Design, structure and plasma binding of ancestral ß-CoV scaffold antigens.

We report the application of ancestral sequence reconstruction on coronavirus spike protein, resulting in stable and highly soluble ancestral scaffold antigens (AnSAs). The AnSAs interact with plasma of patients recovered from COVID-19 but do not bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Cryo-EM analysis of the AnSAs yield high resolution structures (2.6-2.8 Å) indicating a closed pre-fusion conformation in which all three receptor-binding domains (RBDs) are facing downwards. The structures reveal an intricate hydrogen-bonding network mediated by well-resolved loops, both within and across monomers, tethering the N-terminal domain and RBD together. We show that AnSA-5 can induce and boost a broad-spectrum immune response against the wild-type RBD as well as circulating variants of concern in an immune organoid model derived from tonsils. Finally, we highlight how AnSAs are potent scaffolds by replacing the ancestral RBD with the wild-type sequence, which restores ACE2 binding and increases the interaction with convalescent plasma.

Transcriptional regulation of B cell class-switch recombination: the role in development of noninfectious complications.

INTRODUCTION: The process of immunoglobulin class switch recombination (CSR) occurs in secondary lymphoid organs. This highly regulated process is essential for the development of different antibody isotype maturation and long-life memory/plasma cell generation. Patients with impaired CSR present heterogeneous noninfectious complications. AREAS COVERED: We provide an overview of recent advancements in the tight regulation of B cells before and during the CSR at different levels of cytokine stimulations, intracellular signaling, transcription-factor activation, gene transcription, and epigenetic controls. EXPERT OPINION: Besides recurrent infections which result from the lack of production of class-switched immunoglobulins, intrinsic B cell signaling pathways and regulatory component defects have distinct roles in other immune-related clinical manifestations including autoimmunity, atopy, lymphoproliferation, and cancer.

Heterologous immunization with inactivated vaccine followed by mRNA-booster elicits strong immunity against SARS-CoV-2 Omicron variant.

The recent emergence of the Omicron variant has raised concerns on vaccine efficacy and the urgent need to study more efficient vaccination strategies. Here we observed that an mRNA vaccine booster in individuals vaccinated with two doses of inactivated vaccine significantly increased the plasma level of specific antibodies that bind to the receptor-binding domain (RBD) or the spike (S) ectodomain (S1 + S2) of both the G614 and the Omicron variants, compared to two doses of homologous inactivated vaccine. The level of RBD- and S-specific IgG antibodies and virus neutralization titers against variants of concern in the heterologous vaccination group were similar to that in individuals receiving three doses of homologous mRNA-vaccine or a boost of mRNA vaccine after infection, but markedly higher than that in individuals receiving three doses of a homologous inactivated vaccine. This heterologous vaccination regime furthermore significantly enhanced the RBD-specific memory B cell response and S1-specific T cell response, compared to two or three doses of homologous inactivated vaccine. Our study demonstrates that mRNA vaccine booster in individuals vaccinated with inactivated vaccines can be highly beneficial, as it markedly increases the humoral and cellular immune responses against the virus, including the Omicron variant.

Immunity to SARS-CoV-2 up to 15 months after infection.

Information concerning the longevity of immunity to SARS-CoV-2 following natural infection may have considerable implications for durability of immunity induced by vaccines. Here, we monitored the SARS-CoV-2 specific immune response in COVID-19 patients followed up to 15 months after symptoms onset. Following a peak at day 15-28 postinfection, the IgG antibody response and plasma neutralizing titers gradually decreased over time but stabilized after 6 months. Compared to G614, plasma neutralizing titers were more than 8-fold lower against variants Beta, Gamma, and Delta. SARS-CoV-2-specific memory B and T cells persisted in the majority of patients up to 15 months although a significant decrease in specific T cells, but not B cells, was observed between 6 and 15 months. Antiviral specific immunity, especially memory B cells in COVID-19 convalescent patients, is long-lasting, but some variants of concern may at least partially escape the neutralizing activity of plasma antibodies.

Independent association of low IFNλ1 gene expression and type I IFN score/IFNλ1 ratio with obstetric manifestations and triple antiphospholipid antibody positivity in primary antiphospholipid syndrome.

Recent data suggest an important role of type I interferons (IFN) in antiphospholipid syndrome (APS). Here we aimed to evaluate the interplay of type I and type III (or IFNλs) IFNs in APS and potential clinical and serological associations. Our findings suggest that patients with primary APS (PAPS) and systemic lupus erythematosus (SLE)/APS displayed increased type I IFN scores but decreased IFNλ1 gene expression levels compared to healthy individuals, as assessed with real-time qPCR analysis in isolated peripheral blood mononuclear cells (PBMCs). Type I IFN score/IFNλ1 ratio was remarkably higher in patients with PAPS and SLE/APS as well as in SLE patients with or without antiphospholipid antibodies (aPL) vs controls. In conclusion, our results reveal an association between low IFNλ1 expression and obstetric APS. Moreover, the type I IFN score/IFNλ1 ratio seems to be a potential marker of high risk APS given its associations with triple aPL positivity.

Lambda interferons in immunity and autoimmunity.

Type I IFNs are well known players in immunity and autoimmunity. They induce potent innate and adaptive immune responses essential for mediating host defenses against viral and bacterial infections but also driving inflammation during chronic inflammatory and autoimmune diseases. Lambda interferons (IFNλs) or type III IFNs, on the other hand, comprise a relatively new family of cytokines sharing homology and functional resemblance with type I IFNs but whose spectrum of activities remains poorly understood. Although IFNλs induce antiviral responses similar to type I IFNs, their restricted pattern of expression suggested that may have more specialized functions at specific body sites such as barrier surfaces. However, recent developments in the field have revealed broader roles of IFNλs in immunity against a diverse range of pathogens including viral, bacterial and fungal infections, and have highlighted unique non-redundant functions of IFNλs that cannot be compensated by type I IFNs. They have also positioned IFNλs as a non-inflammatory or immunoregulatory form of IFNs that possesses the antimicrobial functions of type I IFNs but lacks their pro-inflammatory effects, playing a crucial role in the fine tuning of immune defenses for optimal host protection and minimal host damage. Beyond infections, IFNλs are also emerging as important players in immunity against cancer and autoimmunity, with several studies now demonstrating up-regulation of these molecules at disease sites, and functional involvement in experimental animal models. Here, we critically assess recent advances in our understanding of the IFNλ biology, with emphasis to their emerging roles in cancer and autoimmune diseases, and discuss their potential therapeutic implications.