T cell responses induced by adenoviral vectored vaccines can be adjuvanted by fusion of antigen to the oligomerization domain of C4b-binding protein.

Journal article

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 (Alpha)-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 (Gamma)-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: Forbes, E; de Cassan, S; Llewellyn, D; Biswas, S; Goodman, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Public Library of Science
• Journal: PloS One
• Volume: 7
• Issue: 9
• Article number: e44943
• Publication date: 2012-01-01
• DOI: 10.1371/journal.pone.0044943
• EISSN: 1932-6203
• ISSN: 1932-6203
• Language: English
• Keywords: Complement C4b-Binding Protein; Malaria; Mice; Protein Structure, Tertiary; Mice, Inbred BALB C; Receptors, IgG; Vaccines; Animals; Genetic Vectors; Antigens, Protozoan; Plasmodium falciparum; Rabbits; Plasmodium yoelii; Merozoite Surface Protein 1; Female; Adenoviridae; T-Lymphocytes; Adjuvants, Immunologic; Malaria Vaccines