Evaluation of waning of IgG antibody responses after rVSVΔG-ZEBOV-GP and Ad26.ZEBOV, MVA-BN-Filo Ebola virus disease vaccines: a modelling study from the PREVAC randomized trial.

rVSVΔG-ZEBOV-GP and Ad26.ZEBOV, MVA-BN-Filo are WHO-prequalified vaccination regimens against Ebola virus disease (EVD). Challenges associated with measuring long-term clinical protection warrant the evaluation of immune response kinetics after vaccination.

Harmonization of Vaccine Ligand Binding Assays Validation.

The urgency and importance of organizing a global effort to harmonize clinical assay validation specific to the vaccine industry was identified during the drafting of the 2020 White Paper in Bioanalysis due to the lack of clarity and regulatory guidance/guidelines in vaccine immunoassay validation. Indeed, the Workshop on Recent Issues in Bioanalysis (WRIB) issues the White Paper in Bioanalysis yearly, which is one of the high-profile articles of the Journal focused on detailed discussions and recommendations on vaccine assay validation. Since 2017, participation in the WRIB working groups by vaccine assay validation experts and regulators has rapidly increased due to its unique format where industry leaders and regulators can meet and exchange ideas on topics of interest to both groups.

2022 White Paper on Recent Issues in Bioanalysis: Enzyme Assay Validation, BAV for Primary End Points, Vaccine Functional Assays, Cytometry in Tissue, LBA in Rare Matrices, Complex NAb Assays, Spectral Cytometry, Endogenous Analytes, Extracellular Vesicles - Recommendations on Biomarkers/CDx, Flow Cytometry, Ligand-Binding Assays Development & Validation; Emerging Technologies; Critical Reagents Deep Characterization.

The 16 Workshop on Recent Issues in Bioanalysis (16 WRIB) took place in Atlanta, GA, USA on September 26-30, 2022. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 16 WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.

Non-human primate to human immunobridging demonstrates a protective effect of Ad26.ZEBOV, MVA-BN-Filo vaccine against Ebola.

Without clinical efficacy data, vaccine protective effect may be extrapolated from animals to humans using an immunologic marker that correlates with protection in animals. This immunobridging approach was used for the two-dose Ebola vaccine regimen Ad26.ZEBOV, MVA-BN-Filo.

First-in-human study to evaluate safety, tolerability, and immunogenicity of heterologous regimens using the multivalent filovirus vaccines Ad26.Filo and MVA-BN-Filo administered in different sequences and schedules: A randomized, controlled study.

Background: Though clinically similar, Ebola virus disease and Marburg virus disease are caused by different viruses. Of the 30 documented outbreaks of these diseases in sub-Saharan Africa, eight were major outbreaks (≥200 cases; five caused by Zaire ebolavirus [EBOV], two by Sudan ebolavirus [SUDV], and one by Marburg virus [MARV]). Our purpose is to develop a multivalent vaccine regimen protecting against each of these filoviruses.

Durable natural killer cell responses after heterologous two-dose Ebola vaccination.

Natural killer (NK) cells are implicated among immune effectors after vaccination against viral pathogens, including Ebola virus. The two-dose heterologous Ebola virus vaccine regimen, adenovirus type 26.ZEBOV followed by modified vaccinia Ankara-BN-Filo (EBOVAC2 consortium, EU Innovative Medicines Initiative), induces NK cell activation and anti-Ebola glycoprotein (GP) antibody-dependent NK cell activation post-dose 1, which is further elevated post-dose 2.

Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine.

Background: Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.

Nonhuman primate to human immunobridging to infer the protective effect of an Ebola virus vaccine candidate.

It has been proven challenging to conduct traditional efficacy trials for Ebola virus (EBOV) vaccines. In the absence of efficacy data, immunobridging is an approach to infer the likelihood of a vaccine protective effect, by translating vaccine immunogenicity in humans to a protective effect, using the relationship between vaccine immunogenicity and the desired outcome in a suitable animal model. We here propose to infer the protective effect of the Ad26.

Ebola virus glycoprotein stimulates IL-18-dependent natural killer cell responses.

BACKGROUNDNK cells are activated by innate cytokines and viral ligands to kill virus-infected cells. These functions are enhanced during secondary immune responses and after vaccination by synergy with effector T cells and virus-specific antibodies. In human Ebola virus infection, clinical outcome is strongly associated with the initial innate cytokine response, but the role of NK cells has not been thoroughly examined.

Antibody-Dependent Natural Killer Cell Activation After Ebola Vaccination.

Background: Antibody Fc-mediated functions, such as antibody-dependent cellular cytotoxicity, contribute to vaccine-induced protection against viral infections. Fc-mediated function of anti-Ebola glycoprotein (GP) antibodies suggest that Fc-dependent activation of effector cells, including natural killer (NK) cells, could play a role in vaccination against Ebola virus disease.

Methods: We analyzed the effect on primary human NK cell activation of anti-Ebola GP antibody in the serum of United Kingdom-based volunteers vaccinated with the novel 2-dose heterologous adenovirus type 26.

Breach of autoreactive B cell tolerance by post-translationally modified proteins.

Objectives: Over 50% of patients with rheumatoid arthritis (RA) harbour a variety of anti-modified protein antibodies (AMPA) against different post-translationally modified (PTM) proteins, including anti-carbamylated protein (anti-CarP) antibodies. At present, it is unknown how AMPA are generated and how autoreactive B cell responses against PTM proteins are induced. Here we studied whether PTM foreign antigens can breach B cell tolerance towards PTM self-proteins.

Mast cell depletion in the preclinical phase of collagen-induced arthritis reduces clinical outcome by lowering the inflammatory cytokine profile.

Background: Rheumatoid arthritis (RA) is a multifactorial autoimmune disease, which is characterized by inflammation of synovial joints leading to the destruction of cartilage and bone. Infiltrating mast cells can be found within the inflamed synovial tissue, however their role in disease pathogenesis is unclear. Therefore we have studied the role of mast cells during different phases of experimental arthritis.

Reduced TCR-dependent activation through citrullination of a T-cell epitope enhances Th17 development by disruption of the STAT3/5 balance.

Citrullination is a post-translational modification of arginine that commonly occurs in inflammatory tissues. Because T-cell receptor (TCR) signal quantity and quality can regulate T-cell differentiation, citrullination within a T-cell epitope has potential implications for T-cell effector function. Here, we investigated how citrullination of an immunedominant T-cell epitope affected Th17 development.

Abatacept decreases disease activity in a absence of CD4(+) T cells in a collagen-induced arthritis model.

Introduction: Abatacept is a fusion protein of human cytotoxic T-lymphocyte-associated protein (CTLA)-4 and the Fc portion of human immunoglobulin G1 (IgG1). It is believed to be effective in the treatment of rheumatoid arthritis by inhibiting costimulation of T cells via blocking CD28-B7 interactions as CTLA-4 binds to both B7.1 (CD80) and B7.

Antibodies specific for carbamylated proteins precede the onset of clinical symptoms in mice with collagen induced arthritis.

Objective: The immune response to post-translationally modified antigens is a key characteristic of rheumatoid arthritis. Carbamylation is such a posttranslational modification. Recently, we demonstrated that autoantibodies recognizing carbamylated proteins are present in sera of rheumatoid arthritis.

Activation of human basophils by combined toll-like receptor- and FcεRI-triggering can promote Th2 skewing of naive T helper cells.

Basophils are mostly known for their involvement in allergic reactions. Recent studies in mice indicate a role for basophils in the induction of adaptive immunity, especially T helper 2 (Th2) responses. Therefore, it would be highly important to understand how basophils respond to pathogen-associated molecules, such as ligands for toll-like receptors (TLRs), and if the basophils could promote Th2 responses via these stimuli.

IL-21 enhances the activity of the TLR-MyD88-STAT3 pathway but not the classical TLR-MyD88-NF-κB pathway in human B cells to boost antibody production.

Both IL-21 and TLR agonists are important regulators of B cell responses, and the combination of IL-21 and TLR stimulation results in increased Ab production. However, it is not clear yet how IL-21 interacts with TLR signaling in B cells. In this study, we show that IL-21 enhances TLR-induced IgG production, whereas it has no effect on TLR-induced IL-6 production by human B cell cultures.

DX5+ CD4+ T cells modulate CD4+ T-cell response via inhibition of IL-12 production by DCs.

DX5(+) CD4(+) T cells have been shown to dampen collagen-induced arthritis and delayed-type hypersensitivity reactions in mice. These cells are also potent modulators of T-helper cell responses through direct effects on CD4(+) T cells in an IL-4 dependent manner. To further characterize this T-cell population, we studied their effect on DCs and the potential consequences on T-cell activation.

The choice of adjuvant determines the cytokine profile of T cells in proteoglycan-induced arthritis but does not influence disease severity.

Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic inflammation of the synovial joints. Collagen-induced arthritis (CIA) and proteoglycan-induced arthritis (PGIA) are mouse models of inflammatory arthritis; CIA is a T helper type 17 (Th17) -dependent disease that is induced with antigen in complete Freund's adjuvant, whereas PGIA is Th1-mediated and is induced using antigen in dimethyldioctadecyl-ammonium bromide (DDA) as an adjuvant. To investigate whether the type of adjuvant determines the cytokine profile of the pathogenic T cells, we have compared the effect of CFA and DDA on T-cell responses in a single arthritis model.

Developing tolerogenic dendritic cell therapy for rheumatoid arthritis: what can we learn from mouse models?

One of the therapeutic strategies under development for the treatment of rheumatoid arthritis is based on reinstating immune tolerance by vaccination with autologous dendritic cells with potent tolerogenic function. These tolerogenic dendritic cells (TolDC) can be generated ex vivo and have beneficial therapeutic effects in animal models of arthritis. Although experimental animal models have been instrumental in the development of this novel immunotherapeutic tool, several outstanding questions regarding the application of TolDC remain to be addressed.

Therapeutic effect of tolerogenic dendritic cells in established collagen-induced arthritis is associated with a reduction in Th17 responses.

Objective: Tolerogenic dendritic cells (DCs) are antigen-presenting cells with an immunosuppressive function. They are a promising immunotherapeutic tool for the attenuation of pathogenic T cell responses in autoimmune arthritis. The aims of this study were to determine the therapeutic action of tolerogenic DCs in a type II collagen-induced arthritis model and to investigate their effects on Th17 cells and other T cell subsets in mice with established arthritis.

Low-strength T-cell activation promotes Th17 responses.

We show that the strength of T-cell stimulation determines the capability of human CD4(+) T cells to become interleukin-17 (IL-17) producers. CD4(+) T cells received either high- (THi) or low (TLo)-strength stimulation via anti-CD3/CD28 beads or dendritic cells pulsed with superantigen in the presence of pro-Th17 cytokines IL-1β, transforming growth factor β, and IL-23. We found that TLo, but not THi, stimulation profoundly promoted Th17 responses by enhancing both the relative proportion and total number of Th17 cells.

Intrahepatic regulatory T cells are phenotypically distinct from their peripheral counterparts in chronic HBV patients.

Peripheral blood CD4+CD25+ regulatory T cells (Treg) prevent the development of strong HBV-specific T cell responses in vitro. In this study, we examined the phenotype of FoxP3+ regulatory T cells in the liver of patients with a chronic HBV infection. We showed that the liver contained a population of CD4+FoxP3+ cells that did not express CD25, while these cells were absent from peripheral blood.

Induction of regulatory T-cells and interleukin-10-producing cells in non-responders to pegylated interferon-alpha therapy for chronic hepatitis B.

Background: Treatment with interferon-alpha (IFN-alpha) leads to a response in only a minority of patients with chronic hepatitis B virus (HBV) infection, but the reasons for this are poorly understood. It was recently shown that in patients with chronic HBV infection, CD4+CD25+ regulatory T-cells (Treg) can suppress the HBV-specific immune response. We aimed to investigate whether in non-responders to IFN-alpha therapy Treg contribute to treatment failure by downregulating the HBV-specific T-cell responses.