Alterations in serotype-specific B cell responses to the 13-valent pneumococcal conjugate vaccine in aging HIV-infected adults
Introduction
The success of ART has led to a substantial increase in life expectancy for HIV+ individuals [1]. Approximately one-half of HIV+ individuals living in the United States are estimated to be ≥50 years old [2]. Aging and HIV infection both result in profound immunological changes due to chronic antigenic stress [2], [3], [4], [5]. Similarities and differences, as well as the synergism, between these processes remain poorly understood.
PPV immunization generates impaired antibody responses in both elderly and HIV+ individuals, and effectiveness in preventing pneumococcal disease is controversial [6], [7], [8], [9]. The Advisory Committee on Immunization Practices (ACIP) currently recommends that HIV+ adults receive a single dose of PCV followed by a dose of PPV 8 weeks later (PCV/PPV) [10]. Superiority of PCV, however, is also questionable, as immunogenicity studies comparing single doses or combined regimens of PCV and PPV have yielded variable results [11], [12], [13], [14], [15], [16].
Further investigation into the underlying cellular mechanisms responsible for pneumococcal vaccine responses is urgently needed. In humans, evidence suggests that both IgM and switched memory B cells generate antibodies to pneumococcal antigens [17]. Several studies have reported an association between reduced memory B cell subsets and impaired responses to vaccination in elderly and HIV+ individuals [18], [19], [20], [21]. However, these analyses were performed on total rather than antigen-specific B cell populations.
We have previously characterized the phenotype of B cells responding to PPV in young adults, elderly, and HIV+ [22], [23], [24], [25]. The majority of serotype-specific B cells are IgM memory B cells in young, immunocompetent adults [22], [23]. Both elderly and HIV+ adults exhibit significant reductions in this subset that may contribute to decreased vaccine responsiveness [23], [24], [25]. However, unlike the elderly, HIV+ adults lack an increase in the proportion of serotype-specific switched memory B cells. Our data suggest that elderly and HIV+ individuals exhibit distinct perturbations in B cell subsets critical for protection against pneumococcal disease.
Older HIV+ individuals may possess a unique cellular response to vaccination reflecting the combined effects of aging and HIV infection. In the present study, we assessed the phenotype of B cells responding to the recommended PCV/PPV regimen compared to a single dose of PPV in HIV+ adults aged 50–65 years. We also sought to identify differences in surface expression of B cell receptors, including complement receptor CD21 and TNFRs CD40, TACI, and B cell-activating factor receptor (BAFF-R), on serotype-specific B cells that may contribute to vaccine responses.
Section snippets
Study design
Volunteers 50–65 years old were recruited between April 2012 and January 2015 in this University of Toledo Institutional Review Board-approved study. Written, informed consent was obtained from all subjects. Exclusion criteria included: active infection (except HIV), PPV <5 years prior, pregnancy, immunosuppressive medications, and prior history of splenectomy or other immunocompromising conditions as defined by ACIP vaccination recommendations [10]. Volunteers were questioned about any past
Subjects
Baseline characteristics are reported in Table 1. Differences in the distribution of sex and race in HIV− compared to HIV+ subjects were noted. Clinical characteristics, including CD4 count at enrollment and use of ART, were similar between HIV+ groups. A larger proportion of HIV+ participants had been immunized with PPV ≥5 years prior (85%) compared to HIV− (7%). Quantitative and qualitative antibody responses to pneumococcal vaccination were assessed in a separate study (submitted
Discussion
In the current study, we assessed B cells responding to the recommended PCV/PPV regimen compared to a single dose of PPV in HIV+ adults 50–65 years old. We identified serotype-specific B cells using fluorescently-labeled PPS as previously described by our laboratory [22], [23], [24], [25]. Serotype-specific B cell percentages post-PPV were significantly lower in the HIV+ PCV/PPV group compared to the HIV+ PPV group, suggesting that an initial dose of PCV limits the frequency of responding B
Funding
This work was supported by National Institutes of Health [RO1A081558 and RO1AG045973 to M.A.J.W.].
Acknowledgements
We thank all study volunteers for their participation and the Division of Infectious Diseases physicians and staff at the University of Toledo Medical Center in Toledo, Ohio for their assistance with recruitment.
Conflict of interest: All authors have no potential conflicts of interest.
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These authors contributed equally to this work.