV infection. Type specific HPV DNA will be assessed using genital swabs and genital warts assessed through physical examination among sexually active participants at enrollment, month 6 &12. Among those that have not become sexually active, or that refuse a genital exam, a self-collected swab will be requested. A sub-set of approximately 30 participants, will receive a booster dose of QHPV, from this subset, PBMC and plasma samples will be collected at enrollment, at month 1 and month 12 to evaluate for memory B and T cell responses. The total duration of study follow up will be 12 months.
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| 3 | BACKGROUNDThe HPV vaccine contains virus-like particles (VLP), highly immunogenic, and induces a robust humoral response. Across populations, women, men, geography, and HIV serostatus, there has been consistent evidence of a steady decline in antibody titers observed over time post-vaccination, more so for HIV-infected individuals. There is currently no established minimum level of antibody that predicts protection against HPV infection or associated disease.
The risk of HPV exposure persists throughout a person’s sexual life; therefore, the duration of protection, especially when the vaccine is given in the pre-adolescent period, is critical to vaccine effectiveness. Among HIV-uninfected women, evidence on HPV vaccine effectiveness for protection from HPV acquisition for over 9 years is well documented from extended follow-up data from the primary proof of concept cohort, albeit with waning anti-HPV titers were noted among participants.
HIV-1 infected pre-adolescents are at high risk for HPV infection and would greatly benefit from long-term vaccine protection as they become sexually active. There is limited data on sustained immunogenicity of HPV vaccine beyond 12 months in HIV infected adolescents, and no published data on HPV infection or cervical intraepithelial lesions as measures of outcome for vaccine effectiveness. We propose extending follow-up and assessing sustained effectiveness of a 3-dose schedule of the QHPV for HIV-infected adolescents vaccinated within the National and WHO stipulated pre-adolescent age group as measured with an assessment of HPV infection, genital warts, and memory B-cell response. OBJECTIVES/AIMS Aim 1: To evaluate the effectiveness of the quadrivalent human papillomavirus vaccine (Gardasil®), assessed by genital and oral persistent HPV infection and genital warts, at nine years post-vaccination among HIV-infected girls and boys vaccinated at ages 9-14 in Kenya. Aim 2: To assess for persistence of memory B and T cell responses to QHPV nine years after vaccination among HIV-infected girls and boys as a proxy for long-term protection. STUDY METHODSStudy Setting Thika PHRD research clinic has conducted clinical trials for HIV prevention in collaboration with the University of Washington International Clinical Research Center (ICRC) for the last 14 years. The study team has conducted 3 HPV vaccine studies, one among HIV-uninfected girls ages 9-26 years and the second among HIV-infected girls and boys ages 9-14 years, both with very high retention rates, and currently, the study site team is conducting a single dose HPV vaccine trial among girls ages 15-20 years. Study Design Longitudinal single-site cohort study and extension of the MISP ID: 38406 and IISP ID: 51802 Immunogenicity and safety of quadrivalent human papillomavirus vaccine in HIV-infected pre-adolescent girls and boys in Kenya. Intervention
All participants previously received the quadrivalent HPV vaccine delivered in 3 doses, month 0,2,6 and a booster dose of QHPV to 30 participants at year 9 post-primary vaccination. STUDY POPULATIONWe enrolled 80 boys and 100 HIV-infected girls and boys age 9-14 years in a Merck sponsored study of immunogenicity and safety to QHPV vaccine, of whom 176 were followed up for 48 months post initial vaccine and exited in 2018. Most participants receive HIV care at nearby established pediatric HIV care clinics and some at the research facility. Total duration of study follow up will be 12 months
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| 4 | BACKGROUNDThe HPV vaccine contains virus-like particles (VLP), highly immunogenic, and induces a robust humoral response. Across populations, women, men, geography, and HIV serostatus, there has been consistent evidence of a steady decline in antibody titers observed over time post-vaccination, more so for HIV-infected individuals. There is currently no established minimum level of antibody that predicts protection against HPV infection or associated disease.
The risk of HPV exposure persists throughout a person’s sexual life; therefore, the duration of protection, especially when the vaccine is given in the pre-adolescent period, is critical to vaccine effectiveness. Among HIV-uninfected women, evidence on HPV vaccine effectiveness for protection from HPV acquisition for over 9 years is well documented from extended follow-up data from the primary proof of concept cohort, albeit with waning anti-HPV titers were noted among participants.
HIV-1 infected pre-adolescents are at high risk for HPV infection and would greatly benefit from long-term vaccine protection as they become sexually active. There is limited data on sustained immunogenicity of HPV vaccine beyond 12 months in HIV infected adolescents, and no published data on HPV infection or cervical intraepithelial lesions as measures of outcome for vaccine effectiveness. We propose extending follow-up and assessing sustained effectiveness of a 3-dose schedule of the QHPV for HIV-infected adolescents vaccinated within the National and WHO stipulated pre-adolescent age group as measured with an assessment of HPV infection, genital warts, and memory B-cell response. OBJECTIVES/AIMS
Aim 1: To evaluate the effectiveness of the quadrivalent human papillomavirus vaccine (Gardasil®), assessed by genital and oral persistent HPV infection and genital warts, at nine years post-vaccination among HIV-infected girls and boys vaccinated at ages 9-14 in Kenya. Aim 2: To assess for persistence of memory B and T cell responses to QHPV nine years after vaccination among HIV-infected girls and boys as a proxy for long-term protection. STUDY METHODSStudy Setting Thika PHRD research clinic has conducted clinical trials for HIV prevention in collaboration with the University of Washington International Clinical Research Center (ICRC) for the last 14 years. The study team has conducted 3 HPV vaccine studies, one among HIV-uninfected girls ages 9-26 years and the second among HIV-infected girls and boys ages 9-14 years, both with very high retention rates, and currently, the study site team is conducting a single dose HPV vaccine trial among girls ages 15-20 years.
Study Design Longitudinal single-site cohort study and extension of the MISP ID: 38406 and IISP ID: 51802 Immunogenicity and safety of quadrivalent human papillomavirus vaccine in HIV-infected pre-adolescent girls and boys in Kenya. Intervention All participants previously received the quadrivalent HPV vaccine delivered in 3 doses, month 0,2,6 and a booster dose of QHPV to 30 participants at year 9 post-primary vaccination. STUDY POPULATIONWe enrolled 80 boys and 100 HIV-infected girls and boys aged 9-14 years in a Merck sponsored study of immunogenicity and safety to QHPV vaccine, of whom 176 were followed up for 48 months post initial vaccine and exited in 2018. Most participants receive HIV care at nearby established pediatric HIV care clinics and some at the research facility. Total duration of study follow up will be 12 months. |