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Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcμR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis., Competing Interests: Declaration of interests C.Q.S. and A.D. are inventors of a patent application that describes the use of engineered proteins as potent complement regulators for therapeutic applications. C.Q.S. received honoraria for speaking at symposia organized by Alexion Pharmaceuticals and Swedish Orphan Biovitrum (Sobi). M.I. participates in advisory boards/consultantship for Asher Biotherapeutics, GentiBio, Clexio Biosciences, Sybilla Biotech, BlueJay Therapeutics, Bristol Myers Squibb, and Aligos Therapeutics and receives funding from Asher Biotherapeutics and VIR Biotechnology., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite the robust immunogenicity of SARS-CoV-2 mRNA vaccines, emerging data have revealed enhanced neutralizing antibody and T cell cross-reactivity among individuals that previously experienced COVID-19, pointing to a hybrid immune advantage with infection-associated immune priming. Beyond neutralizing antibodies and T cell immunity, mounting data point to a potential role for additional antibody effector functions, including opsinophagocytic activity, in the resolution of symptomatic COVID-19. Whether hybrid immunity modifies the Fc-effector profile of the mRNA vaccine-induced immune response remains incompletely understood. Thus, here we profiled the SARS-CoV-2 specific humoral immune response in a group of individuals with and without prior COVID-19. As expected, hybrid Spike-specific antibody titers were enhanced following the primary dose of the mRNA vaccine but were similar to those achieved by naive vaccinees after the second mRNA vaccine dose. Conversely, Spike-specific vaccine-induced Fc-receptor binding antibody levels were higher after the primary immunization in individuals with prior COVID-19 and remained higher following the second dose compared to those in naive individuals, suggestive of a selective improvement in the quality, rather than the quantity, of the hybrid humoral immune response. Thus, while the magnitude of antibody titers alone may suggest that any two antigen exposures-either hybrid immunity or two doses of vaccine alone-represent a comparable prime/boost immunologic education, we find that hybrid immunity offers a qualitatively improved antibody response able to better leverage Fc-effector functions against conserved regions of the virus. IMPORTANCE Recent data indicates improved immunity to SARS-CoV-2 in individuals who experience a combination of two mRNA vaccine doses and infection, "hybrid immunity," compared to individuals who receive vaccination or experience infection alone. While previous infection accelerates the vaccine-induced immune response following the first dose of mRNA vaccination, subsequent doses demonstrate negligible increases in antibody titers or T cell immunity. Here, using systems serology, we observed a unique antibody profile induced by hybrid immunity, marked by the unique induction of robust Fc-recruiting antibodies directed at the conserved region of the viral Spike antigen, the S2-domain, induced at lower levels in individuals who only received mRNA vaccination. Thus, hybrid immunity clearly redirects vaccine-induced immunodominance, resulting in the induction of a robust functional humoral immune response to the most highly conserved region of the SARS-CoV-2 Spike antigen, which may be key to protection against existing and emerging variants of concern. Thus, next-generation vaccines able to mimic hybrid immunity and drive a balanced response to conserved regions of the Spike antigen may confer enhanced protection against disease.

Healthy immune responses require efficient protection without excessive inflammation. Recent discoveries on the degree of fucosylation of a human N-linked glycan at a conserved site in the immunoglobulin IgG-Fc domain might add an additional regulatory layer to adaptive humoral immunity. Specifically, afucosylation of IgG-Fc enhances the interaction of IgG with FcγRIII and thereby its activity. Although plasma IgG is generally fucosylated, afucosylated IgG is raised in responses to enveloped viruses and Plasmodium falciparum proteins expressed on infected erythrocytes, as well as during alloimmune responses. Moreover, while afucosylation can exacerbate some infectious diseases (e.g., COVID-19), it also correlates with traits of protective immunity against malaria and HIV-1. Herein we discuss the implications of IgG afucosylation for health and disease, as well as for vaccination., Competing Interests: Declaration of interests The authors declare no conflicts of interests., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The rapid spread of SARS-CoV-2 has induced a global pandemic. Severe forms of COVID-19 are characterized by dysregulated immune response and "cytokine storm". The role of IgG and IgM antibodies in COVID-19 pathology is reasonably well studied, whereas IgA is neglected. To improve clinical outcome of patients, immune modulatory drugs appear to be beneficial. Such drugs include intravenous immunoglobulin preparations, which were successfully tested in severe COVID-19 patients. Here we established a versatile in vitro model to study inflammatory as well as anti-inflammatory processes by therapeutic human immunoglobulins. We dissect the inflammatory activation on neutrophil-like HL60 cells, using an immune complex consisting of latex beads coated with spike protein of SARS-CoV-2 and opsonized with specific immunoglobulins from convalescent plasma. Our data clarifies the role of Fc-receptor-dependent phagocytosis via IgA-FcαRI and IgG-FcγR for COVID-19 disease followed by cytokine release. We show that COVID-19 associated inflammation could be reduced by addition of human immunoglobulin preparations (IVIG and trimodulin), while trimodulin elicits stronger immune modulation by more powerful ITAMi signaling. Besides IgG, the IgA component of trimodulin in particular, is of functional relevance for immune modulation in this assay setup, highlighting the need to study IgA mediated immune response., Competing Interests: All authors are employees of Biotest AG, Dreieich, Germany. The authors declare that this study received funding from Biotest. The funder had the following involvement in the study: study design, interpretation of data, the writing of this article and the decision to submit it for publication., (Copyright © 2021 Bohländer, Riehl, Weißmüller, Gutscher, Schüttrumpf and Faust.)

Background. Antibody-Dependent Enhancement is an alternative route for virus entry into the target cells. In this process, cross-reactive antiviral antibodies improve the access of the virus to cells through interaction with specific receptors (complement receptors and Fc receptor on the cell surface), which leads to worsening of the infection. This phenomenon has been widely studied in dengue fever, however, at present its contribution to the pathogenesis of other viral infections remains poorly understood.Results. It has been shown that the development of Antibody-Dependent Enhancement in dengue fever occurs with a secondary infection, in the case of infection with a different serotype of the virus from the primary infection. Antibodies produced during a primary infection are not able to completely neutralize another serotype of the virus, but instead bind to the virus and Fc receptors on cells, which contributes to increased penetration of the virus into these cells, increased replication and the development of a "cytokine storm" leading to increased capillary leakage and the development of hemorrhagic form of dengue fever. It has been noted that the development of Antibody-Dependent Enhancement in coronavirus infections in animals seriously aggravates the course of the disease, however, the contribution of this syndrome to the COVID-19 clinic manifestations is poorly understood, while the constant change in the dominant virus genetic variant creates prerequisites for re-infection. Numerous studies of the Antibody-Dependent Enhancement made it possible to describe the possible mechanisms of its occurrence and to determine the necessary conditions for its development.Conclusion. Of particular concern is the phenomenon of a vaccine-associated enhancement of viral infection, which leads to a worsening of the viral infection with the formation of non-protective antibodies in patients after immunization. The introduction of vector vaccines into clinical practice has led to a significant increase in the risk of breakthrough infections and severe forms, which imposes restrictions on the use of these vaccines, and creates increased requirements for their development and testing.

Summary: Recently approved vaccines have shown remarkable efficacy in limiting SARS-CoV-2-associated disease. However, with the variety of vaccines, immunization strategies, and waning antibody titers, defining the correlates of immunity across a spectrum of antibody titers is urgently required. Thus, we profiled the humoral immune response in a cohort of non-human primates immunized with a recombinant SARS-CoV-2 spike glycoprotein (NVX-CoV2373) at two doses, administered as a single- or two-dose regimen. Both antigen dose and boosting significantly altered neutralization titers and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were associated with distinct levels of protection in the upper and lower respiratory tract. Moreover, NVX-CoV2373 elicited antibodies that functionally targeted emerging SARS-CoV-2 variants. Collectively, the data presented here suggest that a single dose may prevent disease via combined Fc/Fab functions but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants.