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Principal Investigator: Scott Eric Hensley
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2022
Award: $398,577
Funding agency: National Institute of Allergy and Infectious Diseases
Modified Project Summary/Abstract Section
Most humans are infected with influenza viruses by the time they reach 3 years of age. Our past studies suggest that early childhood influenza infections can leave lifelong immunological ‘imprints’. During the first funding period (4 years) of this grant, we found that human Ab responses against seasonal influenza viruses are typically focused on epitopes that are conserved between contemporary viral strains and viral strains that circulated during each individual donor’s childhood. We found that immune responses generated against contemporary influenza strains are dominated by memory B cells that recognize conserved epitopes present in past viral strains. Our studies have examined how viral infections with one subtype of influenza virus (i.e. H1N1) influence immune responses against an antigenically distinct version of that same subtype (i.e. H1N1). Although different influenza virus subtypes have very different antigenic properties, there are epitopes that are conserved among these viruses. H1N1, H2N2, and H3N2 viruses have circulated at different times in humans over the past 100 years and an individual’s birth year largely predicts the influenza virus subtype that they were initially infected with in childhood. It is important to elucidate how viral infections with one influenza subtype (i.e. H1N1) influence immune responses against a completely different influenza subtype (i.e. H3N2) since multiple influenza virus subtypes currently co-circulate in humans. Further, epidemiological studies suggest that human susceptibility to pandemic H5N1 and H7N9 viruses is influenced by childhood infections with different subtypes of seasonal influenza viruses. We hypothesize that early childhood seasonal influenza virus infections leave long-lived immunological imprints that bias the immune system to preferentially respond efficiently to more closely related influenza subtypes and poorly to more distant influenza subtypes. In this proposal we will use mouse and ferret models to determine how initial seasonal influenza infections shape the specificity and neutralization efficiency of Abs elicited against distinct seasonal and pandemic influenza virus subtypes. We will then examine sera samples collected for a pediatric cohort study to determine how initial childhood H1N1 versus H3N2 infections affect the development of Ab responses against infections with homologous and heterologous influenza virus subtypes. Finally, we will use mouse and ferret models to determine how different influenza pre-exposures shape the specificity and neutralization efficiency of Abs elicited by a leading ‘universal’ influenza vaccine candidate. Collectively, these studies will determine (1) if infections with one influenza virus subtype influence the specificity of Abs elicited against a second influenza virus subtype, (2) the specificity and functionality of Abs elicited in children with different influenza virus exposure histories and (3) how prior influenza exposures influence the effectiveness of a new ‘universal’ influenza vaccine.
Terms: <0-11 years old><3 year old><3 years of age><Affect><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Repertoire><Antibody Response><Antibody Specificity><Antibody titer measurement><Antigenic Determinants><Binding Determinants><Birth><Child><Child Youth><Childhood><Children (0-21)><Cohort Studies><Concurrent Studies><Development><Distant><Effectiveness><Enrollment><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Epitopes><Ferrets><Flu vaccination><Funding><Goals><Grant><Grippe><H1N1><H1N1 Virus><H2N2><H2N2 Virus><H3N2><H3N2 Virus><H5N1><H5N1 virus><H7N9><History><Human><Immune><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Individual><Infection><Influenza><Influenza A Virus, H1N1 Subtype><Influenza A Virus, H2N2 Subtype><Influenza A Virus, H3N2 Subtype><Influenza A Virus, H5N1 Subtype><Influenza A Virus, H7N9 Subtype><Influenza Vaccines><Influenza Virus><Influenza immunization><Influenza vaccination><Life><Longitudinal Studies><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Nicaraguan><Parturition><Pediatric cohort><Predisposition><Property><Prophylactic vaccination against influenza><Recording of previous events><Sampling><Series><Serology test><Shapes><Specificity><Susceptibility><Testing><Time><Vaccinated><Vaccine Antigen><Vaccines><Viral><Viral Diseases><Virus><Virus Diseases><age 3 years><allergic/immunologic body system><allergic/immunologic organ system><antibody titering><avian influenza H5N1><avian influenza H5N1 virus><base><cohort><developmental><early childhood><enroll><epidemiologic investigation><epidemiology study><flu immunisation><flu infection><flu serotype><flu strain><flu subtype><flu vaccine><flu viral strain><flu virus infection><flu virus pandemic><flu virus strain><flu virus vaccine><host response><immune system response><immunoresponse><imprint><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza serotype><influenza strain><influenza subtype><influenza viral strain><influenza virus infection><influenza virus pandemic><influenza virus strain><influenza virus vaccination><influenza virus vaccine><influenzavirus><interest><long-term study><longitudinal outcome studies><longterm study><mRNA><model of animal><model organism><pandemic><pandemic disease><pandemic flu><pandemic influenza><pandemic strain of influenza><pediatric><public health relevance><response><seasonal flu><seasonal influenza><serology assay><three year old><three years of age><universal flu vaccine><universal influenza vaccine><universal influenza virus vaccine><universal vaccine><universal vaccine against flu><universal vaccine against influenza><vaccination against influenza><vaccine against flu><vaccine against influenza><vaccine candidate><viral infection><virus infection><virus-induced disease><youngster>