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Principal Investigator: Susan L Swain
Organization: UNIV OF MASSACHUSETTS MED SCH WORCESTER
Fiscal Year: 2023
Award: $251,250
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <19S Gamma Globulin><Ab-mediated immunity><Ab-mediated protection><Age><Aging><Antibodies><Antibody Affinity><Antibody immunity><Antibody protection><Antibody titer measurement><Antibody-Secreting Cells><Antibody-mediated protection><Antigens><B blood cells><B cell><B cells><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><Blood Serum><Body Tissues><Body Weight decreased><Bone Marrow><Bone Marrow Reticuloendothelial System><Bronchial Lavages><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID-19><COVID19><CV-19><CV19><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Lineage><Cell Signaling><Cell secretion><Cells><Cellular Secretion><Development><Dose><Effector Cell><Elderly><Exposure to><Generations><Germ-Free><Germinal Center><Grippe><IgA><IgD><IgM><Immune><Immunes><Immunity><Immunize><Immunoglobulin A><Immunoglobulin D><Immunoglobulin M><Immunoglobulin-Secreting Cells><Inactivated Vaccines><Inactivated Virus Vaccine><Infection><Influenza><Influenza Vaccines><Influenza Virus><Intracellular Communication and Signaling><Killed Vaccines><Learning><Length of Life><Life><Location><Longevity><Lower respiratory tract structure><Lung><Lung Respiratory System><Lymphatic Tissue><Lymphoid Tissue><Mediating><Memory><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Mice><Mice Mammals><Murine><Mus><Nasal><Nasal Lavage Fluid><Nasal Passages Nose><Nasal Washing><Nasal Washings><Non-Polyadenylated RNA><Nose><Pathway interactions><Phase><Phenotype><Population><Predisposition><Progenitor Cells><Property><Pulmonary Body System><Pulmonary Organ System><RNA><RNA Gene Products><Residencies><Respiratory System><Respiratory System, Nose, Nasal Passages><Respiratory Tracts><Respiratory tract structure><Rest><Ribonucleic Acid><Role><Route><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Site><Spleen><Spleen Reticuloendothelial System><Structure of germinal center of lymph node><Subunit Vaccines><Susceptibility><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TLR7><TLR7 gene><Testing><Time><Tissues><Toll-Like Receptor 7><Upper respiratory tract><Vaccines><Viral><Virus><Weight Loss><Weight Reduction><Weights and Measures><advanced age><aged><aged population><ages><aging population><antibody titering><antibody-mediated immunity><antigen antibody affinity><biological signal transduction><body weight loss><combat><commensal flora><commensal microbes><commensal microbiota><commensal microflora><corona virus disease 2019><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><developmental><elders><emerging pathogen><flu infection><flu outbreak><flu vaccine><flu virus infection><flu virus pandemic><flu virus vaccine><geriatric><immunization strategy><immunogen><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza outbreak><influenza virus infection><influenza virus pandemic><influenza virus vaccine><influenzavirus><insight><late life><later life><life span><lifespan><lower respiratory tract><mRNA><migration><neutralizing antibody><new pathogen><novel><novel pathogen><older adult><older person><pandemic flu><pandemic influenza><pandemic strain of influenza><pathogen><pathway><population aging><programs><pulmonary><residence><residential building><residential site><respiratory><respiratory pathogen><response><seasonal flu><seasonal influenza><secondary lymph organ><secondary lymphatic organ><secondary lymphoid organ><senior citizen><social role><stem cells><thymus derived lymphocyte><universal flu vaccine><universal influenza vaccine><universal influenza virus vaccine><universal vaccine><universal vaccine against flu><universal vaccine against influenza><upper airway tract><vaccination strategy><vaccine against flu><vaccine against influenza><vaccine strategy><wt-loss>