No abstract

Adjuvants are critical for improving the quality and magnitude of adaptive immune responses to vaccination. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines have shown great efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanism of action of this vaccine platform is not well-characterized. Using influenza virus and SARS-CoV-2 mRNA and protein subunit vaccines, we demonstrated that our LNP formulation has intrinsic adjuvant activity that promotes induction of strong T follicular helper cell, germinal center B cell, long-lived plasma cell, and memory B cell responses that are associated with durable and protective antibodies in mice. Comparative experiments demonstrated that this LNP formulation outperformed a widely used MF59-like adjuvant, AddaVax. The adjuvant activity of the LNP relies on the ionizable lipid component and on IL-6 cytokine induction but not on MyD88-or MAVS-dependent sensing of LNPs. Our study identified LNPs as a versatile adjuvant that enhances the efficacy of traditional and next-generation vaccine platforms.

Highlights d T-bet + B cells are a separate and durable memory subset in mice and humans d T-bet hi memory B cells are absent from the lymphatic circulation d Influenza-specific T-bet hi memory B cells are spleen-resident in mice d B cell-intrinsic T-bet is required for >90% of flu-and HA stalkspecific antibodies

The T-box transcription factors T-bet and Eomesodermin (Eomes) have been well defined as key drivers of immune cell development and cytolytic function. While the majority of studies have defined the roles of these factors in the context of murine T-cells, recent results have revealed that T-bet, and possibly Eomes, are expressed in other immune cell subsets. To date, the expression patterns of these factors in subsets of human peripheral blood mononuclear cells beyond T-cells remain relatively uncharacterized. In this study, we used multiparametric flow cytometry to characterize T-bet and Eomes expression in major human blood cell subsets, including total CD4+ and CD8+ T-cells, γδ T-cells, invariant NKT cells, natural killer cells, B-cells, and dendritic cells. Our studies identified novel cell subsets that express T-bet and Eomes and raise implications for their possible functions in the context of other human immune cell subsets besides their well-known roles in T-cells.

Summary B cells expressing the transcription factor T‐bet have emerged as participants in a number of protective and pathogenic immune responses. T‐bet+ B cells characteristically differentiate in response to combined Toll‐like receptor and cytokine signaling, contribute to protective immunity against intracellular pathogens via IgG2a/c production and antibody‐independent mechanisms, and are prone to produce autoantibodies. Despite recent advances, a number of questions remain regarding the basic biology of T‐bet+ B cells and their functional niche within the immune system. Herein, we review the discovery and defining characteristics of the T‐bet+ B cell subset in both mice and humans. We further discuss their origins, the basis for their persistence, and their potential fate in vivo. Evidence indicates that T‐bet+ B cells represent a distinct, germinal center‐derived memory population that may serve as an important therapeutic target for the improvement of humoral immunity and prevention of autoimmunity.

Objective: To describe the case characteristics and outcomes of patients hospitalised with pandemic (H1N1) 2009 influenza infection during the first 2 months of the epidemic. Design, participants and setting: Prospective case series of 112 patients admitted to seven hospitals in Melbourne with laboratory‐confirmed pandemic (H1N1) 2009 influenza between 1 May and 17 July 2009. Main outcome measures: Details of case characteristics, risk factors for severe disease, treatment and clinical course. Results: Of 112 hospitalised patients, most presented with cough (88%) and/or fever (82%), but several (4%) had neither symptom. A quarter of female patients (15) were pregnant or in the post‐partum period. Patients presenting with multifocal changes on chest x‐ray had significantly longer hospital lengths of stay, and were more likely to require intensive care unit admission. Thirty patients required admission to an intensive care unit, and three died during their acute illness. The median length of intensive care admission was 10.5 days (interquartile range, 5–16 days). Conclusions: This study highlights risk factors for severe disease, particularly pregnancy. Clinical and public health planning for upcoming influenza seasons should take into account the spectrum and severity of clinical infection demonstrated in this report, and the need to concentrate resources effectively in high‐risk patient groups.

The SARS-CoV-2 pandemic has affected more than 185 million people worldwide resulting in over 4 million deaths. To contain the pandemic, there is a continued need for safe vaccines that provide durable protection at low and scalable doses and are easily delivered. Here, AAVCOVID-1, an adeno-associated viral (AAV), Spike gene-based vaccine candidate demonstrates potent immunogenicity in mouse and nonhuman primates following a single injection and confers complete protection from SARS-CoV-2 challenge in macaques. Peak neutralizing antibody titers are sustained at 1 year and complemented by functional memory T-cell responses. The AAVCOVID vector has no relevant pre-existing immunity in humans, does not elicit cross-reactivity to common AAVs used in gene therapy, and its persistence and expression wanes following injection. The single, low dose requirement, high yield manufacturability, and 1-month stability for storage at room-temperature may make this technology well-suited to support effective immunization campaigns for emerging pathogens on a global scale.

T-bet-expressing B cells, first identified as perpetuators of autoimmunity, were recently shown to be critical for murine antiviral responses. While their role in human viral infections remains unclear, B cells expressing T-bet or demonstrating a related phenotype have been described in individuals chronically infected with HIV or HCV, suggesting these cells represent a component of human antiviral responses. In this review, we discuss the induction of T-bet in B cells following both HIV and HCV infections, the factors driving T-bet+ B cell expansions, T-bet’s relationship to atypical memory B cells, and the consequences of T-bet induction. We propose potential antiviral roles for T-bet+ B cells and discuss whether this population poses any utility to the HIV and HCV immune responses.