Minimal determinants for lifelong antiviral antibody responses in BALB/c mice from a single exposure to virus-like immunogens at low doses

Abstract

Class-switched neutralizing antibody production is rapidly induced upon many viral infections and often long-lived, but the underlying mechanisms remain incompletely understood. Here we show that several features of this antibody response can be reconstituted by synthetic virus-like structures containing minimal, highly purified biochemical ingredients commonly found in enveloped viruses, and without viral replication or any other adjuvants. These findings reveal a shared mechanism for the production of neutralizing antibodies upon viral infection. High epitope density is capable but not necessary for driving antibody secretion. Instead, even a few molecules of surface antigen, when combined with nucleic acids within these structures, can trigger strong antiviral IgG production. As a result, B cells integrate both signals from individual viral particulate antigens to initiate a neutralizing IgG response.

Molecular basis for potent B cell responses to antigen displayed on particles of viral size

“…Since pHEL readily drives highly robust NF-κB activation relative to soluble Ag, we hypothesized that Ag displayed on particles of viral size might mimic co-stimulation and bypass the requirement for T cell help. Indeed, immunization with pHEL is sufficient to produce Ab response in the absence of T cell help and without adjuvant (biorxiv preprint 2023) 59 . We therefore stimulated B cells with either sHEL or pHEL in the presence or absence of CD40 ligation.…”

“…We identify a role for inhibitory coreceptors that confers potency to such particles independent of avidity. Addressed in independent work (biorxiv preprint 2023) 59 is understanding how nucleic acid delivered by SVLS or viruses activate B cells synergistically 85–87 . Our data suggests that mature B cells are intrinsically ‘built’ as a sensor for virus-like supramolecular structures and poised to mount rapid, potent, and initially T-independent responses to viral threats.…”