Refocussing antibody responses by chemical modification of vaccine antigens

Item Type:	Article
Title:	Refocussing antibody responses by chemical modification of vaccine antigens
Creators Name:	Schiffner, T. and Leonavicius, K. and Schuster, H. and Kim, H.J. and Kong, L. and Saliba, R. and Brod, F. and Wegmann, F. and Huang, P.S. and Stewart-Jones, G.B. and Schief, W.R. and Ward, A.B. and Moore, J.P. and Sanders, R.W. and Davis, B.G. and Sattentau, Q.J.
Abstract:	BACKGROUND: The HIV-1 envelope glycoprotein (Env) has developed several immune-evasion mechanisms to avoid the induction of neutralizing antibodies, including immuno-dominant non-neutralizing epitopes, conformational flexibility of conserved epitopes, and spontaneous subunit dissociation. Here, site-specific immuno-silencing by glycan masking and chemical fixation of native-like Env trimers are explored to overcome these obstacles. METHODS: Immunogens, including “next-generation“ BG505 SOSIP.664 trimers, were chemically modified in vitro by either site-directed glycan addition or chemical cross-linking, and effects on antibody recognition were characterized in vitro by ELISA and SPR. Immunogenicity was tested in mice and refocussing of antibody responses was analysed by cross-competition with monoclonal antibodies. RESULTS: In vitro, glycan masking led to selective reduction in binding of antibodies recognizing epitopes containing, or proximal to, modification sites (lysine residues) whereas binding of antibodies to epitopes devoid of lysines remained unchanged. Chemical cross-linking of native-like gp140 trimers led to reduced binding of non-neutralizing antibodies including V3-loop directed antibodies, which further significantly increased the existing differential in antibody binding between neutralizing and non-neutralizing antibodies. Immunization with modified antigens led to reduced immunogenicity of “silenced” epitopes compared to unmodified controls. In contrast, some epitopes that were unaffected by chemical modification showed significantly increased cross-competition with sera from immunized animals. CONCLUSIONS: The chemical modifications developed here resulted in improved antibody recognition profiles in vitro and led to selective refocussing of antibody responses in vivo. Thus, chemical modification of vaccine antigens to stabilize antigen and refocus B cell responses presents an attractive tool for vaccine immunogen design.
Source:	AIDS Research and Human Retroviruses
ISSN:	0889-2229
Publisher:	Mary Ann Liebert
Volume:	30
Number:	S1
Page Range:	A66-A67
Date:	October 2014
Official Publication:	https://doi.org/10.1089/aid.2014.5121.abstract

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