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Principal Investigator: Edward N Janoff
Organization: VA EASTERN COLORADO HEALTH CARE SYSTEM
Fiscal Year: 2019
Funding agency: Veterans Affairs
7. Project Summary/Abstract
Both advancing age and HIV-1 infection are associated with an increased frequency of infection, such as those
due to Streptococcus pneumoniae, and a higher rate of complications and death with these infections.
Vaccines are available to prevent a number of infections common in older adults, such as pneumococcal
pneumonia and blood stream infection. However, many older adults, particularly those with underlying
disease, and persons living with HIV-1 infection show a decreased frequency, magnitude, quality and function
of specific antibodies following pneumococcal vaccination, as well as clinical vaccine failure. Underlying these
defects may be limitations in responses to infection and vaccines in both blood and at mucosal sites, where
most infections, such as pneumococcal pneumonia, begin.
Responses to vaccines begin quickly after immunization. We focus on the distinct events at the initiation of
immune responses to a newer pneumococcal vaccine directed against the polysaccharide capsule (PCV-13).
We study the initial generation of both T cell and B cell responses transiently identified in blood at 7 days after
immunization that reflect the key early events occurring in the lymphoid germinal centers. T cell subsets, such
as T follicular helper and regulatory cells (TFH and TFR, respectively) that promote and modulate B cell
activation and differentiation, are mobilized and circulate in blood. These T cells regulate a key protein
expressed in B cells, AID (activation-induced cytidine deaminase) that drives B cells to undergo antibody class
switch recombination (CSR) from IgM to IgG and IgA and to undergo affinity maturation by somatic
hypermutation (SHM). SHM enhances the avidity and function of these antibodies. Both TFH and AID activity
may be compromised in both aging adults and those with HIV-1 infection, potentially causing additive immune
compromise. We will study 80 adults, 40 with and 40 without HIV-1 infection, half of whom are 21-40 years of
age, half 55-64 to distinguish the contributions of both states to the integrity of vaccine responses. The work is
unique in characterizing antibody levels and quality at two relevant mucosal sites before and after vaccine - in
the nasopharynx where colonization begins, in the lung where pneumonia begins, and in the blood, where
invasive infections progress from initial mucosal sites, so effective mucosal defense is essential for protection.
The end point of vaccination is to generate antibodies of high avidity (strength of binding) and function
(opsonophagocytosis). We characterize these outcomes, the impact of aging and HIV-1 infection on acute TFH,
TFR and AID activation, and their impact on the early response of antibody-secreting cells specific for the
vaccine and the molecular basis of antibody quality which is determined by immunoglobulin gene mutations.
By identifying the specific defects associated with aging and HIV-1 infection, we propose to direct development
of improved vaccines to more effectively prevent these serious infections.
Terms: <(TNF)-α><0-11 years old><19S Gamma Globulin><21+ years old><7S Gamma Globulin><AICDA><AICDA protein><AID gene><AID protein><AIDS Virus><Ab response><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Address><Adult><Adult Human><Affect><Affinity><Age><Age-Years><Aging><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antibody-Secreting Cells><Architecture><Autoimmune Diseases><Avidity><B blood cells><B cell><B cell differentiation factor><B cell stimulating factor 2><B cells><B lymphoma><B-Cell Activation><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Lymphomas><B-Cell Stimulatory Factor-2><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><BCDF><BSF-2><BSF2><Bacteremia><Bacteria><Bacterial Pneumonia><Basal Transcription Factor><Basal transcription factor genes><Binding><Blood><Blood Reticuloendothelial System><CDA2 protein><Cachectin><Capsules><Caring><Cell Body><Cell Maturation><Cells><Cellular biology><Cessation of life><Child><Child Youth><Children (0-21)><Chronic><Class Switching><Class Switchings><Clinical><Conjugate Vaccines><Constant Region><D pneumoniae><D. pneumoniae><D.pneumoniae><DNA><Death><Defect><Deoxyribonucleic Acid><Development><Diplococcus pneumoniae><Disease><Disorder><Dysfunction><Elderly><Engineering / Architecture><Enzyme Gene><Enzymes><Epithelial Cells><Event><Failure><Frequencies><Functional disorder><Functional impairment><Gene Alteration><Gene Mutation><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Genetic Alteration><Genetic Change><Genetic defect><Germinal Center><Glycans><HIV><HIV-1><HIV-I><HIV1><HPGF><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hepatocyte-Stimulating Factor><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Ig Constant Region><Ig Genes><Ig Somatic Hypermutation><Ig Variable Region><IgA><IgA1><IgG><IgG1><IgM><Immune><Immune response><Immunes><Immunization><Immunoglobulin A><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin Constant Region><Immunoglobulin G><Immunoglobulin Genes><Immunoglobulin Isotype-Switch Recombination><Immunoglobulin M><Immunoglobulin Somatic Hypermutation><Immunoglobulin Switch Recombination><Immunoglobulin V><Immunoglobulin Variable Region><Immunoglobulin-Secreting Cells><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><Impairment><Incidence><Inducer Cells><Inducer T-Lymphocytes><Infection><Inflammation><Influenza Vaccines><Interleukin-6><Isotype Switching><Isotype Switchings><LAV-HTLV-III><Lobar Pneumonia><Lung><Lung Respiratory System><Lung infections><Lymphadenopathy-Associated Virus><Lymphoid><MGI-2><Macrophage-Derived TNF><Messenger RNA><Micro RNA><MicroRNAs><Modern Man><Molecular><Molecular Interaction><Monocyte-Derived TNF><Mucosa><Mucosal Tissue><Mucous Membrane><Mutation><Myeloid Differentiation-Inducing Protein><Nasal><Nasal Passages Nose><Nasopharynx><Nose><Opportunistic Infections><Outcome><Pathogenicity Factors><Pattern><Persons><Physiopathology><Plasmacytoma Growth Factor><Pneumococcal Pneumonia><Pneumococcal vaccine><Pneumococcus><Pneumonia><Polysaccharides><Population><Prevention><Process><Production><Proteins><Provider><Recruitment Activity><Recurrence><Recurrent><Respiratory Mucosa><Respiratory System, Nose, Nasal Passages><Rhinopharynx><Risk><S pneumoniae><S. pneumoniae><Sepsis><Specificity><Stream><Streptococcus pneumoniae><Streptococcus pneumoniae vaccine><Structure of germinal center of lymph node><Switch Recombination><Syndrome><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Transcript><Transcription Factor Proto-Oncogene><Transcription factor genes><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vaccination><Vaccine Design><Vaccines><Variable Region><Veterans><Virulence Factors><Virus-HIV><Work><activation-induced cytidine deaminase><activation-induced deaminase><active recruitment><adulthood><advanced age><age group><ages><anti-retroviral therapy><anti-retroviral treatment><antibody biosynthesis><antigen antibody binding><antiretroviral therapy><antiretroviral treatment><autoimmune disorder><bacteraemia><blood infection><bloodstream infection><capsule><cell biology><children><childrens'><develop a vaccine><development of a vaccine><developmental><differential expression><differentially expressed><elders><flu vaccine><flu virus vaccine><functional disability><genome mutation><geriatric><host response><immunoglobulin biosynthesis><immunoresponse><improved><influenza virus vaccine><interferon beta 2><late life><later life><mRNA><miRNA><miRNAs><mucosal site><mucosal vaccine><nasopharnygeal><older adult><older person><pathophysiology><prevent><preventing><protein expression><pulmonary><pulmonary infections><response><senior citizen><somatic hypermutation><thymus derived lymphocyte><transcription factor><transcriptional differences><vaccine against flu><vaccine against influenza><vaccine development><vaccine formulation><vaccine response><youngster>