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Principal Investigator: Scott Eric Hensley
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2020
Award: $807,420
Funding agency: National Institute of Allergy and Infectious Diseases
As early as 1960, Thomas Francis Jr. first noted that antibody responses to early childhood influenza virus
infections are preferentially recalled later in life upon exposure to antigenically distinct viral strains. He coined
the phrase ‘original antigenic sin’ to describe this phenomena. We recently demonstrated that human antibody
responses to H1N1 and H3N2 are typically focused on epitopes that are conserved between contemporary
viral strains and viral strains that circulated during an individual’s childhood. Importantly, we found that ferrets
sequentially infected with older and contemporary influenza virus strains possess antibodies that have the
same specificity as humans that were exposed to the same viral strains. Thus, ferrets are good animal models
for studying how prior influenza exposures affect the specificity of antibody responses elicited against
antigenically novel influenza virus strains. We have not yet explored how prior exposures influence antibody
responses against seasonal influenza vaccines that include antigens from H1N1, H3N2, and influenza B
viruses. This is an important consideration since the effectiveness of each influenza vaccine component differs
among different aged individuals with distinct immune histories. We hypothesize that seasonal influenza
vaccines elicit antibody responses that are biased towards the first viral subtype that an individual encounters
early in childhood, and that preferential boosting of antibody responses against these antigens occurs at the
expense of generating robust de novo responses. In Aim 1, we will address this question by defining the fine-
specificities of serum antibodies isolated from vaccinated ferrets and humans with different viral exposure
histories. In Aim 2, we will develop and apply new techniques to characterize B cell responses in ferrets before
and after seasonal influenza vaccination. Finally, in Aim 3 we will determine if a novel mRNA-based vaccine
establishes broader immunological memory compared to initial influenza virus encounters that occur via single
viral infections and inactivated vaccines. Together, these studies will improve our understanding of how prior
influenza virus exposures influence the generation of antibody responses against seasonal influenza vaccines
and will test a new influenza vaccine that has the potential to elicit broad unbiased immune responses.
Terms: <Address><Affect><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Response><Antibody Specificity><Antibody titer measurement><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Blood Serum><Childhood><Clinical Treatment Moab><Clonal Evolution><Clone Cells><Coin><Complement><Complement Proteins><Development><Dreams><Effectiveness><Engineering><Epitopes><Exposure to><Ferrets><Flu vaccination><Generations><Genes><Genetic><Goals><Grippe><H1N1><H1N1 Virus><Ha antigen><History><Human><Ig Genes><Immune><Immune Globulins><Immune memory><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunoglobulin Gene Rearrangement><Immunoglobulin Genes><Immunoglobulins><Immunologic><Immunologic Memory><Immunological><Immunological Memory><Immunological response><Immunologically><Immunologics><Inactivated Vaccines><Inactivated Virus Vaccine><Individual><Infant><Infection><Influenza><Influenza A Virus, H1N1 Subtype><Influenza B><Influenza B Virus><Influenza Vaccines><Influenza Virus><Influenza Viruses Type B><Influenza immunization><Influenza vaccination><Killed Vaccines><Life><Light><Memory><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Monoclonal Antibodies><Murine><Mus><Orthomyxoviruses Type B><Photoradiation><Prophylactic vaccination against influenza><Publishing><Recording of previous events><Serologic><Serological><Serum><Shapes><Specificity><Study models><Techniques><Testing><Vaccinated><Vaccination><Vaccines><Viral><Viral Diseases><Virus><Virus Diseases><aged><allergic/immunologic body system><allergic/immunologic organ system><anamnestic reaction><antibody titering><base><deep sequencing><developmental><dreaming><early childhood><essays><flu immunisation><flu infection><flu vaccine><flu virus strain><flu virus vaccine><host response><human data><immunogen><immunoresponse><imprint><improved><influenza infection><influenza virus strain><influenza virus vaccination><influenza virus vaccine><influenzavirus><mAbs><mRNA><model of animal><model organism><new vaccines><next generation vaccines><novel><novel vaccines><pediatric><phrases><response><scRNA-seq><seasonal flu><seasonal influenza><secondary immune response><single cell RNA-seq><single cell RNAseq><single-cell RNA sequencing><tool><universal flu vaccine><universal influenza vaccine><vaccination against influenza><vaccine against flu><vaccine against influenza><vaccine effectiveness><viral infection><virus infection><virus-induced disease>