<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03802994</url>
  </required_header>
  <id_info>
    <org_study_id>INFB-019-17F</org_study_id>
    <secondary_id>CX001568</secondary_id>
    <nct_id>NCT03802994</nct_id>
  </id_info>
  <brief_title>Pneumococcal Conjugate Vaccine in Aging Renal Transplant</brief_title>
  <official_title>Immune Response to Pneumococcal Vaccination in Aging Renal Transplant Recipients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The goal of the research proposed in the current application is to first define how much&#xD;
      antibody aging renal transplant and dialysis recipients make after they are vaccinated with&#xD;
      the pneumonia vaccine and how this compares to similar aged persons with good renal function&#xD;
      and healthy young adults. The investigators will study differences in the kind of B cells and&#xD;
      markers on the B cells that are known to be important in the response to the pneumonia&#xD;
      vaccine in aging renal transplant and aging dialysis recipients compared to similarly aged&#xD;
      and young healthy controls. Finally, the investigators will study how safe the pneumonia&#xD;
      vaccine is in aging renal transplants. The answers to these questions will help in designing&#xD;
      a better vaccine for older people with a renal transplant or on dialysis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objectives / Specific Aims&#xD;
&#xD;
      Individuals &gt;65 years of age, are the most rapidly growing population amongst those with end&#xD;
      stage renal disease (ESRD) and account for more than 18% of renal transplant (RT) recipients.&#xD;
&#xD;
      The incidence of pneumococcal disease is significantly higher in both elderly and those with&#xD;
      RT and the combination of these factors is likely additive, if not synergistic, for invasive&#xD;
      pneumococcal disease (IPD). It is recommended that both elderly&gt;65 and RT recipients be&#xD;
      vaccinated with a regimen that includes both the 13-valent pneumococcal conjugate vaccine&#xD;
      (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPV23). However, small&#xD;
      immunogenicity studies performed in the transplant populations have not shown superiority of&#xD;
      a PCV containing regimen. Moreover, the addition of PCV to the pneumococcal vaccine regimen&#xD;
      does not improve protective immunity in this population. Studies to date fail to elucidate&#xD;
      the possible foundation of the disappointing immune responses to the PCV regimens.&#xD;
&#xD;
      Specific Aim 1. The investigators will define immune responses by measuring serum antibody&#xD;
      and functional antibody responses to PPS 14, 19A and 23F following PCV13 vaccination in RT&#xD;
      recipients 65-75 years of age and compare these to: RT recipients 35-45 years of age and&#xD;
      persons with DM/HTN but normal function 65-75 years of age to dissect out the age and RT&#xD;
      components respectively. Healthy persons 35-45 and 65-75 years of age will be studied as age&#xD;
      appropriate reference.&#xD;
&#xD;
      Specific Aim 2. The investigators will measure and characterize the antigen-specific B cell&#xD;
      subset response following immunization with PCV13 in the RT recipients 65-75 years of age and&#xD;
      compare them to each of the groups described in Specific Aim 1 using flow cytometry and&#xD;
      fluorescently labeled PPS and monoclonal antibodies. These measures will be correlated with&#xD;
      post-immunization functional antibody activity, a surrogate of protection.&#xD;
&#xD;
      Specific Aim 3. The investigators will measure TNFR expression by B cells following&#xD;
      immunization with PCV13 in 65-75 year old RT and compare them to each of the groups described&#xD;
      in Specific Aim 1. Gene expression, with focus on the B cell activating factor (BAFF) system,&#xD;
      will be measured in PPS-specific and non-PPS specific B cells using single cell genomics and&#xD;
      flow cytometry. These measures will be correlated with post-immunization functional antibody&#xD;
      activity, a surrogate of protection.&#xD;
&#xD;
      The central hypothesis is that the aging RT population responds poorly to PCV13 vaccination&#xD;
      reflecting the combined effects of aging and RT. The investigators postulate that both the&#xD;
      number of memory B cells and expression of tumor necrosis factor (TNF) superfamily receptors,&#xD;
      which play crucial roles in the response to pneumococcal polysaccharides (PPS), are deficient&#xD;
      in the elderly RT population and contribute to poor pneumococcal vaccine responses.&#xD;
&#xD;
      The investigators have developed fluorescently labeled PPS allowing us to study the nature&#xD;
      and surface receptors of PPS-specific B cells. The preliminary data demonstrate that RT&#xD;
      recipients 1. Respond poorly to pneumococcal immunization as measured by antibody titer and&#xD;
      functional antibody activity. 2. RT recipients and healthy elderly have lower absolute number&#xD;
      of both IgM and switched memory B cells. 3. The number of PPS-specific IgM and switched&#xD;
      memory B cells are significantly lower in RT recipients and 4. TACI and BAFF-R, members of&#xD;
      the TNF superfamily receptors, expression is significantly lower in the PPS-specific memory B&#xD;
      cells in the RT population versus healthy controls. The overall objective of this proposal is&#xD;
      to characterize the immune response and explore possible mechanisms of poor vaccine&#xD;
      responsiveness following immunization with PCV in the rapidly growing group of elderly with&#xD;
      RT. As the RT population is a heterogeneous group the investigators will study only those in&#xD;
      whom the underlying cause of renal failure is diabetes mellitus type 2 (DM2) and/or&#xD;
      hypertension (HTN).&#xD;
&#xD;
      Intervention to be studied The intervention to be studied is the immune response to&#xD;
      immunization with PCV13 or Prevnar13. This FDA approved vaccine is given as part of the&#xD;
      standard of care in Groups 1-4. The experimental part of the protocol in these groups will be&#xD;
      blood draws at days 0, 7, 30 and years 1 and 2 in these groups.&#xD;
&#xD;
      In Group 5 two interventions will occur: 1. Immunization with the FDA approved PPV23 or&#xD;
      Pneumovax 23 and 2. PCV13 a FDA approved vaccine. In addition, blood samples will be obtained&#xD;
      at days 0, 7, 30 year 1 and year2.&#xD;
&#xD;
      Both PPV23 and PCV13 are FDA approved vaccines for use in humans. PCV13 is recommended for&#xD;
      all individuals enrolled in Groups 1-4. It is not recommended as routine part of care in&#xD;
      Group 5 enrolled individuals however it has never shown to be harmful in this group of&#xD;
      individuals.&#xD;
&#xD;
      Study Endpoints The primary endpoint of this study is: quantify the antibody titers in mg/mL&#xD;
      and opsonophagocytic antibody titer calculated as serum dilution, number of polysaccharide&#xD;
      specific B cells, and absolute number of cells/mL induced by vaccination with PCV13.&#xD;
&#xD;
      Secondary endpoint of the study is to describe differences in gene expression of 56 genes to&#xD;
      be determined by single cell PCR and comparing these between groups.&#xD;
&#xD;
      The primary safety endpoint of the study is measured as minimal versus moderate local side&#xD;
      effect. Minimal side effect measured as no impairment in activity. Moderate local side effect&#xD;
      is a side effect affecting use of the extremity for less than 24 hours.&#xD;
&#xD;
      Inclusion and Exclusion Criteria/ Study Population: as described in inclusion/exclusion&#xD;
      section&#xD;
&#xD;
      Diversity: the investigators will attempt to mimic the local renal transplant recipient&#xD;
      population consisting of a disproportionately high number of males (&gt;60%) of African-American&#xD;
      decent, 50%.&#xD;
&#xD;
      Number of Subjects 275&#xD;
&#xD;
      Study Sites&#xD;
&#xD;
        1. The MUSC Renal Transplant clinic is located on the 9th floor of the Rutledge Tower&#xD;
&#xD;
        2. The nephrology clinic at the Ralph H. Johnson VA Medical Center&#xD;
&#xD;
        3. the P.I.'s laboratory at the Strom Thurmond Building Room 411&#xD;
&#xD;
      Recruitment Methods&#xD;
&#xD;
        -  Potential study participants will be recruited from Ralph H. Johnson Veterans Affair&#xD;
           Medical Center and Medical University of South Carolina during the appointment with&#xD;
           their treating physician. Flyers will be posted in the waiting room areas of the clinics&#xD;
           and attending physicians and clinic nurses will be asked to keep this study in mind and&#xD;
           mention availability of these studies to their patients when ordering PCV13 for them.&#xD;
&#xD;
        -  Potential study subjects will be identified by reviewing medical records and by&#xD;
           physician's recommendations.&#xD;
&#xD;
        -  Flyers will be used to recruit study subjects as well as broadcast emails for MUSC and&#xD;
           VA employees and volunteers.&#xD;
&#xD;
      Consent Process&#xD;
&#xD;
      Informed Consent will be obtained in a private room from all participants at either:&#xD;
&#xD;
      1. The MUSC Renal Transplant clinic is located on the 9th floor of the Rutledge Tower Or&#xD;
      2.The nephrology clinic at the Ralph H. Johnson VA Medical Center Or 3. the P.I.'s laboratory&#xD;
      at the Strom Thurmond Building Room 411&#xD;
&#xD;
      Consent will be sought of competent adults who express interest in the study. The purpose of&#xD;
      the study, the study details regarding gathering health information and obtaining blood&#xD;
      samples, the potential benefit and risks involved, including risk of blood draw and&#xD;
      vaccination, will be explained in detail and in layman terms, as well as the non-standard of&#xD;
      care explained to the potential subject (i.e. blood draws for groups 1-4, vaccination&#xD;
      protocol and blood draws for group 5).&#xD;
&#xD;
      Study Design / Methods The overall objective of this proposal is to characterize the immune&#xD;
      response and explore possible mechanisms of poor vaccine responsiveness following&#xD;
      immunization with PCV in the rapidly growing group of elderly with RT. As the RT population&#xD;
      is a heterogeneous group the investigators will study only those in whom the underlying cause&#xD;
      of renal failure is diabetes mellitus type 2 (DM2) and/or hypertension (HTN). There will be 5&#xD;
      study groups as outlined above.&#xD;
&#xD;
      results obtained in various groups will be compared.&#xD;
&#xD;
      Timing of blood samples Peripheral blood samples will be collected at day 0 (pre-immune), day&#xD;
      7, and day 30 (4 weeks post-PPV23) for groups 1-4 and at days 366, 373 and 396 for group 5.&#xD;
      BAFF concentration will be measured at day&#xD;
&#xD;
      The vaccine(s) administered to the participants are FDA approved vaccinations and vaccination&#xD;
      protocols. The standard and recommended dose of vaccine will be administered either by a&#xD;
      qualified nurse or physician and both vaccines are considered low risk. In groups 1-4 PCV13&#xD;
      will be administered per standard of care and is not part of the experimental protocol. In&#xD;
      group 5, both PPV23 and PCV 13 are not routine part of care and are part of the experimental&#xD;
      protocol. These vaccines have however been extensively studied in this and other populations&#xD;
      and are considered low risk and 70-80% protective against pneumococcal disease.&#xD;
&#xD;
      The risk associated with blood draws is minimal.&#xD;
&#xD;
        -  Pre- and post-immunization serum antibody titers and opsonophagocytic antibody titers to&#xD;
           PPS14, 19A and 23F in ug/mL determined by ELISA IgM and switched memory B cell number&#xD;
           and percentage determined by flow cytometry&#xD;
&#xD;
        -  PPS+ B cell number and percentage determined by flow cytometry&#xD;
&#xD;
        -  Serum BAFF concentration by ELISA&#xD;
&#xD;
        -  Gene expression of 56 genes will be studies using single cell PCR analysis&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Due to COVID pandemic further recruitment of subjects was unethical.&#xD;
  </why_stopped>
  <start_date type="Actual">November 1, 2018</start_date>
  <completion_date type="Actual">February 28, 2020</completion_date>
  <primary_completion_date type="Actual">February 28, 2020</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Immune response to immunization with Prevnar in elderly aging renal transplant compared to comparison groups: healthy young, healthy elderly, healthy elderly hypertension (HTN) and young renal transplants.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Anti-pneumococcal IgG Antibody (ug/ml) Change</measure>
    <time_frame>Baseline, 30 days</time_frame>
    <description>Measure the opsonic antibody response against streptococcus pneumonia serotypes 14, 19A and 23F at days 0 and 30.&#xD;
Comparing elderly RT recipients versus healthy elderly and elderly with DM/HTN.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Opsonophagocytic Antibody Titer Serum Dilution Difference Between Healthy Elderly, Elderly With DM/HTN and Elderly With RT.</measure>
    <time_frame>Baseline and 30 days</time_frame>
    <description>Measure the serum opsonophagocytic activity against streptococcus pneumonia serotypes 14, 19A and 23F on days 0 and 30 by opsonophagocytic assay.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of Polysaccharide Specific B Cells (% Cells/mL)</measure>
    <time_frame>day 7</time_frame>
    <description>percentage of polysaccharide specific B cells, and percentage of IgM memory B cells/mL in % cells/mL induced by vaccination with PCV13</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Inflammatory Markers Serum Levels Pre-immunization</measure>
    <time_frame>Day 0 pre-immunization</time_frame>
    <description>Measure level of inflammatory markers BAFF, APRIL, IL6, TNF alpha and sCD40L in serum in pg/mL pre-immunization.</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">57</enrollment>
  <condition>Renal Transplantation</condition>
  <condition>Aging</condition>
  <arm_group>
    <arm_group_label>1.Aging RT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Renal transplant recipients between 65-75 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2.Young RT</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Renal transplant recipients between 35-45 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3.Healthy elderly</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Healthy persons between the ages 65-75 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>4.Elderly DMII or HTN and normal renal function</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Persons between the ages 65-75 with DMII or hypertension but normal renal function who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>5.Healthy young</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Healthy persons between the ages 35-45 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23) or are willing to receive PPV23 and 1 year later Prevnar 13.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>23 valent pneumococcal polysaccharide vaccine</intervention_name>
    <description>FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 23 different pneumococcal serotypes. Only group 5 will potentially receive this as an intervention.</description>
    <arm_group_label>5.Healthy young</arm_group_label>
    <other_name>Pneumovax 23 or PPV23</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>13 valent conjugated pneumococcal vaccine</intervention_name>
    <description>FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 13 different pneumococcal serotypes conjugated to CRM197. Only group 5 will receive this as an intervention. In all other groups Prevnar 13 will be given as standard of care.</description>
    <arm_group_label>5.Healthy young</arm_group_label>
    <other_name>Prevnar 23 or PCV13</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Peripheral blood sample</intervention_name>
    <description>Peripheral blood samples (30-60 mL) will be collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) for groups 1-4 and at days 366, 373 and 396 for group 5. In addition, day 5, and 10 blood samples will be obtained from a limited (n=10) number of elderly RT participants to determine the optimal time point for circulation of PPS-specific B cells. Yearly blood samples will be obtained thereafter for serum antibody and OPA analyses to test longevity of antibody and OPA responses. Samples obtained from days 0, 30 and yearly samples will be used for antibody titers and opsonophagocytic assays. Samples from day 0 (day of vaccination with PCV13) and day 7 will be used for flow cytometric analysis.</description>
    <arm_group_label>1.Aging RT</arm_group_label>
    <arm_group_label>2.Young RT</arm_group_label>
    <arm_group_label>3.Healthy elderly</arm_group_label>
    <arm_group_label>4.Elderly DMII or HTN and normal renal function</arm_group_label>
    <arm_group_label>5.Healthy young</arm_group_label>
    <other_name>blood draw</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Inclusion criteria are group specific. HBV, HCV and HIV testing are not necessary in the RT&#xD;
        groups as all RT recipients are tested prior to transplant. The investigators will not&#xD;
        restrict volunteers with respect to gender, ethnic or racial group.&#xD;
&#xD;
        Groups 1 (65-75 yrs) and 2 (35-45 yrs) Renal Transplant populations&#xD;
&#xD;
          -  End stage renal disease cause either DM2 and/or hypertension (HTN)&#xD;
&#xD;
          -  Renal transplant &gt;12 months ago&#xD;
&#xD;
        Group 3: Diabetic/hypertensive 65-75 year old controls&#xD;
&#xD;
          -  With DM2 and/or HTN&#xD;
&#xD;
          -  Previous immunization with PPV23 &gt;1 year prior&#xD;
&#xD;
          -  Willingness to be tested for HIV, HBV and HCV&#xD;
&#xD;
          -  &quot;normal kidney function&quot; defined as glomerular filtration rate (GFR) of 60% or above&#xD;
&#xD;
        Group 4: Healthy Control 65-75 yr old&#xD;
&#xD;
          -  Without DM2&#xD;
&#xD;
          -  May have high blood pressure (systolic&gt;140 and/or diastolic&gt;90) as long as it is well&#xD;
             controlled (systolic&lt;140 and/or diastolic &lt;90) and has not affected kidney function.&#xD;
&#xD;
          -  Previous receipt of PPV23 &gt; 1 year prior&#xD;
&#xD;
          -  Willingness to be tested for HIV, HBV and HCV&#xD;
&#xD;
        Group 5: Healthy Control 35-45 yr old&#xD;
&#xD;
          -  Without DM2.&#xD;
&#xD;
          -  May have high blood pressure (systolic&gt;140 and/or diastolic&gt;90) as long as it is well&#xD;
             controlled (systolic&lt;140 and/or diastolic &lt;90) and has not affected kidney function.&#xD;
&#xD;
          -  Willingness to be tested for HIV, HBV and HCV and filling out a medical questionnaire&#xD;
             that will include diabetes screening.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Exclusion criteria are either applicable to all groups or group specific. Therefore we have&#xD;
        listed the exclusion criteria applicable to ALL groups first. Group specific criteria are&#xD;
        listed under each group.&#xD;
&#xD;
        Exclusion Criteria common to all groups&#xD;
&#xD;
          -  Previous immunization with PCV13.&#xD;
&#xD;
          -  Pregnancy, no contraceptive practice in women of childbearing age, or breastfeeding&#xD;
&#xD;
          -  Known anaphylaxis, hypersensitivity or &quot;bad allergic reaction&quot; to the pneumonia&#xD;
             vaccine. This does not include egg allergy or previous Guillan Barre syndrome.&#xD;
&#xD;
          -  Those who received blood products or gamma globulin within 3 months.&#xD;
&#xD;
          -  Inability to comprehend or sign the informed consent form&#xD;
&#xD;
          -  Previous/present illness that may affect immune response to the vaccine&#xD;
&#xD;
               -  previous pneumococcal disease&#xD;
&#xD;
               -  disease&#xD;
&#xD;
               -  removal of the spleen&#xD;
&#xD;
               -  auto-immune disease such as lupus or rheumatoid arthritis&#xD;
&#xD;
               -  end-stage liver disease&#xD;
&#xD;
               -  cancer&#xD;
&#xD;
          -  Significant abnormalities (3xULN and all those considered to be critical values) in&#xD;
             CBC, chemistries including glucose.&#xD;
&#xD;
          -  HIV, HBsAg or HCV positivity&#xD;
&#xD;
          -  Receipt of PPV23 within 1 year&#xD;
&#xD;
        Groups 1 (65-75 yrs) and 2 (35-45 yrs) Renal Transplant populations&#xD;
&#xD;
          -  Medications that are known to affect immune function (chemotherapy, anti-TNF agents)&#xD;
             with the exception of anti-rejection medication.&#xD;
&#xD;
          -  Episode of acute rejection within the last 6 month period&#xD;
&#xD;
        Group 3: Diabetic/hypertensive 65-75 year old controls&#xD;
&#xD;
          -  Medications that are known to affect immune function (chemotherapy, anti-TNF agents).&#xD;
&#xD;
          -  The inclusion/exclusion criteria will be determined by chart review.&#xD;
&#xD;
        Group 4: Healthy Control 65-75 yr old&#xD;
&#xD;
          -  Medications that are known to affect immune function (chemotherapy, anti-TNF agents).&#xD;
&#xD;
          -  The inclusion/exclusion criteria will be determined by chart review and pregnancy test&#xD;
             for females of child bearing potential.&#xD;
&#xD;
        Group 5: Healthy Control 35-45 yr old&#xD;
&#xD;
          -  Medications that are known to affect immune function (chemotherapy, anti-TNF agents).&#xD;
&#xD;
          -  The inclusion/exclusion criteria will be determined by chart review and pregnancy test&#xD;
             for females of child bearing potential.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Maria J Westerink, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ralph H. Johnson VA Medical Center, Charleston, SC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ralph H. Johnson VA Medical Center, Charleston, SC</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29401-5799</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical University of South Carolina</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29425</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>December 18, 2018</study_first_submitted>
  <study_first_submitted_qc>January 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 14, 2019</study_first_posted>
  <results_first_submitted>January 21, 2021</results_first_submitted>
  <results_first_submitted_qc>April 6, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">April 30, 2021</results_first_posted>
  <last_update_submitted>April 6, 2021</last_update_submitted>
  <last_update_submitted_qc>April 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 30, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Prevnar</keyword>
  <keyword>pneumococcal conjugate vaccine</keyword>
  <keyword>aging</keyword>
  <keyword>renal transplant recipient</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vaccines</mesh_term>
    <mesh_term>Heptavalent Pneumococcal Conjugate Vaccine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>October 23, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT03802994/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>1.Aging RT</title>
          <description>Renal transplant recipients between 65-75 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) will be collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) for groups 1-4 and at days 366, 373 and 396 for group 5. In addition, day 5, and 10 blood samples will be obtained from a limited (n=10) number of elderly RT participants to determine the optimal time point for circulation of PPS-specific B cells. Yearly blood samples will be obtained thereafter for serum antibody and OPA analyses to test longevity of antibody and OPA responses. Samples obtained from days 0, 30 and yearly samples will be used for antibody titers and opsonophagocytic assays. Samples from day 0 (day of vaccination with PCV13) and day 7 will be used for flow cytometric analysis.</description>
        </group>
        <group group_id="P2">
          <title>2.Young RT</title>
          <description>Renal transplant recipients between 35-45 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) will be collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) for groups 1-4 and at days 366, 373 and 396 for group 5. In addition, day 5, and 10 blood samples will be obtained from a limited (n=10) number of elderly RT participants to determine the optimal time point for circulation of PPS-specific B cells. Yearly blood samples will be obtained thereafter for serum antibody and OPA analyses to test longevity of antibody and OPA responses. Samples obtained from days 0, 30 and yearly samples will be used for antibody titers and opsonophagocytic assays. Samples from day 0 (day of vaccination with PCV13) and day 7 will be used for flow cytometric analysis.</description>
        </group>
        <group group_id="P3">
          <title>3.Healthy Elderly</title>
          <description>Healthy persons between the ages 65-75 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) will be collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) for groups 1-4 and at days 366, 373 and 396 for group 5. In addition, day 5, and 10 blood samples will be obtained from a limited (n=10) number of elderly RT participants to determine the optimal time point for circulation of PPS-specific B cells. Yearly blood samples will be obtained thereafter for serum antibody and OPA analyses to test longevity of antibody and OPA responses. Samples obtained from days 0, 30 and yearly samples will be used for antibody titers and opsonophagocytic assays. Samples from day 0 (day of vaccination with PCV13) and day 7 will be used for flow cytometric analysis.</description>
        </group>
        <group group_id="P4">
          <title>4.Elderly DMII or HTN and Normal Renal Function</title>
          <description>Persons between the ages 65-75 with DMII or hypertension but normal renal function who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) will be collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) for groups 1-4 and at days 366, 373 and 396 for group 5. In addition, day 5, and 10 blood samples will be obtained from a limited (n=10) number of elderly RT participants to determine the optimal time point for circulation of PPS-specific B cells. Yearly blood samples will be obtained thereafter for serum antibody and OPA analyses to test longevity of antibody and OPA responses. Samples obtained from days 0, 30 and yearly samples will be used for antibody titers and opsonophagocytic assays. Samples from day 0 (day of vaccination with PCV13) and day 7 will be used for flow cytometric analysis.</description>
        </group>
        <group group_id="P5">
          <title>5.Healthy Young</title>
          <description>Healthy persons between the ages 35-45 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23) or are willing to receive PPV23 and 1 year later Prevnar 13.&#xD;
23 valent pneumococcal polysaccharide vaccine: FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 23 different pneumococcal serotypes. Only group 5 will potentially receive this as an intervention.&#xD;
13 valent conjugated pneumococcal vaccine: FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 13 different pneumococcal serotypes conjugated to CRM197. Only group 5 will receive this as an intervention. In all other groups Prevnar 13 will be given as standard of care.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) will be collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) for groups 1-4 and at days 366, 373 and 396 for group 5. In addition, day 5, and 10 blood samples will be obtained from a limited (n=10) number of elderly RT participants to determine the optimal time point for circulation of PPS-specific B cells. Yearly blood samples will be obtained thereafter for serum antibody and OPA analyses to test longevity of antibody and OPA responses. Samples obtained from days 0, 30 and yearly samples will be used for antibody titers and opsonophagocytic assays. Samples from day 0 (day of vaccination with PCV13) and day 7 will be used for flow cytometric analysis.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="12"/>
                <participants group_id="P3" count="15"/>
                <participants group_id="P4" count="11"/>
                <participants group_id="P5" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="10"/>
                <participants group_id="P3" count="12"/>
                <participants group_id="P4" count="9"/>
                <participants group_id="P5" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>In Groups 1, 3,4 and 5 2 individuals per group were enrolled but did not complete the study which affected parameters of all study objectives: pre- to post-antibody and opsonophagocytic responses, B cell analysis and inflammatory markers.</population>
      <group_list>
        <group group_id="B1">
          <title>1.Aging RT</title>
          <description>Renal transplant recipients between 65-75 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0 and 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 was used for flow cytometric analysis.</description>
        </group>
        <group group_id="B2">
          <title>2.Young RT</title>
          <description>Renal transplant recipients between 35-45 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0, 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
        </group>
        <group group_id="B3">
          <title>3.Healthy Elderly</title>
          <description>Healthy persons between the ages 65-75 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23). Samples obtained from days 0, 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 was used for flow cytometric analysis.</description>
        </group>
        <group group_id="B4">
          <title>4.Elderly DMII or HTN and Normal Renal Function</title>
          <description>Persons between the ages 65-75 with DMII or hypertension but normal renal function who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30. Samples from day 7 were used for flow cytometric analysis.</description>
        </group>
        <group group_id="B5">
          <title>5.Healthy Young</title>
          <description>Healthy persons between the ages 35-45 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23).&#xD;
23 valent pneumococcal polysaccharide vaccine: FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 23 different pneumococcal serotypes. All young healthy participants recruited were already immunized with pneumovax at least one year prior to enrollment&#xD;
13 valent conjugated pneumococcal vaccine: FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 13 different pneumococcal serotypes conjugated to CRM197 was adminstered at day 0. Only group 5 received this as an intervention. In all other groups Prevnar 13 was given as standard of care.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0, 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
        </group>
        <group group_id="B6">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="9"/>
            <count group_id="B2" value="12"/>
            <count group_id="B3" value="15"/>
            <count group_id="B4" value="11"/>
            <count group_id="B5" value="10"/>
            <count group_id="B6" value="57"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="10"/>
                    <measurement group_id="B6" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="15"/>
                    <measurement group_id="B4" value="11"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="67" lower_limit="65" upper_limit="71"/>
                    <measurement group_id="B2" value="41" lower_limit="35" upper_limit="45"/>
                    <measurement group_id="B3" value="66" lower_limit="65" upper_limit="69"/>
                    <measurement group_id="B4" value="66" lower_limit="65" upper_limit="72"/>
                    <measurement group_id="B5" value="40" lower_limit="35" upper_limit="44"/>
                    <measurement group_id="B6" value="65" lower_limit="35" upper_limit="72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="2"/>
                    <measurement group_id="B6" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="15"/>
                    <measurement group_id="B4" value="11"/>
                    <measurement group_id="B5" value="8"/>
                    <measurement group_id="B6" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="6"/>
                    <measurement group_id="B5" value="2"/>
                    <measurement group_id="B6" value="35"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="5"/>
                    <measurement group_id="B5" value="8"/>
                    <measurement group_id="B6" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="15"/>
                    <measurement group_id="B4" value="11"/>
                    <measurement group_id="B5" value="10"/>
                    <measurement group_id="B6" value="57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Anti-pneumococcal IgG Antibody (ug/ml) Change</title>
        <description>Measure the opsonic antibody response against streptococcus pneumonia serotypes 14, 19A and 23F at days 0 and 30.&#xD;
Comparing elderly RT recipients versus healthy elderly and elderly with DM/HTN.</description>
        <time_frame>Baseline, 30 days</time_frame>
        <population>Participants who completed PCV13 immunization and from whom blood samples were obtained on day 0, 7, and 30.&#xD;
There is thus a discrepancy between the number of enrolled and analyzed participants in groups 2,3,4 and 5.</population>
        <group_list>
          <group group_id="O1">
            <title>1.Aging RT</title>
            <description>Renal transplant recipients between 65-75 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0 and 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O2">
            <title>2.Young RT</title>
            <description>Renal transplant recipients between 35-45 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0 and 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O3">
            <title>3.Healthy Elderly</title>
            <description>Healthy persons between the ages 65-75 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0 and 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O4">
            <title>4.Elderly DMII or HTN and Normal Renal Function</title>
            <description>Persons between the ages 65-75 with DMII or hypertension but normal renal function who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0 and 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O5">
            <title>5.Healthy Young</title>
            <description>Healthy persons between the ages 35-45 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
13 valent conjugated pneumococcal vaccine: FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 13 different pneumococcal serotypes conjugated to CRM197 was used for immunization at day 0. Only group 5 received this as an intervention. In all other groups Prevnar 13 will be given as standard of care.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0 and 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Anti-pneumococcal IgG Antibody (ug/ml) Change</title>
          <description>Measure the opsonic antibody response against streptococcus pneumonia serotypes 14, 19A and 23F at days 0 and 30.&#xD;
Comparing elderly RT recipients versus healthy elderly and elderly with DM/HTN.</description>
          <population>Participants who completed PCV13 immunization and from whom blood samples were obtained on day 0, 7, and 30.&#xD;
There is thus a discrepancy between the number of enrolled and analyzed participants in groups 2,3,4 and 5.</population>
          <units>microgram/ml</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="12"/>
                <count group_id="O4" value="9"/>
                <count group_id="O5" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Anti-PPS 14 IgG day 0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.16" spread="10.52"/>
                    <measurement group_id="O2" value="9.29" spread="8.52"/>
                    <measurement group_id="O3" value="6.46" spread="5.34"/>
                    <measurement group_id="O4" value="7.69" spread="7.38"/>
                    <measurement group_id="O5" value="6.51" spread="5.6663"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Anti-PPS14 IgG day 30</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.55" spread="10.94"/>
                    <measurement group_id="O2" value="13.92" spread="11.62"/>
                    <measurement group_id="O3" value="10.42" spread="8.04"/>
                    <measurement group_id="O4" value="13.05" spread="9.44"/>
                    <measurement group_id="O5" value="15.75" spread="10.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Anti-PPS23F IgG day 0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.09" spread="4.04"/>
                    <measurement group_id="O2" value="2.84" spread="3.22"/>
                    <measurement group_id="O3" value="1.10" spread="1.06"/>
                    <measurement group_id="O4" value="3.85" spread="3.73"/>
                    <measurement group_id="O5" value="2.52" spread="2.35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Anti-PPS23F IgG day 30</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.96" spread="5.39"/>
                    <measurement group_id="O2" value="4.57" spread="5.56"/>
                    <measurement group_id="O3" value="5.18" spread="3.80"/>
                    <measurement group_id="O4" value="11.55" spread="7.44"/>
                    <measurement group_id="O5" value="9.69" spread="5.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Anti-PPS19A IgG day 0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.79" spread="2.97"/>
                    <measurement group_id="O2" value="6.66" spread="5.79"/>
                    <measurement group_id="O3" value="5.42" spread="6.62"/>
                    <measurement group_id="O4" value="3.65" spread="5.42"/>
                    <measurement group_id="O5" value="3.42" spread="1.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Anti-PPS 19A IgG day 30</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.82" spread="10.40"/>
                    <measurement group_id="O2" value="9.28" spread="6.84"/>
                    <measurement group_id="O3" value="10.43" spread="7.96"/>
                    <measurement group_id="O4" value="10.54" spread="8.83"/>
                    <measurement group_id="O5" value="8.35" spread="8.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
              <group_id>O5</group_id>
            </group_id_list>
            <groups_desc>Differences between groups were compared using the paired t test</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Differences between groups were compared using the paired t test</non_inferiority_desc>
            <p_value>&lt;0.05</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
              <group_id>O5</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.05</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
              <group_id>O5</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.05</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Opsonophagocytic Antibody Titer Serum Dilution Difference Between Healthy Elderly, Elderly With DM/HTN and Elderly With RT.</title>
        <description>Measure the serum opsonophagocytic activity against streptococcus pneumonia serotypes 14, 19A and 23F on days 0 and 30 by opsonophagocytic assay.</description>
        <time_frame>Baseline and 30 days</time_frame>
        <population>Healthy elderly versus elderly with DM versus elderly with RT</population>
        <group_list>
          <group group_id="O1">
            <title>1.Aging RT</title>
            <description>Renal transplant recipients between 65-75 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0 and 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O2">
            <title>2.Young RT</title>
            <description>Renal transplant recipients between 35-45 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0 and 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O3">
            <title>3.Healthy Elderly</title>
            <description>Healthy persons between the ages 65-75 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0 and 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O4">
            <title>4.Elderly DMII or HTN and Normal Renal Function</title>
            <description>Persons between the ages 65-75 with DMII or hypertension but normal renal function who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0 and 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O5">
            <title>5.Healthy Young</title>
            <description>Healthy persons between the ages 35-45 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
13 valent conjugated pneumococcal vaccine: FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 13 different pneumococcal serotypes conjugated to CRM197 was administered on day 0. Only group 5 received this as an intervention. In all other groups Prevnar 13 was given as standard of care.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples obtained from days 0 and 30 were used for antibody titers and opsonophagocytic assays. Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Opsonophagocytic Antibody Titer Serum Dilution Difference Between Healthy Elderly, Elderly With DM/HTN and Elderly With RT.</title>
          <description>Measure the serum opsonophagocytic activity against streptococcus pneumonia serotypes 14, 19A and 23F on days 0 and 30 by opsonophagocytic assay.</description>
          <population>Healthy elderly versus elderly with DM versus elderly with RT</population>
          <units>titer</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="12"/>
                <count group_id="O4" value="9"/>
                <count group_id="O5" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>opsonophagocytic titer PPS 14 day 0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1081" spread="2810"/>
                    <measurement group_id="O2" value="147" spread="295"/>
                    <measurement group_id="O3" value="3024" spread="6478"/>
                    <measurement group_id="O4" value="256" spread="663"/>
                    <measurement group_id="O5" value="811" spread="2451"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>opsonophagocytic titer PPS14 day 30</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3117" spread="5860"/>
                    <measurement group_id="O2" value="275" spread="552"/>
                    <measurement group_id="O3" value="5954" spread="8117"/>
                    <measurement group_id="O4" value="2477" spread="4857"/>
                    <measurement group_id="O5" value="3687" spread="7288"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>opsonophagocytic titer PPS23F day 0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.4" spread="2.8"/>
                    <measurement group_id="O2" value="28" spread="77"/>
                    <measurement group_id="O3" value="6.3" spread="6.3"/>
                    <measurement group_id="O4" value="3.3" spread="4.1"/>
                    <measurement group_id="O5" value="29" spread="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>opsonophagocytic titer PPS23F day 30</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="617" spread="1617"/>
                    <measurement group_id="O2" value="38" spread="64"/>
                    <measurement group_id="O3" value="1455" spread="4822"/>
                    <measurement group_id="O4" value="469" spread="904"/>
                    <measurement group_id="O5" value="914" spread="2310"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>opsonophagocytic titer PPS19A day 0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="633" spread="1891"/>
                    <measurement group_id="O2" value="7" spread="10"/>
                    <measurement group_id="O3" value="15" spread="21"/>
                    <measurement group_id="O4" value="663" spread="2324"/>
                    <measurement group_id="O5" value="461" spread="1407"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>opsonophagocytic titer PPS 19A day 30</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3893" spread="7711"/>
                    <measurement group_id="O2" value="138" spread="231"/>
                    <measurement group_id="O3" value="4529" spread="7549"/>
                    <measurement group_id="O4" value="4634" spread="7597"/>
                    <measurement group_id="O5" value="2290" spread="5462"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
              <group_id>O5</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.05</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.05</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Polysaccharide Specific B Cells (% Cells/mL)</title>
        <description>percentage of polysaccharide specific B cells, and percentage of IgM memory B cells/mL in % cells/mL induced by vaccination with PCV13</description>
        <time_frame>day 7</time_frame>
        <population>Participants who completed PCV13 immunization and from whom blood samples were obtained on day 0, 7, and 30.&#xD;
Elderly healthy versus elderly with DM/HTN and elderly RT</population>
        <group_list>
          <group group_id="O1">
            <title>1.Aging RT</title>
            <description>Renal transplant recipients between 65-75 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause of renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O2">
            <title>2.Young RT</title>
            <description>Renal transplant recipients between 35-45 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause of renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O3">
            <title>3.Healthy Elderly</title>
            <description>Healthy persons between the ages 65-75 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23).&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O4">
            <title>4.Elderly DMII or HTN and Normal Renal Function</title>
            <description>Persons between the ages 65-75 with DMII or hypertension but normal renal function who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
          <group group_id="O5">
            <title>5.Healthy Young</title>
            <description>Healthy persons between the ages 35-45 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
13 valent conjugated pneumococcal vaccine: FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 13 different pneumococcal serotypes conjugated to CRM197 was administered on day 0. Only group 5 received this as an intervention. In all other groups Prevnar 13 was given as standard of care.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples from day 7 were used for flow cytometric analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Polysaccharide Specific B Cells (% Cells/mL)</title>
          <description>percentage of polysaccharide specific B cells, and percentage of IgM memory B cells/mL in % cells/mL induced by vaccination with PCV13</description>
          <population>Participants who completed PCV13 immunization and from whom blood samples were obtained on day 0, 7, and 30.&#xD;
Elderly healthy versus elderly with DM/HTN and elderly RT</population>
          <units>percentage cells/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="12"/>
                <count group_id="O4" value="9"/>
                <count group_id="O5" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>% of lymphocytes that are CD19+ (B cells)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.87" spread="5.85"/>
                    <measurement group_id="O2" value="5.31" spread="2.31"/>
                    <measurement group_id="O3" value="9.75" spread="4.05"/>
                    <measurement group_id="O4" value="7.91" spread="3.25"/>
                    <measurement group_id="O5" value="10.77" spread="4.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>% of CD19+ B cells that were PPS14+ post-immunization</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.12" spread="0.99"/>
                    <measurement group_id="O2" value="1.55" spread="1.29"/>
                    <measurement group_id="O3" value="1.68" spread="0.75"/>
                    <measurement group_id="O4" value="1.82" spread="1.11"/>
                    <measurement group_id="O5" value="1.67" spread="0.92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>% of CD19+ B cells that were PPS23F+ post-immunization</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.65" spread="1.24"/>
                    <measurement group_id="O2" value="1.79" spread="1.47"/>
                    <measurement group_id="O3" value="1.22" spread="0.78"/>
                    <measurement group_id="O4" value="1.52" spread="1.01"/>
                    <measurement group_id="O5" value="1.29" spread="0.96"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PPS14+ B cells that were IgM+ memory B cells day 7 post-immunization</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.73" spread="16.12"/>
                    <measurement group_id="O2" value="22.95" spread="19.53"/>
                    <measurement group_id="O3" value="20.57" spread="8.49"/>
                    <measurement group_id="O4" value="24.59" spread="15.58"/>
                    <measurement group_id="O5" value="20.62" spread="10.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>% PPS14+ B cells that were switched memory B cells 7 d. post-immunization</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41.48" spread="17.31"/>
                    <measurement group_id="O2" value="51.6" spread="25.31"/>
                    <measurement group_id="O3" value="51.23" spread="17.72"/>
                    <measurement group_id="O4" value="52.46" spread="19.22"/>
                    <measurement group_id="O5" value="44.87" spread="18.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>%PPS23F+ B cells that were IgM memory B cells d7 post-immunization</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30.56" spread="12.34"/>
                    <measurement group_id="O2" value="14.67" spread="8.44"/>
                    <measurement group_id="O3" value="24.21" spread="16.66"/>
                    <measurement group_id="O4" value="32.22" spread="24.95"/>
                    <measurement group_id="O5" value="18.11" spread="10.97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>% PPS23 F B cells that were switched memory B cells d.7 post-immunization</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="40.02" spread="6.23"/>
                    <measurement group_id="O2" value="35.52" spread="14.17"/>
                    <measurement group_id="O3" value="52.48" spread="19.35"/>
                    <measurement group_id="O4" value="47.7" spread="19.71"/>
                    <measurement group_id="O5" value="49.26" spread="27.22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.05</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Inflammatory Markers Serum Levels Pre-immunization</title>
        <description>Measure level of inflammatory markers BAFF, APRIL, IL6, TNF alpha and sCD40L in serum in pg/mL pre-immunization.</description>
        <time_frame>Day 0 pre-immunization</time_frame>
        <population>Participants who completed immunization and a minimal of 30 day follow up.</population>
        <group_list>
          <group group_id="O1">
            <title>1.Aging RT</title>
            <description>Renal transplant recipients between 65-75 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause of renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples from day 0 were used for measuring inflammatory markers.</description>
          </group>
          <group group_id="O2">
            <title>2.Young RT</title>
            <description>Renal transplant recipients between 35-45 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause of renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples from day 0 were used for measuring inflammatory markers.</description>
          </group>
          <group group_id="O3">
            <title>3.Healthy Elderly</title>
            <description>Healthy persons between the ages 65-75 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples from day 0 were used for measuring inflammatory markers.</description>
          </group>
          <group group_id="O4">
            <title>4.Elderly DMII or HTN and Normal Renal Function</title>
            <description>Persons between the ages 65-75 with DMII or hypertension but normal renal function who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples from day 0 were used for measuring inflammatory markers.</description>
          </group>
          <group group_id="O5">
            <title>5.Healthy Young</title>
            <description>Healthy persons between the ages 35-45 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
13 valent conjugated pneumococcal vaccine: FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 13 different pneumococcal serotypes conjugated to CRM197 was administered on day 0. Only group 5 received this as an intervention. In all other groups Prevnar 13 was given as standard of care.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) Samples from day 0 were used for measuring inflammatory markers.</description>
          </group>
        </group_list>
        <measure>
          <title>Inflammatory Markers Serum Levels Pre-immunization</title>
          <description>Measure level of inflammatory markers BAFF, APRIL, IL6, TNF alpha and sCD40L in serum in pg/mL pre-immunization.</description>
          <population>Participants who completed immunization and a minimal of 30 day follow up.</population>
          <units>pg/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="12"/>
                <count group_id="O4" value="9"/>
                <count group_id="O5" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>BAFF serum concentration</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.59" spread="0.10"/>
                    <measurement group_id="O2" value="0.56" spread="0.17"/>
                    <measurement group_id="O3" value="0.57" spread="0.16"/>
                    <measurement group_id="O4" value="0.58" spread="0.29"/>
                    <measurement group_id="O5" value="0.50" spread="0.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>APRIL serum concentration</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="664.84" spread="206.68"/>
                    <measurement group_id="O2" value="664.84" spread="206.68"/>
                    <measurement group_id="O3" value="852.66" spread="216.65"/>
                    <measurement group_id="O4" value="870.09" spread="139.29"/>
                    <measurement group_id="O5" value="619.54" spread="161.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>sCD40L serum concentration</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="199.25" spread="372.37"/>
                    <measurement group_id="O2" value="663.12" spread="899.98"/>
                    <measurement group_id="O3" value="984.92" spread="1292.38"/>
                    <measurement group_id="O4" value="1272.35" spread="1229.85"/>
                    <measurement group_id="O5" value="1639.47" spread="1356.06"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNFalpha serum concentration</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.22" spread="7.82"/>
                    <measurement group_id="O2" value="23.96" spread="18.89"/>
                    <measurement group_id="O3" value="23.05" spread="22.52"/>
                    <measurement group_id="O4" value="20.35" spread="16.78"/>
                    <measurement group_id="O5" value="19.44" spread="16.77"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IL6 serum concentration</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.21" spread="0.83"/>
                    <measurement group_id="O2" value="2.58" spread="1.68"/>
                    <measurement group_id="O3" value="1.71" spread="1.94"/>
                    <measurement group_id="O4" value="1.21" spread="0.48"/>
                    <measurement group_id="O5" value="1.56" spread="1.64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
              <group_id>O5</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.05</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected over the duration of the duration of enrollment thus varying from participant to participant.</time_frame>
      <desc>Adverse events were collected starting at day 7, 1 month, 6 months, 1 year, varying per participant depending on duration of enrollment. Adverse events were collected from every participant enrolled, including those that dropped out of the study after their initial immunization and blood draw..</desc>
      <group_list>
        <group group_id="E1">
          <title>1.Aging RT</title>
          <description>Renal transplant recipients between 65-75 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) .</description>
        </group>
        <group group_id="E2">
          <title>2.Young RT</title>
          <description>Renal transplant recipients between 35-45 years of age, on stable immunosuppression. who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) .</description>
        </group>
        <group group_id="E3">
          <title>3.Healthy Elderly</title>
          <description>Healthy persons between the ages 65-75 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) .</description>
        </group>
        <group group_id="E4">
          <title>4.Elderly DMII or HTN and Normal Renal Function</title>
          <description>Persons between the ages 65-75 with DMII or hypertension but normal renal function who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) .</description>
        </group>
        <group group_id="E5">
          <title>5.Healthy Young</title>
          <description>Healthy persons between the ages 35-45 who previously (&gt;1 year prior) received the 23 valent pneumococcal polysaccharide vaccine&#xD;
Peripheral blood sample: Peripheral blood samples (30-60 mL) were collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) .</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Early termination leading to small numbers of enrolled subjects due to the COVID pandemic</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>ACOS/R, R. Amanda C. LaRue</name_or_title>
      <organization>Ralph H. Johnson VA Medical Center</organization>
      <phone>843-789-6707</phone>
      <email>Rutha.LaRue@va.gov</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03802994
org study id: INFB-019-17F
secondary id: CX001568
nct id: NCT03802994
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The goal of the research proposed in the current application is to first define how much
      antibody aging renal transplant and dialysis recipients make after they are vaccinated with
      the pneumonia vaccine and how this compares to similar aged persons with good renal function
      and healthy young adults. The investigators will study differences in the kind of B cells and
      markers on the B cells that are known to be important in the response to the pneumonia
      vaccine in aging renal transplant and aging dialysis recipients compared to similarly aged
      and young healthy controls. Finally, the investigators will study how safe the pneumonia
      vaccine is in aging renal transplants. The answers to these questions will help in designing
      a better vaccine for older people with a renal transplant or on dialysis.
Objectives / Specific Aims

      Individuals >65 years of age, are the most rapidly growing population amongst those with end
      stage renal disease (ESRD) and account for more than 18% of renal transplant (RT) recipients.

      The incidence of pneumococcal disease is significantly higher in both elderly and those with
      RT and the combination of these factors is likely additive, if not synergistic, for invasive
      pneumococcal disease (IPD). It is recommended that both elderly>65 and RT recipients be
      vaccinated with a regimen that includes both the 13-valent pneumococcal conjugate vaccine
      (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPV23). However, small
      immunogenicity studies performed in the transplant populations have not shown superiority of
      a PCV containing regimen. Moreover, the addition of PCV to the pneumococcal vaccine regimen
      does not improve protective immunity in this population. Studies to date fail to elucidate
      the possible foundation of the disappointing immune responses to the PCV regimens.

      Specific Aim 1. The investigators will define immune responses by measuring serum antibody
      and functional antibody responses to PPS 14, 19A and 23F following PCV13 vaccination in RT
      recipients 65-75 years of age and compare these to: RT recipients 35-45 years of age and
      persons with DM/HTN but normal function 65-75 years of age to dissect out the age and RT
      components respectively. Healthy persons 35-45 and 65-75 years of age will be studied as age
      appropriate reference.

      Specific Aim 2. The investigators will measure and characterize the antigen-specific B cell
      subset response following immunization with PCV13 in the RT recipients 65-75 years of age and
      compare them to each of the groups described in Specific Aim 1 using flow cytometry and
      fluorescently labeled PPS and monoclonal antibodies. These measures will be correlated with
      post-immunization functional antibody activity, a surrogate of protection.

      Specific Aim 3. The investigators will measure TNFR expression by B cells following
      immunization with PCV13 in 65-75 year old RT and compare them to each of the groups described
      in Specific Aim 1. Gene expression, with focus on the B cell activating factor (BAFF) system,
      will be measured in PPS-specific and non-PPS specific B cells using single cell genomics and
      flow cytometry. These measures will be correlated with post-immunization functional antibody
      activity, a surrogate of protection.

      The central hypothesis is that the aging RT population responds poorly to PCV13 vaccination
      reflecting the combined effects of aging and RT. The investigators postulate that both the
      number of memory B cells and expression of tumor necrosis factor (TNF) superfamily receptors,
      which play crucial roles in the response to pneumococcal polysaccharides (PPS), are deficient
      in the elderly RT population and contribute to poor pneumococcal vaccine responses.

      The investigators have developed fluorescently labeled PPS allowing us to study the nature
      and surface receptors of PPS-specific B cells. The preliminary data demonstrate that RT
      recipients 1. Respond poorly to pneumococcal immunization as measured by antibody titer and
      functional antibody activity. 2. RT recipients and healthy elderly have lower absolute number
      of both IgM and switched memory B cells. 3. The number of PPS-specific IgM and switched
      memory B cells are significantly lower in RT recipients and 4. TACI and BAFF-R, members of
      the TNF superfamily receptors, expression is significantly lower in the PPS-specific memory B
      cells in the RT population versus healthy controls. The overall objective of this proposal is
      to characterize the immune response and explore possible mechanisms of poor vaccine
      responsiveness following immunization with PCV in the rapidly growing group of elderly with
      RT. As the RT population is a heterogeneous group the investigators will study only those in
      whom the underlying cause of renal failure is diabetes mellitus type 2 (DM2) and/or
      hypertension (HTN).

      Intervention to be studied The intervention to be studied is the immune response to
      immunization with PCV13 or Prevnar13. This FDA approved vaccine is given as part of the
      standard of care in Groups 1-4. The experimental part of the protocol in these groups will be
      blood draws at days 0, 7, 30 and years 1 and 2 in these groups.

      In Group 5 two interventions will occur: 1. Immunization with the FDA approved PPV23 or
      Pneumovax 23 and 2. PCV13 a FDA approved vaccine. In addition, blood samples will be obtained
      at days 0, 7, 30 year 1 and year2.

      Both PPV23 and PCV13 are FDA approved vaccines for use in humans. PCV13 is recommended for
      all individuals enrolled in Groups 1-4. It is not recommended as routine part of care in
      Group 5 enrolled individuals however it has never shown to be harmful in this group of
      individuals.

      Study Endpoints The primary endpoint of this study is: quantify the antibody titers in mg/mL
      and opsonophagocytic antibody titer calculated as serum dilution, number of polysaccharide
      specific B cells, and absolute number of cells/mL induced by vaccination with PCV13.

      Secondary endpoint of the study is to describe differences in gene expression of 56 genes to
      be determined by single cell PCR and comparing these between groups.

      The primary safety endpoint of the study is measured as minimal versus moderate local side
      effect. Minimal side effect measured as no impairment in activity. Moderate local side effect
      is a side effect affecting use of the extremity for less than 24 hours.

      Inclusion and Exclusion Criteria/ Study Population: as described in inclusion/exclusion
      section

      Diversity: the investigators will attempt to mimic the local renal transplant recipient
      population consisting of a disproportionately high number of males (>60%) of African-American
      decent, 50%.

      Number of Subjects 275

      Study Sites

        1. The MUSC Renal Transplant clinic is located on the 9th floor of the Rutledge Tower

        2. The nephrology clinic at the Ralph H. Johnson VA Medical Center

        3. the P.I.'s laboratory at the Strom Thurmond Building Room 411

      Recruitment Methods

        -  Potential study participants will be recruited from Ralph H. Johnson Veterans Affair
           Medical Center and Medical University of South Carolina during the appointment with
           their treating physician. Flyers will be posted in the waiting room areas of the clinics
           and attending physicians and clinic nurses will be asked to keep this study in mind and
           mention availability of these studies to their patients when ordering PCV13 for them.

        -  Potential study subjects will be identified by reviewing medical records and by
           physician's recommendations.

        -  Flyers will be used to recruit study subjects as well as broadcast emails for MUSC and
           VA employees and volunteers.

      Consent Process

      Informed Consent will be obtained in a private room from all participants at either:

      1. The MUSC Renal Transplant clinic is located on the 9th floor of the Rutledge Tower Or
      2.The nephrology clinic at the Ralph H. Johnson VA Medical Center Or 3. the P.I.'s laboratory
      at the Strom Thurmond Building Room 411

      Consent will be sought of competent adults who express interest in the study. The purpose of
      the study, the study details regarding gathering health information and obtaining blood
      samples, the potential benefit and risks involved, including risk of blood draw and
      vaccination, will be explained in detail and in layman terms, as well as the non-standard of
      care explained to the potential subject (i.e. blood draws for groups 1-4, vaccination
      protocol and blood draws for group 5).

      Study Design / Methods The overall objective of this proposal is to characterize the immune
      response and explore possible mechanisms of poor vaccine responsiveness following
      immunization with PCV in the rapidly growing group of elderly with RT. As the RT population
      is a heterogeneous group the investigators will study only those in whom the underlying cause
      of renal failure is diabetes mellitus type 2 (DM2) and/or hypertension (HTN). There will be 5
      study groups as outlined above.

      results obtained in various groups will be compared.

      Timing of blood samples Peripheral blood samples will be collected at day 0 (pre-immune), day
      7, and day 30 (4 weeks post-PPV23) for groups 1-4 and at days 366, 373 and 396 for group 5.
      BAFF concentration will be measured at day

      The vaccine(s) administered to the participants are FDA approved vaccinations and vaccination
      protocols. The standard and recommended dose of vaccine will be administered either by a
      qualified nurse or physician and both vaccines are considered low risk. In groups 1-4 PCV13
      will be administered per standard of care and is not part of the experimental protocol. In
      group 5, both PPV23 and PCV 13 are not routine part of care and are part of the experimental
      protocol. These vaccines have however been extensively studied in this and other populations
      and are considered low risk and 70-80% protective against pneumococcal disease.

      The risk associated with blood draws is minimal.

        -  Pre- and post-immunization serum antibody titers and opsonophagocytic antibody titers to
           PPS14, 19A and 23F in ug/mL determined by ELISA IgM and switched memory B cell number
           and percentage determined by flow cytometry

        -  PPS+ B cell number and percentage determined by flow cytometry

        -  Serum BAFF concentration by ELISA

        -  Gene expression of 56 genes will be studies using single cell PCR analysis
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Immune response to immunization with Prevnar in elderly aging renal transplant compared to comparison groups: healthy young, healthy elderly, healthy elderly hypertension (HTN) and young renal transplants.
primary purpose: Prevention
masking: None (Open Label)
measure: Anti-pneumococcal IgG Antibody (ug/ml) Change
time frame: Baseline, 30 days
description: Measure the opsonic antibody response against streptococcus pneumonia serotypes 14, 19A and 23F at days 0 and 30.
Comparing elderly RT recipients versus healthy elderly and elderly with DM/HTN.
measure: Opsonophagocytic Antibody Titer Serum Dilution Difference Between Healthy Elderly, Elderly With DM/HTN and Elderly With RT.
time frame: Baseline and 30 days
description: Measure the serum opsonophagocytic activity against streptococcus pneumonia serotypes 14, 19A and 23F on days 0 and 30 by opsonophagocytic assay.
measure: Percentage of Polysaccharide Specific B Cells (% Cells/mL)
time frame: day 7
description: percentage of polysaccharide specific B cells, and percentage of IgM memory B cells/mL in % cells/mL induced by vaccination with PCV13
measure: Inflammatory Markers Serum Levels Pre-immunization
time frame: Day 0 pre-immunization
description: Measure level of inflammatory markers BAFF, APRIL, IL6, TNF alpha and sCD40L in serum in pg/mL pre-immunization.
arm group label: 1.Aging RT
arm group type: Experimental
description: Renal transplant recipients between 65-75 years of age, on stable immunosuppression. who previously (>1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.
arm group label: 2.Young RT
arm group type: Active Comparator
description: Renal transplant recipients between 35-45 years of age, on stable immunosuppression. who previously (>1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23). Cause or renal failure was either DMII or HTN.
arm group label: 3.Healthy elderly
arm group type: Active Comparator
description: Healthy persons between the ages 65-75 who previously (>1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)
arm group label: 4.Elderly DMII or HTN and normal renal function
arm group type: Active Comparator
description: Persons between the ages 65-75 with DMII or hypertension but normal renal function who previously (>1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23)
arm group label: 5.Healthy young
arm group type: Experimental
description: Healthy persons between the ages 35-45 who previously (>1 year prior) received the 23 valent pneumococcal polysaccharide vaccine (pneumovax23) or are willing to receive PPV23 and 1 year later Prevnar 13.
intervention type: Drug
intervention name: 23 valent pneumococcal polysaccharide vaccine
description: FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 23 different pneumococcal serotypes. Only group 5 will potentially receive this as an intervention.
arm group label: 5.Healthy young
other name: Pneumovax 23 or PPV23
intervention type: Biological
intervention name: 13 valent conjugated pneumococcal vaccine
description: FDA approved pneumococcal polysaccharide vaccine containing capsular polysaccharide of 13 different pneumococcal serotypes conjugated to CRM197. Only group 5 will receive this as an intervention. In all other groups Prevnar 13 will be given as standard of care.
arm group label: 5.Healthy young
other name: Prevnar 23 or PCV13
intervention type: Other
intervention name: Peripheral blood sample
description: Peripheral blood samples (30-60 mL) will be collected at day 0 (pre-immune), day 7, and day 30 (4 weeks post-PPV23) for groups 1-4 and at days 366, 373 and 396 for group 5. In addition, day 5, and 10 blood samples will be obtained from a limited (n=10) number of elderly RT participants to determine the optimal time point for circulation of PPS-specific B cells. Yearly blood samples will be obtained thereafter for serum antibody and OPA analyses to test longevity of antibody and OPA responses. Samples obtained from days 0, 30 and yearly samples will be used for antibody titers and opsonophagocytic assays. Samples from day 0 (day of vaccination with PCV13) and day 7 will be used for flow cytometric analysis.
arm group label: 1.Aging RT
arm group label: 2.Young RT
arm group label: 3.Healthy elderly
arm group label: 4.Elderly DMII or HTN and normal renal function
arm group label: 5.Healthy young
other name: blood draw
criteria: 
gender: All
minimum age: 35 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Maria J Westerink, MD
role: Principal Investigator
affiliation: Ralph H. Johnson VA Medical Center, Charleston, SC
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Vaccines
mesh term: Heptavalent Pneumococcal Conjugate Vaccine
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Early termination leading to small numbers of enrolled subjects due to the COVID pandemic
point of contact: 