title: T cells control the generation of nanomolar-affinity anti-glycan antibodies.
abstract: Vaccines targeting glycan structures at the surface of pathogenic microbes must overcome the inherent T cell-independent nature of immune responses against glycans. Carbohydrate conjugate vaccines achieve this by coupling bacterial polysaccharides to a carrier protein that recruits heterologous CD4 T cells to help B cell maturation. Yet they most often produce low- to medium-affinity immune responses of limited duration in immunologically fit individuals and disappointing results in the elderly and immunocompromised patients. Here, we hypothesized that these limitations result from suboptimal T cell help. To produce the next generation of more efficacious conjugate vaccines, we have explored a synthetic design aimed at focusing both B cell and T cell recognition to a single short glycan displayed at the surface of a virus-like particle. We tested and established the proof of concept of this approach for 2 serotypes of Streptococcus pneumoniae. In both cases, these vaccines elicited serotype-specific, protective, and long-lasting IgG antibodies of nanomolar affinity against the target glycans in mice. We further identified a requirement for CD4 T cells in the anti-glycan antibody response. Our findings establish the design principles for improved glycan conjugate vaccines. We surmise that the same approach can be used for any microbial glycan of interest.
authors.forename: Zinaida
authors.initials: Z
authors.lastname: Polonskaya
authors.forename: Shenglou
authors.initials: S
authors.lastname: Deng
authors.forename: Anita
authors.initials: A
authors.lastname: Sarkar
authors.forename: Lisa
authors.initials: L
authors.lastname: Kain
authors.forename: Marta
authors.initials: M
authors.lastname: Comellas-Aragones
authors.forename: Craig S
authors.initials: CS
authors.lastname: McKay
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kaczanowska
authors.forename: Marie
authors.initials: M
authors.lastname: Holt
authors.forename: Ryan
authors.initials: R
authors.lastname: McBride
authors.forename: Valle
authors.initials: V
authors.lastname: Palomo
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Self
authors.forename: Seth
authors.initials: S
authors.lastname: Taylor
authors.forename: Adriana
authors.initials: A
authors.lastname: Irimia
authors.forename: Sanjay R
authors.initials: SR
authors.lastname: Mehta
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Dan
authors.forename: Matthew
authors.initials: M
authors.lastname: Brigger
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Schoenberger
authors.forename: James C
authors.initials: JC
authors.lastname: Paulson
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.forename: M G
authors.initials: MG
authors.lastname: Finn
authors.forename: Luc
authors.initials: L
authors.lastname: Teyton
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood* / Q000737:chemistry; D000915:Antibody Affinity; D001402:B-Lymphocytes / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D018360:Crystallography, X-Ray; D005260:Female; D006020:Glycopeptides / Q000276:immunology; D006801:Humans; D006825:Hybridomas; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008958:Models, Molecular; D011008:Pneumococcal Infections / Q000276:immunology* / Q000517:prevention & control; D022242:Pneumococcal Vaccines / Q000737:chemistry / Q000276:immunology; D011135:Polysaccharides, Bacterial / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding; D013296:Streptococcus pneumoniae / Q000276:immunology; D014611:Vaccination; D064166:Vaccine Potency
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D006020:Glycopeptides; D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D011135:Polysaccharides, Bacterial