Lipid Gb3 as adjuvant for anti-viral vaccination

Background

• Adjuvants are vaccine components added to enhance the magnitude, breadth, and durability of response.
• Selection of appropriate adjuvants requires improved understanding of immune responses to pathogens/antigens by B cells (white blood cells). B cells develop in the bone marrow and are responsible for making antibodies, functioning as antigen-presenting cells, and thus are common vaccine targets.
• Germinal centers (GC) are sites that form within B cell follicles upon infection or immunization that are vital for B cell antibody maturation, i.e. the process by which antibodies with high affinity capable of eliciting strong secondary immune responses evolve from lower-affinity precursors through random mutation and targeted selection.
• However, key determinants of GC B cell clonal expansion, competition, and selection of antibodies with high affinity and breadth are not fully understood. Thus, improved understanding of B cell stimulatory and co-stimulatory molecules like CD19 can help in development of vaccine adjuvants that can enhance vaccine potency.

Technology Overview

• The current invention describes how binding of the lipid molecule Globotriaosylceramide (Gb3) to the CD19 protein on B cells activates B cell receptor downstream signaling, which in turn fosters the GC reaction and selection of high-affinity antibodies.
• Gb3 supports the surface expression of MHC-II levels on B cells, which facilitates the activation of TFH cells. Through this mechanism, Gb3 amplifies antibody diversity by promoting selection of B cell clones reactive with subdominant epitopes. 
• Gb3 also helps to break the immunodominance of epitopes, i.e. clusters of amino acids on antigens that are recognized by secreted antibodies or B cell receptors to elicit an immune response, to select broadly neutralizing antibodies with specific induction of IgG2c immunoglobulins.
• Using genetic mouse models, the researchers demonstrate how Gb3-deficient mice had poor anti-viral immunity, and Gb3 abundance on GC B cells resulted in a broader selection of antibodies which were protective against infection with heterotypic influenza strains.

Applications

• Gb3 or its analogs can serve as an adjuvant for anti-viral, and cancer vaccinations.
• Gb3 and its interaction with CD19 and MHC-II as an active mechanism in human GC B cells can eventually be targeted for vaccination for a broad range of pathological inflammatory disorders, or chronic disorders.

Advantages

• As Gb3 can help guide GC formation and selection of high-affinity as well as broadly neutralizing antibodies, it has the potential to protect against a wide range of viral infections and it might work as an adjuvant in cancer vaccination.

Publications

The lipid globotriaosylceramide promotes germinal center B cell responses and antiviral immunity. Science. 2024 Feb 16; 383(6684):eadg0564.