title: Generation of a universal CD4 memory T cell recall peptide effective in humans, mice and non-human primates.
abstract: CD4T cells play a key role in humoral immunity by providing help to B cells, enabling effective antibody class switching and affinity maturation. Some vaccines may generate a poor response due to a lack of effective MHC class II epitopes, resulting in ineffective helper T cell activation and recall and consequently poor humoral immunity. It may be beneficial to provide a CD4T cell helper peptide with a vaccine particularly in the case of a poorly immunogenic antigen. Such a T cell helper peptide must be promiscuous in its ability to bind a broad range of MHC class II alleles due to broad allelic variation in the human population. We designed a chimeric MHC class II peptide (TpD) with epitopes from tetanus toxoid and diphtheria toxoid, separated by an internal cathepsin cleavage site. TpD was capable of inducing a memory recall response in peripheral blood mononuclear cells from 20/20 human donors. T cells responding to TpD showed a central memory phenotype. Immunization of mice with a synthetic nicotine nanoparticle vaccine containing TpD showed that the peptide was required for robust antibody production and resulted in a long term CD4 memory T cell recall response. As a pre-clinical model two non-human primate species, rhesus macaques and cynomolgus monkeys, were immunized with a nicotine nanoparticle vaccine and evaluated for an anti-nicotine antibody response and TpD specific memory T cells. We found that 4/4 rhesus monkeys had both sustained antibody production and TpD memory T cells for the duration of the experiment (119 days). In addition 30/30 cynomolgus monkeys dosed with nicotine vaccine nanoparticles showed dose-dependent antibody generation and T cell recall response compared to saline injected controls. In summary we have developed a potent universal memory T cell helper peptide (TpD) that is active in vitro in human PBMCs and in vivo in mice and non-human primates.
authors.affiliation: Selecta Biosciences, 480 Arsenal Street, Building One, Watertown, MA 02472, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Fraser
authors.affiliation: Selecta Biosciences, 480 Arsenal Street, Building One, Watertown, MA 02472, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Altreuter
authors.affiliation: Selecta Biosciences, 480 Arsenal Street, Building One, Watertown, MA 02472, USA.
authors.forename: Petr
authors.initials: P
authors.lastname: Ilyinskii
authors.affiliation: Selecta Biosciences, 480 Arsenal Street, Building One, Watertown, MA 02472, USA.
authors.forename: Lynnelle
authors.initials: L
authors.lastname: Pittet
authors.affiliation: Selecta Biosciences, 480 Arsenal Street, Building One, Watertown, MA 02472, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: LaMothe
authors.affiliation: Selecta Biosciences, 480 Arsenal Street, Building One, Watertown, MA 02472, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Keegan
authors.affiliation: Selecta Biosciences, 480 Arsenal Street, Building One, Watertown, MA 02472, USA.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Johnston
authors.affiliation: Selecta Biosciences, 480 Arsenal Street, Building One, Watertown, MA 02472, USA. Electronic address: kkishimoto@selectabio.com.
authors.forename: Takashi Kei
authors.initials: TK
authors.lastname: Kishimoto
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004168:Diphtheria Toxoid / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D005802:Genes, MHC Class II; D006801:Humans; D007156:Immunologic Memory; D008252:Macaca fascicularis; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D009538:Nicotine / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D004168:Diphtheria Toxoid; D000939:Epitopes; D010455:Peptides; D013745:Tetanus Toxoid; D014614:Vaccines, Synthetic; D009538:Nicotine
keywords: Antibodies; Epitope; Memory T cell; Nanoparticle; Vaccine