Immune Response to Pneumococcal Vaccination in Aging HIV Positive Adults

Immune Response to Pneumococcal Vaccination in Aging HIV Positive Individuals

The investigators hypothesized that pneumococcal vaccination with either the 23-valent pneumococcal polysaccharide vaccine PPV-23 (Pneumovax-23) alone or the 13-valent pneumococcal conjugate vaccine PCV-13 (Prevnar-13) followed by PPV-23 results in a similar antibody levels/functional antibody activity and induce similar pneumococcal polysaccharide (PPS)-specific B cell response in HIV positive individuals > 50 years of age, HIV positive individuals 21-40 years of age as compared to HIV negative > 50 years of age. The investigators immunized the study groups HIV+ persons >50, HIV+ persons 21-40 and controls (HIV negative) with PCV 13 followed by PPV23 and HIV>50 with PPV alone and examined immune responses to polysaccharide (PPS) 23 (F),14, 3, 7 (F) and 19 (A) using polysaccharide specific ELISA and opsonophagocytic assays (OPA). Pre- and post-immunization peripheral blood samples were obtained. Extensive B cell phenotype analysis using fluorescent antibodies was used to characterize PPS-labeled B cells. Specific phenotypes were correlated with antibody levels and OPA and compared to populations immunized with PPV

Study Overview

• Status: Completed
• Conditions: Aging; HIV Lipodystrophy
• Intervention / Treatment: Biological: Pneumococcal polysaccharide vaccine 23 valent; Biological: 13 valent conjugated pneumococcal vaccine

Detailed Description

The purpose of this study is to learn more about how older people with HIV respond to the pneumococcal or pneumonia vaccine. Pneumonia occurs very frequently in in older persons AND in persons who are infected with HIV. Therefore, it is common practice to vaccinate against pneumonia in these patient populations. Because older patients with HIV fit both of these categories, it is believed that they are at an increased risk of pneumonia.

There are two types of pneumonia vaccines available for adults approved by the Federal Drug Administration (FDA). One is called the pneumococcal polysaccharide vaccine (PPV23) and protects against 23 different strains of the pneumonia bacteria. The other type of vaccine called the pneumococcal conjugate vaccine (PCV13) protects against different strains of the pneumonia bacteria.

Until 2012, it was recommended that all HIV-positive adults receive PPV23 when diagnosed with HIV and again 5 years later. More recently, the guidelines have changed to all HIV-positive adults are to receive PCV13, followed later with PPV23. At this point in time, it is not clear which regimen works better in aging HIV positive adults. Investigators are doing this study to compare the effectiveness of each vaccine regimen in aging HIV positive adults compared to healthy adults. Although several studies show short-term efficacy or increased antibody response in HIV+ persons with this vaccine, others do not, in either HIV+ population or in elderly. Large efficacy trials necessary to establish clinical superiority of PCV compared to PPV will likely not be conducted, particularly in the aging HIV+ population. It is therefore essential to define immune responses to conjugated and free-polysaccharide preparations by examining traditional antibody and functional levels as well as B cell subsets, critically affected by aging and HIV. Will either PCV or PPV elicit an immune response compatible with protection in this population? Based on persistent B cell perturbations in HAART-treated persons, it is hypothesized that immunization of aging HIV+ persons with PPV23 will be as effective as a PCV13 containing regimen on a quantitative, qualitative, B and T cell level and that the magnitude of this response will be related to the degree of chronic inflammation. The proposed studies are highly significant as they will define the B and T cell responses to a TI-2 and T-cell dependent form of pneumococcal vaccine in the aging HIV+ population. These data will provide the necessary basis for development of a rational vaccination approach, including the potential use of novel adjuvant. In this study the investigators will:

1. Test the hypothesis that vaccination with either PPV alone (TI-2) or a PCV containing regimen (TD) results in similar antibody levels/functional activity, that are determined by levels of chronic inflammation in aging HIV+. The investigators will immunize the study group HIV+ persons 50-65 and controls (HIV+21-40 and HIV- 50-65 years) with PCV13 followed by PPV23 and HIV+ 50-65 and HIV- 50-65 with PPV alone. The investigators will examine immune responses to pneumococcal polysaccharides (PPS) 23 (F), 14, 3, 7 (F) and 19 (A) on a quantitative and qualitative level using ELISA and opsonophagocytic assays (OPA) and correlate the response to the degree of inflammation measured in each participant.
2. To test the hypothesis that the levels of antigen specific B cells identified with PPS will be comparable between the PPV and PCV vaccine recipients. Pre- and post-immunization peripheral blood samples will be obtained. Extensive phenotype analysis using antibodies against cluster of differentiation (CD)19, 20, 21, 27, 38, 40, immunoglobulin M (IgM) , B-cell activating factor (BAFF), trans-membrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antigen (BCMA) markers will be used to characterize PPS-labeled B cells. Specific phenotypes will be correlated with antibody levels, OPA and inflammatory markers and compared to the control populations immunized with PPV.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:HIV+ 21-40 years of age HIV+ 50-65 years of age HIV- 50-65 years of age

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Exclusion Criteria:

• Previous immunization with pneumococcal vaccine less than 5 years ago
• pregnancy and absence of contraceptive practice in women of childbearing age and breast feeding
• known anaphylaxis, hypersensitivity to the pneumonia vaccine
• those who received blood products or gammaglobulin in last 3 months
• inability to comprehend or sihn informed consent
• Medications known to affect immune function (chemotherapy, an angiotensin-converting-enzyme (ACE) inhibitors, corticosteroids, anti-TNFalpha agents)
• previous disease/present illness that may affect response to vaccination: previous pneumococcal disease, removal of spleen, auto-immune disease, end stage renal disease (ESRD) or end stage liver disease, cancer)
• significant (3x upper limit of normal) in complete blood count (CBC), chemistries, immunoglobulin levels

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HIV+ 50-65, CD4>200 PCV/PPV; HIV+ individuals , 50-65 years of age with a nadir cluster of differentiation (CD) 4 count >200 to receive PCV13 vaccine followed 8 weeks later by PPV23 Intervention: 13 valent Pneumococcal conjugate vaccine (PCV13) followed 8 weeks later by 23 valent pneumococcal polysaccharide vaccine	Biological: Pneumococcal polysaccharide vaccine 23 valent; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 23 serotypes of Streptococcus pneumoniae; Other Names: Pneumovax; Biological: 13 valent conjugated pneumococcal vaccine; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 13 serotypes of Streptococcus pneumoniae conjugated to non-toxic diphtheria carrier protein 197; Other Names: Prevnar 13
Experimental: HIV+ 50-65, CD4<200 PCV/PPV; HIV+ individuals , 50-65 years of age with a nadir CD4 count <200 to receive PCV13 vaccine followed 8 weeks later by PPV23 Intervention: 13 valent Pneumococcal conjugate vaccine (PCV13) followed 8 weeks later by 23 valent pneumococcal polysaccharide vaccine	Biological: Pneumococcal polysaccharide vaccine 23 valent; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 23 serotypes of Streptococcus pneumoniae; Other Names: Pneumovax; Biological: 13 valent conjugated pneumococcal vaccine; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 13 serotypes of Streptococcus pneumoniae conjugated to non-toxic diphtheria carrier protein 197; Other Names: Prevnar 13
Experimental: HIV+ 50-65, CD4>200 PPV; HIV+ individuals , 50-65 years of age with a nadir CD4 count >200 to receive PPV23 only Intervention: 23 valent pneumococcal polysaccharide vaccine only	Biological: Pneumococcal polysaccharide vaccine 23 valent; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 23 serotypes of Streptococcus pneumoniae; Other Names: Pneumovax
Experimental: HIV+ 50-65, CD4<200 PCV; HIV+ individuals , 50-65 years of age with a nadir CD4 count <200 to receive PPV23 only Intervention: 23 valent pneumococcal polysaccharide vaccine only	Biological: Pneumococcal polysaccharide vaccine 23 valent; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 23 serotypes of Streptococcus pneumoniae; Other Names: Pneumovax
Active Comparator: HIV- 50-65, PCV/PPV; HIV- individuals , 50-65 years of age immunized with PCV13 followed by PPV23 Intervention: 13 valent Pneumococcal conjugate vaccine (PCV13) followed 8 weeks later by 23 valent pneumococcal polysaccharide vaccine	Biological: Pneumococcal polysaccharide vaccine 23 valent; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 23 serotypes of Streptococcus pneumoniae; Other Names: Pneumovax; Biological: 13 valent conjugated pneumococcal vaccine; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 13 serotypes of Streptococcus pneumoniae conjugated to non-toxic diphtheria carrier protein 197; Other Names: Prevnar 13
Active Comparator: HIV- 50-65, PPV; HIV- individuals, 50-65 years of age immunized with PPV23 only. Intervention: 23 valent pneumococcal polysaccharide vaccine only	Biological: Pneumococcal polysaccharide vaccine 23 valent; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 23 serotypes of Streptococcus pneumoniae; Other Names: Pneumovax
Active Comparator: HIV+ 21-40, CD4>200 PCV/PPV; HIV+ individuals , 21-40 years of age with a nadir CD4 count >200 to receive PCV13 vaccine followed 8 weeks later by PPV23 Intervention: 13 valent Pneumococcal conjugate vaccine (PCV13) followed 8 weeks later by 23 valent pneumococcal polysaccharide vaccine	Biological: Pneumococcal polysaccharide vaccine 23 valent; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 23 serotypes of Streptococcus pneumoniae; Other Names: Pneumovax; Biological: 13 valent conjugated pneumococcal vaccine; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 13 serotypes of Streptococcus pneumoniae conjugated to non-toxic diphtheria carrier protein 197; Other Names: Prevnar 13
Active Comparator: HIV+ 21-40, CD4<200 PCV/PPV; HIV+ individuals , 21-40 years of age with a nadir CD4 count <200 to receive PCV13 vaccine followed 8 weeks later by PPV23 Intervention: 13 valent Pneumococcal conjugate vaccine (PCV13) followed 8 weeks later by 23 valent pneumococcal polysaccharide vaccine	Biological: Pneumococcal polysaccharide vaccine 23 valent; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 23 serotypes of Streptococcus pneumoniae; Other Names: Pneumovax; Biological: 13 valent conjugated pneumococcal vaccine; This is the pneumococcal vaccine consisting of the capsular polysaccharides of 13 serotypes of Streptococcus pneumoniae conjugated to non-toxic diphtheria carrier protein 197; Other Names: Prevnar 13

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antibody response	Measure antibody response by ELISA (ug/mL)	Change in ug/mL from day 0 to 30 days after receipt of PPV23
opsonophagocytic antibody activity	opsonophagocytic antibody response measured by opsonophagocytic assay (OPA)	Change in opsonophagocytic titer from day 0 to 30 days after receipt of PPV23

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PPS-specific B cell phenotype	Measure: B cell phenotype of PPS-specific B cells expressing CD27+IgM+: flowcytometry (%)	Change from day 0 to day 7 post-vaccination
PPS-specific B cell phenotype	Measure: B cell phenotype of PPS-specific B cells expressing CD27+IgM+: flowcytometry (%)	Change from day 56 to day 63 post-vaccination
Expression of TACI on PPS-specific B cells	Measure:Flow cytometry: percentage of PPS-specific B cells expressing TACI on their surface (%)	change from day 0 to day 7
Expression of TACI on PPS-specific B cells	Measure:Flow cytometry: percentage of PPS-specific B cells expressing TACI on their surface (%)	change from day 56 to day 63
Expression of BAFFR on PPS-specific B cells	Measure:Flow cytometry: percentage of PPS-specific B cells expressing BAFFR on their surface (%)	change from day 0 to day 7
Expression of BAFFR on PPS-specific B cells	Measure:Flow cytometry: percentage of PPS-specific B cells expressing BAFFR on their surface (%)	change from day 56 to day 63
Expression of BCMA on PPS-specific B cells	Measure:Flow cytometry: percentage of PPS-specific B cells expressing BAFFR on their surface (%)	change from day 0 to day 7
Expression of BCMA on PPS-specific B cells	Measure:Flow cytometry: percentage of PPS-specific B cells expressing BAFFR on their surface (%)	change from day 7 to day 63
Expression of CD40 on PPS-specific B cells	Measure:Flow cytometry: percentage of PPS-specific B cells expressing CD40 on their surface (%)	change from day 0 to day 7
Expression of CD40 on PPS-specific B cells	Measure:Flow cytometry: percentage of PPS-specific B cells expressing CD40 on their surface (%)	change from day 56 to day 63
Expression of cluster of differentiation 21 (CD21) on PPS-specific B cells	Measure:Flow cytometry: percentage of PPS-specific B cells expressing CD21 on their surface (%)	change from day 0 to day 7
Expression of CD21 on PPS-specific B cells	Measure:Flow cytometry: percentage of PPS-specific B cells expressing CD21 on their surface (%)	change from day 56 to day 63
Serum interleukin-6 (IL-6)	Measure serum levels IL-6	Day 0
Serum BAFF	Measure serum levels BAFF	Day 0
Serum APRIL	Measure serum levels APRIL	Day 0
Serum IL-10	Measure serum levels IL-10	Day 0
Serum IL-1(RA)	Measure serum levels IL-1RA	Day 0
Serum IL-1(B)	Measure serum levels IL-1B	Day 0
Serum IL-8	Measure serum levels IL-8	Day 0
Serum TNFalpha	Measure serum levels TNFalpha	Day 0

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Investigators: Principal Investigator: Maria A. Julia Westerink, MD, Medical University of South Carolina

Publications and helpful links

General Publications

• Crum-Cianflone NF, Huppler Hullsiek K, Roediger M, Ganesan A, Patel S, Landrum ML, Weintrob A, Agan BK, Medina S, Rahkola J, Hale BR, Janoff EN; Infectious Disease Clinical Research Program HIV Working Group. A randomized clinical trial comparing revaccination with pneumococcal conjugate vaccine to polysaccharide vaccine among HIV-infected adults. J Infect Dis. 2010 Oct 1;202(7):1114-25. doi: 10.1086/656147.
• de Roux A, Schmole-Thoma B, Siber GR, Hackell JG, Kuhnke A, Ahlers N, Baker SA, Razmpour A, Emini EA, Fernsten PD, Gruber WC, Lockhart S, Burkhardt O, Welte T, Lode HM. Comparison of pneumococcal conjugate polysaccharide and free polysaccharide vaccines in elderly adults: conjugate vaccine elicits improved antibacterial immune responses and immunological memory. Clin Infect Dis. 2008 Apr 1;46(7):1015-23. doi: 10.1086/529142. Erratum In: Clin Infect Dis. 2008 May 1;46(9):1488. Schmoele-Thoma, B [corrected to Schmole-Thoma, B].
• French N, Gordon SB, Mwalukomo T, White SA, Mwafulirwa G, Longwe H, Mwaiponya M, Zijlstra EE, Molyneux ME, Gilks CF. A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected adults. N Engl J Med. 2010 Mar 4;362(9):812-22. doi: 10.1056/NEJMoa0903029.
• Baxendale HE, Keating SM, Johnson M, Southern J, Miller E, Goldblatt D. The early kinetics of circulating pneumococcal-specific memory B cells following pneumococcal conjugate and plain polysaccharide vaccines in the elderly. Vaccine. 2010 Jul 5;28(30):4763-70. doi: 10.1016/j.vaccine.2010.04.103. Epub 2010 May 14.
• Penaranda M, Payeras A, Cambra A, Mila J, Riera M; Majorcan Pneumococcal Study Group. Conjugate and polysaccharide pneumococcal vaccines do not improve initial response of the polysaccharide vaccine in HIV-infected adults. AIDS. 2010 May 15;24(8):1226-8. doi: 10.1097/QAD.0b013e3283389de5.
• Khaskhely N, Mosakowski J, Thompson RS, Khuder S, Smithson SL, Westerink MA. Phenotypic analysis of pneumococcal polysaccharide-specific B cells. J Immunol. 2012 Mar 1;188(5):2455-63. doi: 10.4049/jimmunol.1102809. Epub 2012 Jan 23.
• Happe M, Samuvel DJ, Ohtola JA, Korte JE, Westerink MAJ. Race-related differences in functional antibody response to pneumococcal vaccination in HIV-infected individuals. Vaccine. 2019 Mar 14;37(12):1622-1629. doi: 10.1016/j.vaccine.2019.01.084. Epub 2019 Feb 21.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2015
• Primary Completion (Actual): March 30, 2020
• Study Completion (Actual): March 30, 2020

Study Registration Dates

• First Submitted: January 30, 2017
• First Submitted That Met QC Criteria: January 30, 2017
• First Posted (Estimate): February 1, 2017

Study Record Updates

• Last Update Posted (Actual): June 16, 2020
• Last Update Submitted That Met QC Criteria: June 12, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: pneumococcal vaccination
• Additional Relevant MeSH Terms: Metabolic Diseases; Skin Diseases; Lipid Metabolism Disorders; Skin Diseases, Metabolic; Lipodystrophy; Physiological Effects of Drugs; Immunologic Factors; Vaccines; Heptavalent Pneumococcal Conjugate Vaccine
• Other Study ID Numbers: MUSC vaccine study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The data will be made available once analysis is completed through publications in peer reviewed journals.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes