Mechanisms of Impaired HIV-associated B Cell and Pneumococcal Vaccine Responses

Human Immunodeficiency Virus (HIV) infection is complicated by high rates of infections and cancers which are often the cause of death rather than the HIV/acquired immune deficiency syndrome (AIDS) virus itself. Treatment of HIV with antiretroviral medications has decreased the frequency of many complications by over 90%, but bacterial pneumonia remains extremely high. Current vaccines are not very effective in preventing these infections in patients with HIV infection. The investigators are studying the cells (B cells) that make antibodies to fight infection by binding to and killing bacteria. The goal is to understand how HIV impairs the ability of B cells to make antibodies in sufficient quantity and of sufficient quality to protect patients with HIV to learn how to enhance protection against these infections. The investigators also seek to understand the role of the bacteria (specifically Streptococcus pneumoniae) that normally live in the nose and throat in the development of pneumonia and other infections.

Study Overview

• Status: Unknown
• Conditions: Pneumococcal Infections; HIV; Pneumococcal Vaccines
• Intervention / Treatment: Biological: PCV-13; Biological: PPSV-23

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado-Denver
    • Denver, Colorado, United States, 80220
      • Denver VA Medical Center
    • Denver, Colorado, United States, 80204
      • Denver Health and Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

For HIV-infected subjects:

• adults aged 18-55 years
• >200 CD4+ T-cells/microliter
• no antiretroviral therapy (at the time of nasal swab/week 0)
• receiving antiretroviral therapy for >6 weeks (at the time of vaccination/week 12)

For HIV-seronegative controls:

• adults aged 18-55 years

Exclusion Criteria:

For all subjects:

• age <18 or >55 years
• history of prior pneumococcal vaccination
• immunosuppressive therapy, defined as: prednisone >15mg/day currently or >14 days in the past 3 months, cytotoxic agents, anti-metabolites, cyclosporine, anti-tumor necrosis factor, B cell monoclonal antibodies
• current or chronic pulmonary infection (bacterial, fungal, mycobacterial), pneumonia, or rhinosinusitis within 2 months
• chronic lung disease
• renal insufficiency, defined as serum creatinine >1.6
• active liver disease, including hepatitis C virus infection
• history of splenectomy
• history of antibacterial therapy within 3 months of nasal swab (week 0)
• current alcohol abuse
• chronic heart disease
• diabetes
• current cigarette smoking

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HIV-seronegative; HIV-seronegative subjects will receive Prevnar (PCV-13) at week 0.	Biological: PCV-13; Other Names: Prevnar
Experimental: HIV-infected; HIV-infected subjects will receive Prevnar (PCV-13) at week 0, and Pneumovax (PPSV-23) at week 8 per Advisory Committee on Immunization Practices (ACIP) guidelines.	Biological: PCV-13; Other Names: Prevnar; Biological: PPSV-23; Other Names: Pneumovax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
B and T cell subsets	Activation and subset distribution of B and T cell subsets and cluster of differentiation positive (CD4+) T cells and T follicular helper (TFH) cells on days 0 and 7 after stimulation	Weeks -12, 0, 1, 8, 9, 16
Total IgG, IgM and IgA	Total immunoglobulin G (IgG), immunoglobulin M (IgM) and immunoglobulin A (IgA) produced from culture of peripheral blood mononuclear cells (PBMC) stimulated in triplicate with B cell stimuli on day 7 by enzyme-linked immunosorbent assay (ELISA)	Weeks -12, 0, 1, 8, 9, 16
Antibody-secreting cells	Total IgG, IgM and IgA antibody-secreting cells (ASC) enumerated by enzyme-linked immunospot (ELISPOT) on day 0 and day 7	Weeks 0, 1, 8, 9
AID and BCL-6 production	RNA extraction for activation-induced cytidine deaminase (AID) and B cell lymphoma protein 6 (BCL6) expression and mutation from stimulated B cells	Weeks -12, 0, 1, 8, 9, 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
S.pneumoniae colonization and nasopharyngeal microbiome	Prevalence of nasopharyngeal S. pneumoniae determined by quantitative polymerase chain reaction(Q-PCR) and 16S ribosomal RNA (rRNA) sequencing, related microbiota (commensal bacteria) and correlation between colonization and levels of pneumococcal capsule-specific IgG	Weeks -12, 0, 8, 16
S.pneumoniae urine antigen positivity	S. pneumoniae urine antigen positivity in relation to colonization	Week -12

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Edward N Janoff, MD, University of Colorado-Denver, Denver VA Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2014
• Primary Completion (Anticipated): June 1, 2021
• Study Completion (Anticipated): June 1, 2021

Study Registration Dates

• First Submitted: December 10, 2013
• First Submitted That Met QC Criteria: December 10, 2013
• First Posted (Estimate): December 16, 2013

Study Record Updates

• Last Update Posted (Actual): November 18, 2020
• Last Update Submitted That Met QC Criteria: November 17, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: HIV; Streptococcus pneumoniae infection; Streptococcus pneumoniae colonization; Pneumococcal vaccines; Prevnar; Pneumovax; Nasopharyngeal microbiome
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Streptococcal Infections; Gram-Positive Bacterial Infections; Pneumococcal Infections; Physiological Effects of Drugs; Immunologic Factors; Heptavalent Pneumococcal Conjugate Vaccine
• Other Study ID Numbers: 13-2405; R01AI108479 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No