Immunogenicity of Gardasil-9 HPV Vaccine in People Living With HIV

Brief Title

Immunogenicity of Gardasil-9 HPV Vaccine in People Living With HIV

Official Title

Prospective Observational Immunogenicity Trial of Gardasil-9 HPV Vaccine in People Living With Adequately Managed HIV

Brief Summary

      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.
    

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 Phase

Phase 4

Study Type

Interventional

Primary Outcome

change in serological response to Gardasil-9

Secondary Outcome

 change in HPV infection status: resolution of prevalent HPV infection

Condition

Papillomavirus Vaccines

Intervention

Human papillomavirus 9-valent vaccine, recombinant

Study Arms / Comparison Groups

 Gardasil-9 recipients

Description:  Participants receive 3-dose Gardasil-9 vaccine series.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Biological

Estimated Enrollment

150

Start Date

November 30, 2022

Completion Date

March 2025

Primary Completion Date

June 2024

Eligibility Criteria

        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
      

Gender

All

Ages

18 Years - 45 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Jennifer E Cameron, PhD, 504-568-4804, [email protected]

Location Countries

United States

Location Countries

United States

NCT ID

NCT05266898

Organization ID

2070

Secondary IDs

MISP61476

Responsible Party

Principal Investigator

Study Sponsor

Louisiana State University Health Sciences Center in New Orleans

Collaborators

 Merck Sharp & Dohme LLC

Study Sponsor

Jennifer E Cameron, PhD, Principal Investigator, Louisiana State University Health Sciences Center

Verification Date

March 2023