title: Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans.
abstract: The emergence of pandemic influenza viruses poses a major public health threat. Therefore, there is a need for a vaccine that can induce broadly cross-reactive antibodies that protect against seasonal as well as pandemic influenza strains. Human broadly neutralizing antibodies directed against highly conserved epitopes in the stem region of influenza virus HA have been recently characterized. However, it remains unknown what the baseline levels are of antibodies and memory B cells that are directed against these conserved epitopes. More importantly, it is also not known to what extent anti-HA stem B-cell responses get boosted in humans after seasonal influenza vaccination. In this study, we have addressed these two outstanding questions. Our data show that: (i) antibodies and memory B cells directed against the conserved HA stem region are prevalent in humans, but their levels are much lower than B-cell responses directed to variable epitopes in the HA head; (ii) current seasonal influenza vaccines are efficient in inducing B-cell responses to the variable HA head region but they fail to boost responses to the conserved HA stem region; and (iii) in striking contrast, immunization of humans with the avian influenza virus H5N1 induced broadly cross-reactive HA stem-specific antibodies. Taken together, our findings provide a potential vaccination strategy where heterologous influenza immunization could be used for increasing the levels of broadly neutralizing antibodies and for priming the human population to respond quickly to emerging pandemic influenza threats.
authors.affiliation: Emory Vaccine Center, and Department of Microbiology and Immunology.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Ellebedy
authors.affiliation: Department of Microbiology.
authors.forename: Florian
authors.initials: F
authors.lastname: Krammer
authors.affiliation: Emory Vaccine Center, and Department of Microbiology and Immunology.
authors.forename: Gui-Mei
authors.initials: GM
authors.lastname: Li
authors.affiliation: Department of Microbiology.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Miller
authors.affiliation: Emory Vaccine Center, and Department of Microbiology and Immunology.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chiu
authors.affiliation: Emory Vaccine Center, and Department of Pediatrics.
authors.forename: Jens
authors.initials: J
authors.lastname: Wrammert
authors.affiliation: Emory Vaccine Center, and Department of Microbiology and Immunology.
authors.forename: Cathy Y
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Emory Vaccine Center, and Department of Microbiology and Immunology.
authors.forename: Carl W
authors.initials: CW
authors.lastname: Davis
authors.affiliation: Emory Vaccine Center, and Department of Microbiology and Immunology.
authors.forename: Megan
authors.initials: M
authors.lastname: McCausland
authors.affiliation: Emory Transplant Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Rivka
authors.initials: R
authors.lastname: Elbein
authors.affiliation: Division of Infectious Diseases, Department of Medicine.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Edupuganti
authors.affiliation: Department of Pediatrics.
authors.forename: Paul
authors.initials: P
authors.lastname: Spearman
authors.affiliation: Department of Medicine, Section of Rheumatology, Committee on Immunology, The Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Andrews
authors.affiliation: Department of Medicine, Section of Rheumatology, Committee on Immunology, The Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
authors.affiliation: Department of Microbiology, Department of Medicine, and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; and.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Hope Clinic of the Emory Vaccine Center.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mulligan
authors.affiliation: Emory Transplant Center, Emory University School of Medicine, Atlanta, GA 30322; Division of Infectious Diseases, Department of Medicine, Hope Clinic of the Emory Vaccine Center.
authors.forename: Aneesh K
authors.initials: AK
authors.lastname: Mehta
authors.affiliation: Department of Microbiology, Department of Medicine, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
authors.affiliation: Emory Vaccine Center, and Department of Microbiology and Immunology, rahmed@emory.edu.
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000328:Adult; D000917:Antibody Formation / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007156:Immunologic Memory; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000097:blood / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D010950:Plasma Cells / Q000276:immunology; D014611:Vaccination
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007074:Immunoglobulin G; D007252:Influenza Vaccines
keywords: breadth; immunoglobulin; neutralization; stalk