Immune Response to Pneumococcal Polysaccharides 4 and 14 in Elderly and Young Adults: Analysis of the Variable Heavy Chain Repertoire

Streptococcus pneumoniae is a leading cause of morbidity and mortality in both developed and developing countries. The current pneumococcal polysaccharide (PPS) vaccine is highly effective in young adults; however, vaccine efficacy is dramatically decreased in the elderly population. We hypothesized that the decreased vaccine efficacy in the elderly results from altered variable gene family usage. We have characterized the immunoglobulin G gene usage of the antibody response to PPS4 and PPS14 in 20 young and 20 elderly adults. The variable heavy (V(H)) gene repertoire of human peripheral B cells was amplified by using PCR. A total of 364 heavy chain sequences with specificity for PPS4 and 305 heavy chain sequences for PPS14 were analyzed from young adults. In addition, a total of 325 sequences for PPS4 and 291 sequences for PPS14 were obtained from elderly adults. Complete sequence identity, somatic mutation frequencies, and V(H) gene usage was determined in response to PPS4 and PPS14. In all volunteers, the immune response to both polysaccharides consisted predominantly of heavy chains belonging to the V(H)3 gene family. There were significant differences in the variable gene repertoire between young and elderly adults. Somatic mutation occurred more frequently in sequences derived from young compared to elderly derived sequences. With aging, a loss of oligoclonality was noted in response to PPS4 and PPS14 compared to young adults. The observed differences in V(H) repertoire, somatic mutation, and loss of oligoclonality may contribute to decreased vaccine efficacy in the elderly

Inflammatory Markers and Immune Response to Pneumococcal Vaccination in HIV-Positive and -Negative Adults.

BACKGROUND:Members of the Tumor Necrosis Factor (TNF)-superfamily have speculated roles in the response against T-independent type II antigens (TI-II) including pneumococcal polysaccharides (PPS). Dysregulation in their expression is associated with an enhanced risk for pneumococcal disease in neonates but their expression in other high-risk populations including HIV-positive individuals remains to be elucidated. OBJECTIVE:To investigate signals that contribute towards PPS-response and identify potential anomalies that may account for diminished serological response in HIV-positive individuals post Pneumovax (PPV23) immunization. METHODS:Markers of inflammation, C-reactive protein (CRP), IL-6, sCD27 and sCD30, were assessed in HIV-positive and -negative individuals as potential predictors of PPV23 response. Serum levels of B cell activating factor (BAFF), transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI), B cell maturation antigen (BCMA) and B cell expression of BAFF-R, TACI, BCMA, CD40 and CD21 were assessed in total (unselected) and PPS23F (antigen)-specific B cells of PPV23 immunized HIV-positive and -negative individuals. RESULTS:CRP, sCD27, sCD30 and BAFF were significantly elevated in the serum of HIV-positive individuals but did not adversely affect PPV23 response. Assessment of PPS-specific B cells revealed enhanced TACI and reduced BAFF-R expression compared to unselected B cells in HIV-positive and -negative individuals. Surface TACI was similar but soluble TACI was significantly lower in HIV-positive compared to HIV-negative individuals. CONCLUSION:Current studies highlight a potential role for TACI in PPV23 response based on its enhanced expression on PPS-specific B cells. Although surface levels of TACI were similar, diminished soluble TACI (sTACI) in HIV-positive compared to HIV-negative individuals could potentially decrease BAFF responsiveness and Ig response. A better understanding of the role of TNF receptors could contribute to the design of improved pneumococcal vaccines. TRIAL REGISTRATION:ClinicalTrials.gov NCT02515240

PPS23F-specific memory B cells showed enhanced expression of TACI in HIV-positive and HIV-negative individuals.

<p>Surface expression of BAFF-R (A), CD40 (D) and CD21 (E) on day 7 PPS23F-selected B cells of HIV-positive (grey bars with slanted stripes) and HIV-negative (white bars slanted stripes) individuals compared to day 0 unselected B cells in HIV-positive (plain grey bars) and HIV-negative (plain white bars) individuals. Data is represented as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.</p

Baseline Characteristics of HIV-negative, HIV-positive HAART naïve and experienced individuals enrolled in the current study.

<p>Baseline Characteristics of HIV-negative, HIV-positive HAART naïve and experienced individuals enrolled in the current study.</p

Pro-inflammatory markers are elevated in HIV-positive compared to HIV-negative individuals.

<p>Serum levels of CRP ng/ml (A), IL-6 pg/ml (B), sCD27 U/ml (C) and sCD30 ng/ml (D) were tested in HIV-positive (black bars) and -negative (white bars) individuals. Data is represented as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.</p

PPS23F-specific B cells showed enhanced expression of CD40 in HIV-positive compared to HIV-negative individuals.

<p>Post-vaccination (Day7) analysis of PPS-specific B cells against the tested serotype 23F showed similar levels of BAFF-R, BCMA, TACI, CD21 but higher levels of CD40 in HIV-positive (black bars) compared to HIV-negative (white bars) individuals. Data is represented as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.</p

Serum BAFF and sTACI are dysregulated in HIV-positive individuals.

<p>Serum levels of soluble sBAFF pg/ml (A), sTACI pg/ml (B) and sBCMA pg/ml (C) were tested in HIV-positive (black bars) and -negative (white bars) individuals. Data is represented as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.</p

TNF and complement receptor CD21 expression is similar in the total B cells of HIV-positive and HIV-negative individuals.

<p>Expression of receptors BAFF-R, BCMA, TACI, CD40 and CD21 were analyzed in total B cells of HIV-positive (black bars) and -negative (white bars) individuals. Data is represented as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.</p