TNF inhibitors affect the induction and maintenance of spike-specific B-cell responses after mRNA vaccination.

Objectives: Tumour necrosis factor inhibitors (TNFi) are widely used and effective as treatment for immune-mediated inflammatory diseases (IMIDs). However, TNFi therapy causes a faster waning of antibody responses following vaccination. The underlying cause by which TNFi affect humoral immunity remains to be elucidated.

Fusion of Complement Fragment C3d Enhances Germinal Center Responses to HIV-1 Envelope Glycoproteins.

Eliciting sustained germinal center (GC) responses is critical for the development of an effective HIV-1 vaccine, yet HIV-1 envelope glycoprotein (Env) immunogens often fail to elicit GC responses required for the maturation of cognate B cells that secrete broadly neutralizing antibodies (bNAbs). Effective antigen recognition is important for initial B cell priming, activation, and GC engagement. Since complement opsonization contributes to antigen recognition, we investigated whether C3d fusion could enhance the GC response of the stabilized HIV-1 Env immunogen based on a consensus sequence (ConM Env).

Innovative Single-Cell Sequencing Techniques for B-Cell Analysis and Their Implications for Rational HIV-1 Vaccine Design.

The application of single-cell analysis to investigate immune cell diversity has historically been considered a complex task. Recently, innovative techniques have emerged revolutionizing the way immune cells can be explored, offering unprecedented insights into the dynamics of this complex system. In particular, novel approaches have enabled a detailed characterization of B-cell responses, encompassing immune repertoire, gene expression, and phenotype analysis at an individual cell level.

Deep profiling of B cells responding to various pathogens uncovers compartments in IgG memory B cell and antibody-secreting lineages.

Improving our understanding of B cell transition to memory B cells (MBCs) and antibody-secreting cells (ASCs) is crucial for clinical monitoring and vaccine strategies. To explore these dynamics, we compared prepandemic antigen responses (influenza hemagglutinin, respiratory syncytial virus fusion glycoprotein, and tetanus toxoid) with recently encountered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen responses in convalescent COVID-19 patients using spectral flow cytometry. Our analysis revealed the CD43+CD71+IgG+ activated B cell subset, highly enriched for SARS-CoV-2 specificities, as a juncture for ASC and MBC differentiation, with CD86+ phenotypically similar to ASCs and CD86- to IgG+ MBCs.

Longevity of antibody responses is associated with distinct antigen-specific B cell subsets early after infection.

Introduction: Upon infection, T cell-driven B cell responses in GC reactions induce memory B cells and antibody-secreting cells that secrete protective antibodies. How formation of specifically long-lived plasma cells is regulated via the interplay between specific B and CD4+ T cells is not well understood. Generally, antibody levels decline over time after clearance of the primary infection.

Mosaic and mixed HIV-1 glycoprotein nanoparticles elicit antibody responses to broadly neutralizing epitopes.

An effective human immunodeficiency virus 1 (HIV-1) vaccine will most likely have to elicit broadly neutralizing antibodies (bNAbs) to overcome the sequence diversity of the envelope glycoprotein (Env). So far, stabilized versions of Env, such as SOSIP trimers, have been able to induce neutralizing antibody (NAb) responses, but those responses are mainly strain-specific. Here we attempted to broaden NAb responses by using a multivalent vaccine and applying a number of design improvements.

Primary SARS-CoV-2 variant of concern infections elicit broad antibody Fc-mediated effector functions and memory B cell responses.

Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by human sera is a strong correlate of protection against symptomatic and severe Coronavirus Disease 2019 (COVID-19). The emergence of antigenically distinct SARS-CoV-2 variants of concern (VOCs) and the relatively rapid waning of serum antibody titers, however, raises questions about the sustainability of serum protection. In addition to serum neutralization, other antibody functionalities and the memory B cell (MBC) response are suggested to help maintaining this protection.

A Robust Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-Specific T- and B-Cell Response Is Associated With Early Viral Clearance in SARS-CoV-2 Omicron-Infected Immunocompromised Individuals.

Background: The immunological determinants of delayed viral clearance and intrahost viral evolution that drive the development of new pathogenic virus strains in immunocompromised individuals are unknown. Therefore, we longitudinally studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immune responses in relation to viral clearance and evolution in immunocompromised individuals.

Methods: Among Omicron-infected immunocompromised individuals, we determined SARS-CoV-2-specific T- and B-cell responses, anti-spike immunoglobulin G (IgG) and IgG3 titers, neutralization titers, and monoclonal antibody (mAb) resistance-associated mutations.

Systematic evaluation of B-cell clonal family inference approaches.

The reconstruction of clonal families (CFs) in B-cell receptor (BCR) repertoire analysis is a crucial step to understand the adaptive immune system and how it responds to antigens. The BCR repertoire of an individual is formed throughout life and is diverse due to several factors such as gene recombination and somatic hypermutation. The use of Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) using next generation sequencing enabled the generation of full BCR repertoires that also include rare CFs.

Broad SARS-CoV-2 neutralization by monoclonal and bispecific antibodies derived from a Gamma-infected individual.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has remained a medical threat due to the evolution of multiple variants that acquire resistance to vaccines and prior infection. Therefore, it is imperative to discover monoclonal antibodies (mAbs) that neutralize a broad range of SARS-CoV-2 variants. A stabilized spike glycoprotein was used to enrich antigen-specific B cells from an individual with a primary Gamma variant infection.

Distinct dynamics of antigen-specific induction and differentiation of different CD11cTbet B-cell subsets.

Background: CD11cTbet B cells are enriched in autoimmunity and chronic infections and also expand on immune challenge in healthy individuals. CD11cTbet B cells remain an enigmatic B-cell population because of their intrinsic heterogeneity.

Objectives: We investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen-specific development and differentiation properties of 3 separate CD11c B-cell subsets-age-associated B cells (ABCs), double-negative 2 (DN2) B cells, and activated naive B cells-and compared them to their canonical CD11c counterparts.

Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection.

The Lassa virus is endemic in parts of West Africa, and it causes hemorrhagic fever with high mortality. The development of a recombinant protein vaccine has been hampered by the instability of soluble Lassa virus glycoprotein complex (GPC) trimers, which disassemble into monomeric subunits after expression. Here, we use two-component protein nanoparticles consisting of trimeric and pentameric subunits to stabilize GPC in a trimeric conformation.

Broad SARS-CoV-2 Neutralization by Monoclonal and Bispecific Antibodies Derived from a Gamma-infected Individual.

The worldwide pandemic caused by SARS-CoV-2 has remained a human medical threat due to the continued evolution of multiple variants that acquire resistance to vaccines and prior infection. Therefore, it is imperative to discover monoclonal antibodies (mAbs) that neutralize a broad range of SARS-CoV-2 variants for therapeutic and prophylactic use. A stabilized autologous SARS-CoV-2 spike glycoprotein was used to enrich antigen-specific B cells from an individual with a primary Gamma variant infection.

A public antibody class recognizes an S2 epitope exposed on open conformations of SARS-CoV-2 spike.

Delineating the origins and properties of antibodies elicited by SARS-CoV-2 infection and vaccination is critical for understanding their benefits and potential shortcomings. Therefore, we investigate the SARS-CoV-2 spike (S)-reactive B cell repertoire in unexposed individuals by flow cytometry and single-cell sequencing. We show that ∼82% of SARS-CoV-2 S-reactive B cells harbor a naive phenotype, which represents an unusually high fraction of total human naive B cells (∼0.

Decreased Passive Immunity to Respiratory Viruses through Human Milk during the COVID-19 Pandemic.

Infants may develop severe viral respiratory tract infections because their immune system is still developing in the first months after birth. Human milk provides passive humoral immunity during the first months of life. During the COVID-19 pandemic, circulation of common respiratory viruses was virtually absent due to the preventative measures resulting in reduced maternal exposure.

From affinity selection to kinetic selection in Germinal Centre modelling.

Affinity maturation is an evolutionary process by which the affinity of antibodies (Abs) against specific antigens (Ags) increases through rounds of B-cell proliferation, somatic hypermutation, and positive selection in germinal centres (GC). The positive selection of B cells depends on affinity, but the underlying mechanisms of affinity discrimination and affinity-based selection are not well understood. It has been suggested that selection in GC depends on both rapid binding of B-cell receptors (BcRs) to Ags which is kinetically favourable and tight binding of BcRs to Ags, which is thermodynamically favourable; however, it has not been shown whether a selection bias for kinetic properties is present in the GC.

Influenza A Virus Hemagglutinin Trimer, Head and Stem Proteins Identify and Quantify Different Hemagglutinin-Specific B Cell Subsets in Humans.

Antibody responses against the influenza A virus hemagglutinin (HA)-protein are studied intensively because they can protect against (re)infection. Previous studies have focused on antibodies targeting the head or stem domains, while other possible specificities are often not taken into account. To study such specificities, we developed a diverse set of HA-domain proteins based on an H1N1-like influenza virus strain, including monomeric head and trimeric stem domain, as well as the full HA-trimer.

Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein.

Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a large impact on global health, travel, and economy. Therefore, preventative and therapeutic measures are urgently needed. Here, we isolated monoclonal antibodies from three convalescent coronavirus disease 2019 (COVID-19) patients using a SARS-CoV-2 stabilized prefusion spike protein.

DNA Vaccination by Electroporation Amplifies Broadly Cross-Restricted Public TCR Clonotypes Shared with HIV Controllers.

Rare patients who spontaneously control HIV replication provide a useful model to inform HIV vaccine development. HIV controllers develop particularly efficient antiviral CD4 T cell responses mediated by shared high-affinity TCRs. To determine whether the candidate DNA vaccine ADVAX could induce similar responses, we analyzed Gag-specific primary CD4 T cells from healthy volunteers who received ADVAX DNA by electroporation.

MHC Class II Tetramer Labeling of Human Primary CD4 T Cells from HIV Infected Patients.

Major Histocompatibility Complex (MHC) tetramers have been used for two decades to detect, isolate and characterize T cells specific for various pathogens and tumor antigens. In the context of Human Immunodeficiency Virus (HIV) infection, antigen-specific CD8 T cells have been extensively studied , as they can be readily detected by HIV peptide-loaded MHC class I tetramers. In contrast, the detection of HIV-specific CD4 T cells has proven more challenging, due to the intrinsically lower clonal expansion rates of CD4 T cells, and to the preferential depletion of HIV-specific CD4 T cells in the course of HIV infection.