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

Study Overview
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Brief Summary
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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.

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

Conditions
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HIV, Pneumococcal Infections, Pneumococcal Vaccines

Intervention / Treatment
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* Biological: PCV-13
* Biological: PPSV-23


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIV-seronegative<br>HIV-seronegative subjects will receive Prevnar (PCV-13) at week 0. | Biological: PCV-13<br> <br> * Other names: Prevnar;|
| Experimental: HIV-infected<br>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<br> <br> * Other names: Prevnar;Biological: PPSV-23<br> <br> * Other names: Pneumovax;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Streptococcus pneumoniae infection, Streptococcus pneumoniae colonization, Pneumococcal vaccines, Prevnar, Pneumovax, Nasopharyngeal microbiome