title: Immune-complex mimics as a molecular platform for adjuvant-free vaccine delivery.
abstract: Protein-based vaccine development faces the difficult challenge of finding robust yet non-toxic adjuvants suitable for humans. Here, using a molecular engineering approach, we have developed a molecular platform for generating self-adjuvanting immunogens that do not depend on exogenous adjuvants for induction of immune responses. These are based on the concept of Immune Complex Mimics (ICM), structures that are formed between an oligomeric antigen and a monoclonal antibody (mAb) to that antigen. In this way, the roles of antigens and antibodies within the structure of immune complexes are reversed, so that a single monoclonal antibody, rather than polyclonal sera or expensive mAb cocktails can be used. We tested this approach in the context of Mycobacterium tuberculosis (MTB) infection by linking the highly immunogenic and potentially protective Ag85B with the oligomeric Acr (alpha crystallin, HspX) antigen. When combined with an anti-Acr monoclonal antibody, the fusion protein formed ICM which bound to C1q component of the complement system and were readily taken up by antigen-presenting cells in vitro. ICM induced a strong Th1/Th2 mixed type antibody response, which was comparable to cholera toxin adjuvanted antigen, but only moderate levels of T cell proliferation and IFN-γ secretion. Unfortunately, the systemic administration of ICM did not confer statistically significant protection against intranasal MTB challenge, although a small BCG-boosting effect was observed. We conclude that ICM are capable of inducing strong humoral responses to incorporated antigens and may be a suitable vaccination approach for pathogens other than MTB, where antibody-based immunity may play a more protective role.
authors: Infection and Immunity Research Centre, St. George's University of London, London, United Kingdom.
authors: Ilaria
authors: I
authors: Pepponi
authors: Elena
authors: E
authors: Stylianou
authors: Craig
authors: C
authors: van Dolleweerd
authors: Gil Reynolds
authors: GR
authors: Diogo
authors: Matthew J
authors: MJ
authors: Paul
authors: Pascal M W
authors: PM
authors: Drake
authors: Julian K-C
authors: JK
authors: Ma
authors: Rajko
authors: R
authors: Reljic
mesh_terms: D000217:Acyltransferases / Q000737:chemistry / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000737:chemistry* / Q000276:immunology*; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology; D058491:Bacterial Load / Q000276:immunology; D001426:Bacterial Proteins / Q000737:chemistry / Q000276:immunology; D001428:Bacterial Vaccines / Q000276:immunology*; D040761:Biomimetic Materials / Q000737:chemistry*; D002460:Cell Line; D049109:Cell Proliferation; D004337:Drug Carriers / Q000737:chemistry*; D000939:Epitopes / Q000276:immunology; D005240:Feasibility Studies; D005260:Female; D007117:Immunization, Secondary; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D038201:alpha-Crystallins / Q000737:chemistry
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D004337:Drug Carriers; D000939:Epitopes; D007074:Immunoglobulin G; D038201:alpha-Crystallins; D007371:Interferon-gamma; D000217:Acyltransferases; C121433:antigen 85B, Mycobacterium tuberculosis
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