B-Cell Immunophenotyping to Predict Vaccination Outcome in the Immunocompromised - A Systematic Review

Abstract

Vaccination is the most effective measure to prevent infections in the general population. Its efficiency strongly depends on the function and composition of the immune system. If the immune system lacks critical components, patients will not be fully protected despite a completed vaccination schedule. Antigen-specific serum immunoglobulin levels are broadly used correlates of protection. These are the products of terminally differentiated B cells - plasma cells. Here we reviewed the literature on how aberrancies in B-cell composition and function influence immune responses to vaccinations. In a search through five major literature databases, 6,537 unique articles published from 2000 and onwards were identified. 75 articles were included along three major research lines: extremities of life, immunodeficiency and immunosuppression. Details of the protocol can be found in the International Prospective Register of Systematic Reviews [PROSPERO (registration number CRD42021226683)]. The majority of articles investigated immune responses in adults, in which vaccinations against pneumococci and influenza were strongly represented. Lack of baseline information was the most common reason of exclusion. Irrespective of study group, three parameters measured at baseline seemed to have a predictive value in assessing vaccine efficacy: (1) distribution of B-cell subsets (mostly a reduction in memory B cells), (2) presence of exhausted/activated B cells, or B cells with an aberrant phenotype, and (3) pre-existing immunological memory. In this review we showed how pre-immunization (baseline) knowledge of circulating B cells can be used to predict vaccination efficacy. We hope that this overview will contribute to optimizing vaccination strategies, especially in immunocompromised patients.

Keywords: B cells; extremities of life; immune monitoring; immunodeficiency; immunosuppression; vaccination.

Figure 1

Simplified representation of major B-cell subsets detectable in blood (A) along with an overview of markers (B) used to define atypical B-cell populations. (A) From left to right: Immature/Transitional B cells are recent bone marrow migrants and present in low numbers in the peripheral blood. They mature into naive B cells, which constitute the major part of the circulating B-cell population. The number of naive B cells with unique B-cell receptors forms the naive B-cell repertoire, which is crucial for recognition of neoantigens (primary antigen encounters). Naive B cells which encountered T-cell dependent antigens (e.g. a protein), will enter germinal centers to receive T-cell help. As a consequence, they will upregulate AID (Activation Induced Cytidine Deaminase) and subsequently improve affinity for antigen by introducing Somatic Hypermutations (SHM) and change effector functions in the process of Class-Switch Recombination (CSR). Only B cells that express receptors with increased affinity to the encountered antigen survive and can leave the germinal center as class-switched memory B cells (MBC) or as plasma cells. When a B cell is activated by a T-cell independent antigen (e.g. a polysaccharide, nucleic acid or lipid), it does not enter the germinal center, but differentiates into a non class-switched MBC instead. Class-switched and non class-switched MBCs make up a large part of the circulating B-cell compartment, and are present in other parts of the peripheral lymphoid system, such as the spleen or lymph nodes. These MBCs are important during recall responses (recall antigen encounter) when they can re-enter germinal centers and undergo further processes of affinity maturation and class-switching. Lastly, plasma cells are the terminal effector B cells and responsible for massive antibody production after antigen encounter. Upon infection or vaccination, a transient peak of plasma cell numbers is observed, but in steady state, plasma cell numbers are low. Part of the plasma cells generated during an immune response becomes long-lived plasma cells that migrate to the bone marrow, where they can stay for many years and produce low quantities of antibodies, which are detectable in serum. Underneath each phenotypic description we provide reference values for each of the populations. The median % (of total B cells) and median cell count in the periphery (cells/µl) are indicated (12). These values are based on the publication by Blanco et al., JACI, 2018, who derived these numbers from a cohort of 32 healthy adults, aged 18-39 years. (B) An overview of different cellular and genetic markers that were used in the reviewed publications to define atypical B-cell subsets, such as exhausted, tissue-like, anergic, activated or immunesenescent phenotypes. The right column indicates the most prominent function or process involvement for each marker.

Figure 2

Prisma 2009 Flow Diagram. Overview of the screening process and article selection.

Figure 3

Overview of B-cell parameters predictive of vaccine efficacy. The different evaluation levels (serum-, cell- or molecular-based) are indicated in the rows, whereas the different B-cell parameters are indicated in the columns. Proposed detection techniques are shown in the yellow boxes. Blue boxes contain the general conclusions per parameter. Positive impact is indicated with green arrows (and a plus-symbol), while negative impact is indicated with red arrows (and a minus-symbol). In the ‘B-cell composition’ column, colors show general trends in polysaccharide and protein vaccines, whereas in the ‘aberrant phenotype/additional markers’ column, colors indicate in which vaccination settings markers were evaluated. PPV, pneumococcal polysaccharide vaccine; ELISA, Enzyme-Linked Immunosorbent Assay; HAI, hemagglutinin inhibition; OPK, opsonophagocytic killing; SBA, serum bactericidal assay; ELISpot, Enzyme-linked ImmunoSpot; w/o, without; esp., especially; RT-PCR, reverse-transcriptase polymerase chain reaction; RT qPCR, real-time quantitative polymerase chain reaction; BCR, B-cell receptor.