Vaccines, Immunization & B2B

Biography

Biography: Sudhir Paul

Abstract

Our studies suggest covalently reactive electrophilic immunogens (E-immunogens) as candidate vaccines for microbes that use superantigen epitopes to bind the immunoglobulin framework regions (FRs) expressed as B cell receptors (BCRs), thereby suppressing the adaptive antibody response needed for protection against infection. The superantigenic gp120 residues 421-433 (C^LIN) bind the CD4 receptor and are essential for establishment of HIV-1 infection. Consistent with C^LIN designation as a superantigen, non-infected humans innately produce IgM+ BCRs and secreted IgMs with FRs that recognized C^LIN and catalyzed the degradation of gp120 monomers. However, only the C^LIN-directed variable (V)-domains of IgGs/IgAs, not IgMs, bound intact HIV and neutralized genetically diverse HIV strains, suggesting that IgM→IgG/IgA class-switching (CS) is a prerequisite for effective HIV vaccination. Study of infected humans and gp120 immunized mice indicated that noncovalent C^LIN-BCR binding selectively suppresses IgM→IgG CS of C^LIN-directed antibodies. The use of C^LIN-containing E-immunogens that bound nucleophilic BCRs covalently corrected the CS defect in animals. Upregulated IgG synthesis appears to result from high energy covalent FR binding to E-C^LIN, together with CDR binding to a neighboring epitope. The C^LIN-directed IgGs neutralized HIV subtype A/B/C/D/AE infection of cultured lymphocytes/macrophages and suppressed HIV infection in immunodeficient mice. A further advantage was improved IgG neutralization potency due to E-immunogen driven acquisition of catalytic and irreversible HIV binding activities. The foregoing E-vaccine principles to correct antibody specificity and improve effector function will likely be useful for other microbes that depend on superantigens to establish infection, e.g., Staphylococcus aureus.