- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05266898
Immunogenicity of Gardasil-9 HPV Vaccine in People Living With HIV (AGO-Gard)
Prospective Observational Immunogenicity Trial of Gardasil-9 HPV Vaccine in People Living With Adequately Managed HIV
The primary objective of this study is to determine the magnitude and breadth of the serum antibody response to the nonavalent HPV vaccine (Gardasil-9) in adults with well-controlled HIV infection.
The secondary objective of the study is to observe short term clinical outcomes of prevalent HPV genotype-specific anogenital infections in adults living with HIV who complete the three-dose Gardasil-9 vaccine series.
The clinical hypothesis is that adults with virologically controlled HIV mount a serum antibody response to the nonavalent HPV vaccine that is comparable to HIV negative counterparts. We also postulate that HPV vaccination will provide short-term clinical benefit against HPV infections and disease associated with vaccine genotypes.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
BACKGROUND AND SIGNIFICANCE
HPV is the etiological agent for most if not all cervical and anal cancer and for over 50% of head and neck squamous cell carcinomas. HPV infection, pre-cancerous and cancerous lesions are more prevalent in people living with HIV (PLWHIV), including those with HIV infection that is well-controlled with anti-retroviral therapy. HPV vaccines have been developed based on expression of the L1 major capsid protein to make virus-like particles and demonstrate impressive efficacy, with type-specific protection against persistent infection and incident pre-cancer (cervical/anal intraepithelial neoplasia, CIN/AIN) in HIV uninfected populations. These vaccines include quadrivalent Gardasil (4vHPV) and the more recent nonavalent Gardasil (Gardasil-9).
The 4vHPV has been utilized to immunize PLWHIV. In general, excellent seroconversion rates (over 90%) were seen with slightly lower rates seen for HPV-18, and in those with low CD4 cell count, low CD4 cell count nadir or uncontrolled HIV replication. The seroconversion rates appear to be slightly lower than that seen in HIV-negative populations (>95%). Additionally, titers for HPV-6 and 18 were noted to be lower compared to HIV-negative historical controls in children ages 7-12. This is consistent with observations that vaccination of PLWHIV for influenza, hepatitis A or hepatitis B has resulted in lower than desirable seroconversion rates (50-70%) with higher rates in those on cART and with higher CD4 cell count. To date, only one study has described immunogenicity of Gardasil-9 in adult PLWHIV. Investigators have reported seroconversion to all 9 HPV types in all 100 immune-intact/virally suppressed PLWHIV who received Gardasil-9, and higher antibody GMTs in those with pre-existing seroreactivity. This cohort study conducted in Belgium included predominantly Caucasian (68%) males (85%) with a mean age of 38 years at enrollment. There is a paucity of literature exploring the immunogenicity of Gardasil-9 in diverse demographic populations of adults living with HIV.
Efficacy studies using 4vHPV in HIV-positive adults have provided mixed results at best. One study in HIV-positive men and women who had significant prior HPV exposure showed no efficacy of HPV vaccination in preventing future AIN2/3 development. This may be related to the inclusion of men and women with AIN2/3 at baseline (30% and 50%, respectively) and the older age (average, 47) of this cohort. In another study of females aged 9-65 (average, 39) with 2 years of follow up, 4vHPV showed modest efficacy with rates of 1.0/100 patient-years for a composite endpoint of the development of warts or persistent infection with the vaccine types. This compares to rates of 0.1/100 patient-years for HIV-uninfected women and 1.5 for HIV-negative unvaccinated women. The reason for this modest efficacy is not clear but may be due to deficiencies in cellular immunity and/or the age of the cohorts. In addition, many of these HIV infected individuals have been previously exposed to some of the vaccine types and they often have concurrent infections with other oncogenic HPV types. These excessive HPV exposures may promote CIN/AIN and confound efficacy endpoints. Importantly, HIV positive women with CIN3+ have a nearly 4-fold higher prevalence of non-traditional oncogenic HPV types compared to HIV negative women with CIN3+. This finding suggests that the modest efficacy of 4vHPV in HIV positive women may be improved substantially by use of Gardasil-9. To date, no studies have reported efficacy of Gardasil-9 for prevention of HPV infections, CIN or AIN in adult PLWHIV.
There is clearly an unmet need to evaluate the immunogenicity and immune protection generated by Gardasil-9 vaccination in diverse populations of PLWHIV, who remain at increased risk of HPV infection and related pathology despite adequate management of their HIV. We hypothesize that people with well-controlled HIV will seroconvert following Gardasil-9 vaccination and will develop high titer antibodies to all 9 HPV types. In addition, we postulate that the well-controlled HIV-positive individual will also show short-term efficacy with fewer incident HPV infections and reduced incidence of CIN/AIN attributed to HPV types in the vaccine. This efficacy will primarily be seen in those who are seronegative and HPV DNA negative for a given type at baseline. It is predicted that those who are seropositive but HPV DNA negative for a given vaccine type will demonstrate higher titers of response after vaccination. Efficacy in this subset (seropositive, DNA negative) as well as the other subsets has not been studied in detail. The goal of these proposed studies is to show immunogenicity and short-term efficacy of Gardasil-9 in a well-controlled HIV-positive population.
STUDY DESIGN AND PROCEDURES
This study is a single-center, prospective, intervention trial evaluating the immunogenicity of Gardasil-9 in adult men and women living with adequately managed HIV infection. The study will include both men and women and will reflect the gender, race, ethnicity, sexual orientation and socioeconomic status of the patient population seeking care at University Medical Center.
After informed consent is secured, all enrolled participants will receive the 3-dose Gardasil-9 vaccine per product label at 0, 1 and 6 months. Subjects will be observed for at least 30 minutes after the vaccination is given. Participants consenting to the study will complete a sociodemographic survey at the enrollment visit. At 0, 7, 12, and 18-month visits, participants will complete a social history survey and whole venous blood, saliva, and anal swabs will be collected. A cervical/vaginal swab will also be collected from female participants. Whole blood will be processed to obtain serum, which will be aliquoted and stored at -80C. Serum samples will be tested for HPV antibodies by the competitive Luminex immunoassay (cLIA, Merck) to determine seroconversion rates and antibody titers. Genomic DNA isolates from saliva and swabs will be tested for HPV genotype-specific infection by high-throughput sequencing (HPV MY-Seq). Results of clinical laboratory tests pertinent to the study will be captured from the participant's electronic medical record. For patients who undergo cervical colposcopy or anoscopy with biopsy for clinical care, residual biopsy specimens will be obtained from UMC Pathology for HPV DNA genotype testing.
The immunological response of study participants will be compared to previously published historical (HIV negative adult) controls. Additionally, clinical outcomes of prevalent and incident HPV genotype-specific infection and anogenital dysplasia will be evaluated, comparing those participants who seroconvert/generate high titer antibodies to those who do not seroconvert/generate low titer antibodies, and comparing high-risk HPV genotypes included in the vaccine to high-risk HPV genotypes that are not included in the vaccine.
PLANNED ANALYSIS
The primary outcome of the study is seroconversion to the 9 HPV genotypes in the Gardasil-9 vaccine. This outcome will be analyzed as a binary variable (seropositive/seronegative) and as a continuous numerical value (antibody titers). Secondary outcomes of the study will evaluate the impact of vaccination on HPV infection and disease. Variables of interest include prevalent HPV infection, incident HPV infection, prevalent HPV-associated dysplasia, and incident dysplasia. Clinical outcome variables will also be interpolated from the data, including clearance and/or persistence of HPV infection and clearance, persistence or progression of HPV-associated disease. All disease will be evaluated on a per-site (mucosal tissue) basis and definitions for HPV related variables will depend on genotype-specificity. All variables will be collected at each 6-month timepoint. Time-to-event (e.g. viral clearance, progression of lesion) will also be extracted from the prospective data to evaluate clinical impacts of vaccination. Data will be stratified by demographic and social history variables to identify predictors of seroconversion and clinical outcomes and control for confounding factors.
Statistical Methods: Categorical covariates will be described by reporting counts and percentages, while continuous covariates will be reported using means and standard deviations. Categorical covariate distributions will be compared between seropositive/negative groups using a Fisher exact test, and continuous covariates will be compared using Wilcoxon rank sum tests. To test the primary hypothesis - that seropositivity rates do not differ from published rates of 95% in HIV-negative populations - a one-sided one-sample test of proportions will be used.
In order to determine what demographic factors influence variables in this population after potential confounder adjustment, several regression analyses will be used. For binary variables, logistic regression will be used, while for continuous variables typical linear regression is used. For time to event variables, Cox regression will be used, and for variables that are proportions, Beta regression will be used. When using repeated measurements, independence will be maintained by controlling for subject ID as a random or fixed effect. If necessary, Bayesian methods will be used.
Power/Sample Size: Assuming a seroconversion rate of 95% in HIV-negative patients, 150 enrolled patients would give power of about 99% to detect a seroconversion rate of 80%. The design also has a power of 80% if the true seroconversion rate in Gardasil patients is 89%. The design will not be well powered to detect decreases <6% in seroconversion rates from the published literature.
Study Type
Enrollment (Anticipated)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
Louisiana
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New Orleans, Louisiana, United States, 70112
- Recruiting
- University Medical Center New Orleans
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- HIV seropositive
- immune intact (CD4+ T cell count in peripheral blood >200 cells/ml)
- HIV controlled (peripheral blood HIV viral load <1,000 genome copies/mL)
- Stable on antiretroviral regimen for ≥3 months
- Gardasil-9 naive
Exclusion Criteria:
- Medical contraindication for vaccination
- Women who are pregnant
- Acute illness
- Taking chronic steroids, >0.5mg/kg prednisone or equivalent
- Taking immune modulating medications
- Received blood transfusion/blood products within the past 6 months
- Recipients of other vaccine products within the past month
- Inability to provide informed written consent
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Gardasil-9 recipients
Participants receive 3-dose Gardasil-9 vaccine series.
|
Subunit vaccine against 9 genotypes of human papillomavirus (6, 11, 16, 18, 31, 33, 45, 52, 58)
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
change in serological response to Gardasil-9
Time Frame: 18 months
|
serum antibodies against human papillomavirus genotypes 6,11,16,18,31,33,45,52, and 58
|
18 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
change in HPV infection status: resolution of prevalent HPV infection
Time Frame: 18 months
|
time-to-clearance of prevalent HPV infection of the oral cavity, vaginal tract and/or anal canal
|
18 months
|
change in HPV infection status: protection against incident HPV infection
Time Frame: 18 months
|
acquisition of genotype-specific HPV infection following Gardasil-9 immunization at mucosal sites (oral cavity, genital tract, anal canal)
|
18 months
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
change in mucosal antibody response to Gardasil-9
Time Frame: 18 months
|
HPV-16 antibodies in saliva
|
18 months
|
Collaborators and Investigators
Collaborators
Publications and helpful links
General Publications
- Levin MJ, Moscicki AB, Song LY, Fenton T, Meyer WA 3rd, Read JS, Handelsman EL, Nowak B, Sattler CA, Saah A, Radley DR, Esser MT, Weinberg A; IMPAACT P1047 Protocol Team. Safety and immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-infected children 7 to 12 years old. J Acquir Immune Defic Syndr. 2010 Oct;55(2):197-204. doi: 10.1097/QAI.0b013e3181de8d26.
- Hagensee ME, Yaegashi N, Galloway DA. Self-assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of the L1 and L2 capsid proteins. J Virol. 1993 Jan;67(1):315-22. doi: 10.1128/JVI.67.1.315-322.1993.
- Kamolratanakul S, Pitisuttithum P. Human Papillomavirus Vaccine Efficacy and Effectiveness against Cancer. Vaccines (Basel). 2021 Nov 30;9(12):1413. doi: 10.3390/vaccines9121413.
- Kim HN, Harrington RD, Crane HM, Dhanireddy S, Dellit TH, Spach DH. Hepatitis B vaccination in HIV-infected adults: current evidence, recommendations and practical considerations. Int J STD AIDS. 2009 Sep;20(9):595-600. doi: 10.1258/ijsa.2009.009126.
- Shire NJ, Welge JA, Sherman KE. Efficacy of inactivated hepatitis A vaccine in HIV-infected patients: a hierarchical bayesian meta-analysis. Vaccine. 2006 Jan 16;24(3):272-9. doi: 10.1016/j.vaccine.2005.07.102. Epub 2005 Aug 18.
- Bickel M, Wieters I, Khaykin P, Nisius G, Haberl A, Stephan C, Von Hentig N, Herrmann E, Doerr HW, Brodt HR, Allwinn R. Low rate of seroconversion after vaccination with a split virion, adjuvanted pandemic H1N1 influenza vaccine in HIV-1-infected patients. AIDS. 2010 Jun 1;24(9):F31-5. doi: 10.1097/QAD.0b013e3283398da1.
- Boey L, Curinckx A, Roelants M, Derdelinckx I, Van Wijngaerden E, De Munter P, Vos R, Kuypers D, Van Cleemput J, Vandermeulen C. Immunogenicity and Safety of the 9-Valent Human Papillomavirus Vaccine in Solid Organ Transplant Recipients and Adults Infected With Human Immunodeficiency Virus (HIV). Clin Infect Dis. 2021 Aug 2;73(3):e661-e671. doi: 10.1093/cid/ciaa1897.
- Lacey CJ. HPV vaccination in HIV infection. Papillomavirus Res. 2019 Dec;8:100174. doi: 10.1016/j.pvr.2019.100174. Epub 2019 Jun 25.
- Wilkin TJ, Chen H, Cespedes MS, Leon-Cruz JT, Godfrey C, Chiao EY, Bastow B, Webster-Cyriaque J, Feng Q, Dragavon J, Coombs RW, Presti RM, Saah A, Cranston RD. A Randomized, Placebo-Controlled Trial of the Quadrivalent Human Papillomavirus Vaccine in Human Immunodeficiency Virus-Infected Adults Aged 27 Years or Older: AIDS Clinical Trials Group Protocol A5298. Clin Infect Dis. 2018 Oct 15;67(9):1339-1346. doi: 10.1093/cid/ciy274.
- McClymont E, Lee M, Raboud J, Coutlee F, Walmsley S, Lipsky N, Loutfy M, Trottier S, Smaill F, Klein MB, Harris M, Cohen J, Yudin MH, Wobeser W, Money D; CTN 236 HPV in HIV Study Team. The Efficacy of the Quadrivalent Human Papillomavirus Vaccine in Girls and Women Living With Human Immunodeficiency Virus. Clin Infect Dis. 2019 Feb 15;68(5):788-794. doi: 10.1093/cid/ciy575.
- Massad LS, Xie X, Burk RD, D'Souza G, Darragh TM, Minkoff H, Colie C, Burian P, Palefsky J, Atrio J, Strickler HD. Association of cervical precancer with human papillomavirus types other than 16 among HIV co-infected women. Am J Obstet Gynecol. 2016 Mar;214(3):354.e1-6. doi: 10.1016/j.ajog.2015.09.086. Epub 2015 Nov 14.
- Wilkin T, Lee JY, Lensing SY, Stier EA, Goldstone SE, Berry JM, Jay N, Aboulafia D, Cohn DL, Einstein MH, Saah A, Mitsuyasu RT, Palefsky JM. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1-infected men. J Infect Dis. 2010 Oct 15;202(8):1246-53. doi: 10.1086/656320.
- Roberts C, Green T, Hess E, Matys K, Brown MJ, Haupt RM, Luxembourg A, Vuocolo S, Saah A, Antonello J. Development of a human papillomavirus competitive luminex immunoassay for 9 HPV types. Hum Vaccin Immunother. 2014;10(8):2168-74. doi: 10.4161/hv.29205.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- RNA Virus Infections
- Virus Diseases
- Blood-Borne Infections
- Sexually Transmitted Diseases, Viral
- Sexually Transmitted Diseases
- Lentivirus Infections
- Retroviridae Infections
- Immune System Diseases
- Neoplasms by Histologic Type
- Carcinoma
- Neoplasms, Glandular and Epithelial
- Disease Attributes
- DNA Virus Infections
- Tumor Virus Infections
- Slow Virus Diseases
- Neoplasms
- HIV Infections
- Carcinoma in Situ
- Cervical Intraepithelial Neoplasia
- Infections
- Communicable Diseases
- Acquired Immunodeficiency Syndrome
- Immunologic Deficiency Syndromes
- Papillomavirus Infections
Other Study ID Numbers
- 2070 (Other Grant/Funding Number: National Cattlemen's Beef Association)
- MISP61476 (Other Grant/Funding Number: Merck Sharp & Dohme Corp)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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