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

Not Applicable

Brief Summary: 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.

Recruitment & Eligibility

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:

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

Arm && Interventions

Group	Intervention	Description
HIV-seronegative	PCV-13	HIV-seronegative subjects will receive Prevnar (PCV-13) at week 0.
HIV-infected	PCV-13	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.
HIV-infected	PPSV-23	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.

Primary Outcome Measures

Name	Time	Method
B and T cell subsets	Weeks -12, 0, 1, 8, 9, 16	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
Antibody-secreting cells	Weeks 0, 1, 8, 9	Total IgG, IgM and IgA antibody-secreting cells (ASC) enumerated by enzyme-linked immunospot (ELISPOT) on day 0 and day 7
Total IgG, IgM and IgA	Weeks -12, 0, 1, 8, 9, 16	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)
AID and BCL-6 production	Weeks -12, 0, 1, 8, 9, 16	RNA extraction for activation-induced cytidine deaminase (AID) and B cell lymphoma protein 6 (BCL6) expression and mutation from stimulated B cells

Secondary Outcome Measures

Name	Time	Method
S.pneumoniae colonization and nasopharyngeal microbiome	Weeks -12, 0, 8, 16	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
S.pneumoniae urine antigen positivity	Week -12	S. pneumoniae urine antigen positivity in relation to colonization

Locations (3): University of Colorado-Denver
🇺🇸
Aurora, Colorado, United States
Denver Health and Hospitals
🇺🇸
Denver, Colorado, United States
Denver VA Medical Center
🇺🇸
Denver, Colorado, United States