Antigen co‐encapsulated with adjuvants efficiently drive protective T cell immunity

• Published in: European Journal of Immunology Vol. 37; no. 8; pp. 2063 - 2074
• Main Authors: Heit, Antje, Schmitz, Frank, Haas, Tobias, Busch, Dirk H., Wagner, Hermann
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag 01.08.2007
• Subjects: Adjuvants, Immunologic - chemical synthesis; Animals; Antigen Presentation - immunology; Antigens - immunology; Dendritic cells; Dendritic Cells - immunology; Endosomes - immunology; Endosomes - metabolism; Lactic Acid - immunology; Lymphocyte Activation - immunology; Mice; Mice, Transgenic; Microscopy, Confocal; Microspheres; Oligodeoxyribonucleotides - immunology; Ovalbumin - immunology; Polyglycolic Acid; Polymers; T cells; T-Lymphocytes - immunology; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism; Vaccination; Vaccines, Synthetic - immunology
• ISSN: 0014-2980; 1521-4141; 1365-2567
• DOI: 10.1002/eji.200737169

Compared to "live" vaccines, the immunogenicity of "subunit" vaccines based on recombinant antigen (Ag) is poor, presumably because exogenous Ag fails to effectively access the endosomal Ag‐processing pathways of Ag‐presenting cells (APC). To overcome this limitation, we exploited biodegradable poly(lactic‐co‐glycolic) microspheres (MP) co‐entrapping Ag and Toll‐like receptor (TLR) 9 or 7 ligands as an endosomal delivery device. In vitro, microspheres were rapidly phagocytosed by APC and translocated into phago‐endosomal compartments, followed by degradation of the Ag and concurrent activation of endosomal TLR. As a consequence, full maturation of and cytokine secretion by APC as well as Ag‐cross‐presentation ensued. In vivo, "loaded" microspheres triggered clonal expansion of primary and secondary Ag‐specific CD4 and CD8 T cells. The efficacy of CD8 T cell cross‐priming was comparable to that of live vectors. The potency of T cell vaccination was demonstrated by protective and therapeutic interventions using infection‐ and tumor‐model systems. These preclinical "subunit" vaccination data thus recommend MP as a generally applicable and powerful endosomal delivery device of exogenous Ag plus TLR‐based adjuvants to vaccinate for protective and therapeutic CD4 and CD8 T cell immunity.