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Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses

Abstract

Vaccines based on recombinant proteins avoid the toxicity and antivector immunity associated with live vaccine (for example, viral) vectors, but their immunogenicity is poor, particularly for CD8+ T-cell responses. Synthetic particles carrying antigens and adjuvant molecules have been developed to enhance subunit vaccines, but in general these materials have failed to elicit CD8+ T-cell responses comparable to those for live vectors in preclinical animal models. Here, we describe interbilayer-crosslinked multilamellar vesicles formed by crosslinking headgroups of adjacent lipid bilayers within multilamellar vesicles. Interbilayer-crosslinked vesicles stably entrapped protein antigens in the vesicle core and lipid-based immunostimulatory molecules in the vesicle walls under extracellular conditions, but exhibited rapid release in the presence of endolysosomal lipases. We found that these antigen/adjuvant-carrying vesicles form an extremely potent whole-protein vaccine, eliciting endogenous T-cell and antibody responses comparable to those for the strongest vaccine vectors. These materials should enable a range of subunit vaccines and provide new possibilities for therapeutic protein delivery.

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Figure 1: Synthesis of ICMVs.
Figure 2: Protein encapsulation and release from ICMVs.
Figure 3: In vitro stimulation of immune responses by ICMVs supplemented with the TLR agonist MPLA.
Figure 4: In vivo immunization with ICMVs versus soluble antigen or antigen encapsulated in non-crosslinked vesicles.
Figure 5: ICMVs carrying antigen in the aqueous core and MPLA embedded in the vesicle walls elicit potent antibody and CD8T responses.

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Acknowledgements

This work was supported in part by the Ragon Institute of MGH, MIT and Harvard, the Gates Foundation, the Department. of Defense (contract W911NF-07-D-0004) and the National Institutes of Health (P41RR002250 and RC2GM092599). The authors would like to thank A. Yadava for providing the VMP antigen. D.J.I. is an investigator of the Howard Hughes Medical Institute.

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J.J.M. and D.J.I. designed the experiments. J.J.M. carried out the experiments; H.S. assisted in the in vivo characterization and immunization studies. A.B., H.K., J.T.G., J.R. and W.C. contributed cryoelectron microscope imaging. M.T.S. and S.H.U. contributed experimental suggestions. H.L., B.H., M.S. and S.L. provided technical support. J.J.M. and D.J.I. analysed the data and wrote the paper.

Corresponding author

Correspondence to Darrell J. Irvine.

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The authors declare no competing financial interests.

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Moon, J., Suh, H., Bershteyn, A. et al. Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses. Nature Mater 10, 243–251 (2011). https://doi.org/10.1038/nmat2960

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