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Abstract
For many infectious diseases there is still no vaccine, even though potential protective antigens have been identified. Suitable platforms and conjugation routes are urgently needed to convert the promise of such antigens into broadly protective and scalable vaccines. Here we apply a newly established peptide-peptide ligation approach, SnoopLigase, for specific and irreversible coupling of antigens onto an oligomerization platform. SnoopLigase was engineered from a Streptococcus pneumoniae adhesin and enables isopeptide bond formation between two peptide tags: DogTag and SnoopTagJr. We expressed in bacteria DogTag linked to the self-assembling coiled-coil nanoparticle IMX313. This platform was stable over months at 37 °C when lyophilized, remaining reactive even after boiling. IMX-DogTag was efficiently coupled to two blood-stage malarial proteins (from PfEMP1 or CyRPA), with SnoopTagJr fused at the N- or C-terminus. We also showed SnoopLigase-mediated coupling of a telomerase peptide relevant to cancer immunotherapy. SnoopLigase-mediated nanoassembly enhanced the antibody response to both malaria antigens in a prime-boost model. Including or depleting SnoopLigase from the conjugate had little effect on the antibody response to the malarial antigens. SnoopLigase decoration represents a promising and accessible strategy for modular plug-and-display vaccine assembly, as well as providing opportunities for robust nanoconstruction in synthetic biology.
Highlights
Successful vaccines, such as against smallpox or polio, mediate protection primarily via antibodies targeting low variability antigens[1]
We explore the potential of SnoopLigase for nanoassembly of modular vaccines, using malaria antigens for proof-of-concept
Adding SnoopLigase would lead to covalent coupling of DogTag to SnoopTagJr through isopeptide bond formation, enabling modular oligomerization of the antigen (Fig. 1)
Summary
Successful vaccines, such as against smallpox or polio, mediate protection primarily via antibodies targeting low variability antigens[1]. Diseases resistant to vaccination, such as malaria or HIV, show high antigen sequence diversity and transient antigen availability for targeting by the immune system[2,3,4,5] Such characteristics present a great challenge when vaccine efficacy requires high serum antibody titers, combined with long-lived antibody responses[6]. A single immunization is required for Cervarix and Gardasil to induce long-lasting protective antibody responses[11,12] These virus-like particle (VLP) vaccines present the antigen in dense arrays on a multimerizing scaffold. Post-translational approaches provide an important alternative way to connect a display platform to an antigen These methods include click chemistry[32], sortase-mediated attachment[33,34], affinity tag conjugations[35,36], Ni-NTA:His-tagged interaction[37], and chemical cross-linking[38,39]. We explore the potential of SnoopLigase for nanoassembly of modular vaccines, using malaria antigens for proof-of-concept
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