Increased B Cell Selection Stringency In Germinal Centers Can Explain Improved COVID-19 Vaccine Efficacies With Low Dose Prime or Delayed Boost

The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal center (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.

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Low dose prime and delayed boost can improve COVID-19 vaccine efficacies by increasing B cell selection stringency in germinal centres

10.1101/2021.09.08.21263248 ◽

2021 ◽

Author(s):

Amar K Garg ◽

Soumya Mittal ◽

Pranesh Padmanabhan ◽

Rajat Desikan ◽

Narendra M Dixit

Keyword(s):

B Cells ◽

Low Dose ◽

Antibody Responses ◽

Target Antigen ◽

Dosing Interval ◽

Germinal Centres ◽

Paradoxical Effects ◽

Stochastic Simulation Model ◽

Dosing Intervals ◽

Selection Of

The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal centre (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.

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B cells rapidly target antigen and surface-derived MHCII into peripheral degradative compartments

10.1101/775882 ◽

2019 ◽

Author(s):

S Hernández-Pérez ◽

M Vainio ◽

E Kuokkanen ◽

V Sustar ◽

P Petrov ◽

...

Keyword(s):

B Cells ◽

Antigen Processing ◽

Antibody Responses ◽

Cathepsin S ◽

Target Antigen ◽

Peptide Loading ◽

Antigen Trafficking ◽

Specific Antigens ◽

Acidic Vesicles ◽

Acidic Compartments

AbstractIn order to mount high-affinity antibody responses, B cells internalise specific antigens and process them into peptides loaded onto MHCII for presentation to Th cells. While the biochemical principles of antigen processing and MHCII loading have been well dissected, how the endosomal vesicle system is wired to enable these specific functions remains much less studied. Here, we performed a systematic microscopy-based analysis of antigen trafficking in B cells to reveal its route to the MHCII peptide-loading compartment (MIIC). Surprisingly, we detected fast targeting of internalised antigen into peripheral acidic compartments that possessed the hallmarks of MIIC and also showed degradative capacity. In these vesicles, internalised antigen converged rapidly with membrane-derived MHCII and partially overlapped with Cathepsin-S and H2-M, both required for peptide loading. These early compartments appeared heterogenous and atypical as they contained a mixture of both early and late markers, indicating specialized endosomal route. Together, our data suggests that, in addition to previously-reported perinuclear late endosomal MIICs, antigen processing and peptide loading could start already in these specialized early peripheral acidic vesicles (eMIIC) to support fast peptide-MHCII presentation.

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Transfer of Small Resting B Cells into Immunodeficient Hosts Results in the Selection of a Self-renewing Activated B Cell Population

Journal of Experimental Medicine ◽

10.1084/jem.189.2.319 ◽

1999 ◽

Vol 189 (2) ◽

pp. 319-330 ◽

Cited By ~ 86

Author(s):

Fabien Agenès ◽

António A. Freitas

Keyword(s):

Bone Marrow ◽

B Cells ◽

B Cell ◽

Terminal Differentiation ◽

Cell Renewal ◽

Cell Selection ◽

Feedback Mechanisms ◽

Selection Of ◽

Activated B Cells

We studied the role of bone marrow B cell production in the renewal of peripheral B cells and the feedback mechanisms that control the entry of newly formed B cells into the peripheral B cell pools. When resting lymph node B cells are injected into B cell–deficient hosts, a fraction of the transferred cells expands and constitutes a highly selected population that survives for prolonged periods of time by continuous cell renewal at the periphery. Although the number of donor B cells recovered is low, a significant fraction shows an activated phenotype, and the serum immunoglobulin (Ig)M levels are as in normal mice. This population of activated B cells is resistant to replacement by a new cohort of B cells and is able to feedback regulate both the entry of newly formed B cells into the peripheral pool and terminal differentiation. These findings suggest that peripheral B cell selection follows the first come, first served rule and that IgM-secreting cells are generated from a pool of stable activated B cells with an independent homeostasis.

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Germinal center B cells separate signals for selection and division like compact discs

10.1101/2020.01.29.925479 ◽

2020 ◽

Author(s):

Michael Meyer-Hermann

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Cell Selection ◽

Audio Signals ◽

Common Concept ◽

Global Understanding ◽

Fate Decision ◽

Concept Of Information ◽

Selection Of

SummarySelection of B cells in germinal center (GC) reactions is pivotal to the generation of high affinity antibodies and memory B cells. Knowledge about B cell selection is limited to individual interactions and lacks global understanding. Here, seemingly contradictory experiments are unified in a common concept by separation of signals for the frequency of fate decision from the strength of cell division, which can then be controlled independently, similar to the separation of frequency and amplitude in digital audio signals. Based on this concept of information processing, three theories of B cell selection are developed that can be distinguish by predicted experiments drawn from computer simulations. Understanding encoding of information in molecular states is critical for targeted immune interventions.

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AIRE expression controls the peripheral selection of autoreactive B cells

immuneACCESS ◽

10.21417/b7v926 ◽

2019 ◽

Author(s):

J Sng ◽

B Ayoglu ◽

JW Chen ◽

JN Schickel ◽

EMN Ferre ◽

...

Keyword(s):

B Cells ◽

Autoreactive B Cells ◽

Selection Of

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Hyper‐metabolic B cells in the spleens of old mice make antibodies with autoimmune specificities

Immunity & Ageing ◽

10.1186/s12979-021-00222-3 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Daniela Frasca ◽

Maria Romero ◽

Denisse Garcia ◽

Alain Diaz ◽

Bonnie B. Blomberg

Keyword(s):

B Cells ◽

B Cell ◽

Inflammatory Markers ◽

Cell Subset ◽

Antibody Responses ◽

Metabolic Phenotype ◽

Cellular Mechanisms ◽

Autoimmune Antibodies ◽

B Cell Subsets ◽

Old Mice

Abstract Background Aging is associated with increased intrinsic B cell inflammation, decreased protective antibody responses and increased autoimmune antibody responses. The effects of aging on the metabolic phenotype of B cells and on the metabolic programs that lead to the secretion of protective versus autoimmune antibodies are not known. Methods Splenic B cells and the major splenic B cell subsets, Follicular (FO) and Age-associated B cells (ABCs), were isolated from the spleens of young and old mice and left unstimulated. The RNA was collected to measure the expression of markers associated with intrinsic inflammation and autoimmune antibody production by qPCR. B cells and B cell subsets were also stimulated with CpG and supernatants collected after 7 days to measure autoimmune IgG secretion by ELISA. Metabolic measures (oxygen consumption rate, extracellular acidification rate and glucose uptake) were performed using a Seahorse XFp extracellular flux analyzer. Results Results have identified the subset of ABCs, whose frequencies and numbers increase with age and represent the most pro-inflammatory B cell subset, as the cell type mainly if not exclusively responsible for the expression of inflammatory markers and for the secretion of autoimmune antibodies in the spleen of old mice. Hyper-inflammatory ABCs from old mice are also hyper-metabolic, as compared to those from young mice and to the subset of FO B cells, a feature needed not only to support their higher expression of RNA for inflammatory markers but also their higher autoimmune antibody secretion. Conclusions These results identify a relationship between intrinsic inflammation, metabolism and autoimmune B cells and suggest possible ways to understand cellular mechanisms that lead to the generation of pathogenic B cells, that are hyper-inflammatory and hyper-metabolic, and secrete IgG antibodies with autoimmune specificities.

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Influenza virus infection expands the breadth of antibody responses through IL-4 signalling in B cells

Nature Communications ◽

10.1038/s41467-021-24090-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kosuke Miyauchi ◽

Yu Adachi ◽

Keisuke Tonouchi ◽

Taiki Yajima ◽

Yasuyo Harada ◽

...

Keyword(s):

B Cells ◽

Virus Infection ◽

Influenza Virus Infection ◽

Public Health Problem ◽

Influenza Viruses ◽

Antibody Responses ◽

Major Public Health Problem ◽

Follicular Helper ◽

Protective Antibodies ◽

Shared Epitopes

AbstractInfluenza viruses are a major public health problem. Vaccines are the best available countermeasure to induce effective immunity against infection with seasonal influenza viruses; however, the breadth of antibody responses in infection versus vaccination is quite different. Here, we show that nasal infection controls two sequential processes to induce neutralizing IgG antibodies recognizing the hemagglutinin (HA) of heterotypic strains. The first is viral replication in the lung, which facilitates exposure of shared epitopes that are otherwise hidden from the immune system. The second process is the germinal center (GC) response, in particular, IL-4 derived from follicular helper T cells has an essential role in the expansion of rare GC-B cells recognizing the shared epitopes. Therefore, the combination of exposure of the shared epitopes and efficient proliferation of GC-B cells is critical for generating broadly-protective antibodies. These observations provide insight into mechanisms promoting broad protection from virus infection.

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A Novel Gene Delivery Vector of Agonistic Anti-Radioprotective 105 Expressed on Cell Membranes Shows Adjuvant Effect for DNA Immunization Against Influenza

Frontiers in Immunology ◽

10.3389/fimmu.2020.606518 ◽

2020 ◽

Vol 11 ◽

Author(s):

Tatsuya Yamazaki ◽

Mrityunjoy Biswas ◽

Kouyu Kosugi ◽

Maria Nagashima ◽

Masanori Inui ◽

...

Keyword(s):

Influenza Virus ◽

B Cells ◽

Intracellular Signaling ◽

Transmembrane Domain ◽

Lethal Dose ◽

Influenza Virus Infection ◽

Target Antigen ◽

Dna Immunization ◽

Adjuvant Effect ◽

Specific Antibodies

Radioprotective 105 (RP105) (also termed CD180) is an orphan and unconventional Toll-like receptor (TLR) that lacks an intracellular signaling domain. The agonistic anti-RP105 monoclonal antibody (mAb) can cross-link RP105 on B cells, resulting in the proliferation and activation of B cells. Anti-RP105 mAb also has a potent adjuvant effect, providing higher levels of antigen-specific antibodies compared to alum. However, adjuvanticity is required for the covalent link between anti-RP105 mAb and the antigen. This is a possible obstacle to immunization due to the link between anti-RP105 mAb and some antigens, especially multi-transmembrane proteins. We have previously succeeded in inducing rapid and potent recombinant mAbs in mice using antibody gene-based delivery. To simplify the covalent link between anti-RP105 mAb and antigens, we generated genetic constructs of recombinant anti-RP105 mAb (αRP105) bound to the transmembrane domain of the IgG-B cell receptor (TM) (αRP105-TM), which could enable the anti-RP105 mAb to link the antigen via the cell membrane. We confirmed the expression of αRP105-TM and the antigen hemagglutinin, which is a membrane protein of the influenza virus, on the same cell. We also found that αRP105-TM could activate splenic B cells, including both mature and immature cells, depending on the cell surface RP105 in vitro. To evaluate the adjuvanticity of αRP105-TM, we conducted DNA immunization in mice with the plasmids encoding αRP105-TM and hemagglutinin, followed by challenge with an infection of a lethal dose of an influenza virus. We then obtained partially but significantly hemagglutinin-specific antibodies and observed protective effects against a lethal dose of influenza virus infection. The current αRP105-TM might provide adjuvanticity for a vaccine via a simple preparation of the expression plasmids encoding αRP105-TM and of that encoding the target antigen.

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