Dual Plug-and-Display Synthetic Assembly Using Orthogonal Reactive Proteins for Twin Antigen Immunization

Bioconjug Chem. 2017 May 17;28(5):1544-1551. doi: 10.1021/acs.bioconjchem.7b00174. Epub 2017 May 5.

Abstract

Engineering modular platforms to control biomolecular architecture can advance both the understanding and the manipulation of biological systems. Icosahedral particles uniformly displaying single antigens stimulate potent immune activation and have been successful in various licensed vaccines. However, it remains challenging to display multiple antigens on a single particle and to induce broader immunity protective across strains or even against distinct diseases. Here, we design a dually addressable synthetic nanoparticle by engineering the multimerizing coiled-coil IMX313 and two orthogonally reactive split proteins. SpyCatcher protein forms an isopeptide bond with SpyTag peptide through spontaneous amidation. SnoopCatcher forms an isopeptide bond with SnoopTag peptide through transamidation. SpyCatcher-IMX-SnoopCatcher provides a modular platform, whereby SpyTag-antigen and SnoopTag-antigen can be multimerized on opposite faces of the particle simply upon mixing. We demonstrate efficient derivatization of the platform with model proteins and complex pathogen-derived antigens. SpyCatcher-IMX-SnoopCatcher was expressed in Escherichia coli and was resilient to lyophilization or extreme temperatures. For the next generation of malaria vaccines, blocking the transmission of the parasite from human to mosquito is an important goal. SpyCatcher-IMX-SnoopCatcher multimerization of the leading transmission-blocking antigens Pfs25 and Pfs28 greatly enhanced the antibody response to both antigens in comparison to the monomeric proteins. This dual plug-and-display architecture should help to accelerate vaccine development for malaria and other diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Complement C4b-Binding Protein / chemistry
  • Complement C4b-Binding Protein / immunology*
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / immunology*
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / immunology*
  • Vaccination
  • Vaccines, Synthetic / chemistry
  • Vaccines, Synthetic / immunology

Substances

  • Complement C4b-Binding Protein
  • Escherichia coli Proteins
  • Pfs25 protein, Plasmodium falciparum
  • Protozoan Proteins
  • Vaccines, Synthetic