Harnessing Age-Associated B cells for a Universal Influenza Vaccine for the Aged

ABSTRACT: Harnessing Age-Associated B Cells for a Universal Influenza Vaccine for the Aged. With age, the generation of T follicular helpers from naive CD4 T cells, and germinal center B cells from follicular B cells, that are both needed for the generation of high affinity antibody (Ab), become highly compromised. Most current vaccines for influenza in the elderly are not effective at inducing these critical responses. Thus, the elderly, though protected by Ab already in place for pathogens encountered earlier in life, are highly susceptible to new strains of virus (e.g. influenza) and newly emerged pathogens (e.g. pandemic influenzas, COVID-19). We described the generation of an unusual population of Ab-secreting B cells that developed to live influenza infection in aged mice. We found they were derived from stimulation of recently described "age-associated B cells" (ABC) of a naïve sIgD+ phenotype. In the aged, these influenza-induced ABC (iABC) are generated independently of CD4 T cell help, but strictly depend on stimulation by pathogen-associated "danger" signals and thus they are generated well in aged infected mice. Notably, ABC are the predominant naïve B cells that respond in aged mice. Here we will determine the potential of IgD ABC to respond to influenza infection and generate Ab-secreting cells (AbSC) effector iABC that are either recirculating or are tissue resident. We will determine if they give rise to B cell memory, both resting memory and long-lived Ab-secreting cells, and if these are found in the lower respiratory tract (lung) and upper respiratory tract (URT):nasal tissues and nasal associated lymphoid tissue- NALT), as well as the spleen and BM. We will determine the contribution of ABC-derived effector and memory subsets and the Ab they produce in these the different sites to protection from reinfection. We will ask how long- lived are the memory cells in distinct sites. We will compare the ability of live influenza virus, whole inactivated virus, and mRNA-LNP HA vaccine to generate the recirculating and tissue resident effector and memory subsets and to induce protective immunity. These results will give us new insights into this novel age-associated immune pathway and give us important new insights into whether harnessing the aged ABC response can provide superior protection in the aged. It will provide indications of what general vaccine strategies are likely to be needed to immunize the ABC in the elderly. These findings could lead to a more Universal vaccines that can provide robust protection to the elderly, who are currently highly vulnerable.