title: T cell responses induced by adenoviral vectored vaccines can be adjuvanted by fusion of antigen to the oligomerization domain of C4b-binding protein.
abstract: Viral vectored vaccines have been shown to induce both T cell and antibody responses in animals and humans. However, the induction of even higher level T cell responses may be crucial in achieving vaccine efficacy against difficult disease targets, especially in humans. Here we investigate the oligomerization domain of the α-chain of C4b-binding protein (C4 bp) as a candidate T cell "molecular adjuvant" when fused to malaria antigens expressed by human adenovirus serotype 5 (AdHu5) vectored vaccines in BALB/c mice. We demonstrate that i) C-terminal fusion of an oligomerization domain can enhance the quantity of antigen-specific CD4(+) and CD8(+) T cell responses induced in mice after only a single immunization of recombinant AdHu5, and that the T cells maintain similar functional cytokine profiles; ii) an adjuvant effect is observed for AdHu5 vectors expressing either the 42 kDa C-terminal domain of Plasmodium yoelii merozoite surface protein 1 (PyMSP1(42)) or the 83 kDa ectodomain of P. falciparum strain 3D7 apical membrane antigen 1 (PfAMA1), but not a candidate 128kDa P. falciparum MSP1 biallelic fusion antigen; iii) following two homologous immunizations of AdHu5 vaccines, antigen-specific T cell responses are further enhanced, however, in both BALB/c mice and New Zealand White rabbits no enhancement of functional antibody responses is observed; and iv) that the T cell adjuvant activity of C4 bp is not dependent on a functional Fc-receptor γ-chain in the host, but is associated with the oligomerization of small (<80 kDa) antigens expressed by recombinant AdHu5. The oligomerization domain of C4 bp can thus adjuvant T cell responses induced by AdHu5 vectors against selected antigens and its clinical utility as well as mechanism of action warrant further investigation.
authors.affiliation: The Jenner Institute, University of Oxford, Oxford, United Kingdom.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Forbes
authors.forename: Simone C
authors.initials: SC
authors.lastname: de Cassan
authors.forename: David
authors.initials: D
authors.lastname: Llewellyn
authors.forename: Sumi
authors.initials: S
authors.lastname: Biswas
authors.forename: Anna L
authors.initials: AL
authors.lastname: Goodman
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Cottingham
authors.forename: Carole A
authors.initials: CA
authors.lastname: Long
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Pleass
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Fergal
authors.initials: F
authors.lastname: Hill
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000276:Adjuvants, Immunologic / Q000235:genetics; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics; D050716:Complement C4b-Binding Protein / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors; D008288:Malaria / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000235:genetics; D020066:Merozoite Surface Protein 1 / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D010963:Plasmodium falciparum / Q000235:genetics; D010967:Plasmodium yoelii / Q000235:genetics; D017434:Protein Structure, Tertiary; D011817:Rabbits; D017452:Receptors, IgG / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism / Q000821:virology; D014612:Vaccines / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D000953:Antigens, Protozoan; D050716:Complement C4b-Binding Protein; D017780:Malaria Vaccines; D020066:Merozoite Surface Protein 1; D017452:Receptors, IgG; D014612:Vaccines