Innate immunity and training to subvert original antigenic sin by the humoral immune response

Originally defined in the context of influenza vaccines by Thomas Francis Jr. in the late 1950s, original antigenic sin (OAS) refers to the tendency of the immune system to preferentially recall B cell memory against primary antigen after secondary exposure to different but related antigen. This competes with the elicitation of <i>de novo</i> antibodies by lowering the frequency of antigen reception by the naïve B cell lymphocyte pool residing within secondary lymphoid organs. Consequently, OAS imposes a 'primary addiction' that modulates the target epitope specificity of the secondary antibody response and has wide-reaching consequences for vaccines that require seasonal updating, including influenza and SARS-CoV-2. Rationally designed vaccines that preferentially stimulate the production of <i>de novo</i> antibodies rather than those derived from recalled B cell memory are of central interest, particularly for universal vaccine formulations tasked with directing robust humoral immunity against these viruses which, due to their ongoing evolution, have 'resisted' conventional vaccine approaches. Largely absent from this discussion is an integrated evaluation of what Janeway famously called 'the immunologists dirty secret', that humoral immune reactions require stimulation by the innate immune system. In this perspective piece, we present a hypothesis that innate immune cells and trained immunity, a collective term for the epigenetic reprogramming that enhances responsiveness upon re-stimulation, provides a template for promoting <i>de novo</i> expansion of the naïve B cell repertoire over recallable memory. This natural control axis may inform the design of vaccines that seek to avoid primary addiction and OAS.