Overcoming Symmetry Mismatch in Vaccine Nanoassembly through Spontaneous Amidation

Matching of symmetry at interfaces is a fundamental obstacle in molecular assembly. Virus-like particles (VLPs) are important vaccine platforms against pathogenic threats, including Covid-19. However, symmetry mismatch can prohibit vaccine nanoassembly. We established an approach for coupling VLPs to diverse antigen symmetries. SpyCatcher003 enabled efficient VLP conjugation and extreme thermal resilience. Many people had pre-existing antibodies to SpyTag:SpyCatcher but less to the 003 variants. We coupled the computer-designed VLP not only to monomers (SARS-CoV-2) but also to cyclic dimers (Newcastle disease, Lyme disease), trimers (influenza hemagglutinins), and tetramers (influenza neuraminidases). Even an antigen with dihedral symmetry could be displayed. For the global challenge of influenza, SpyTag-mediated display of trimer and tetramer antigens strongly induced neutralizing antibodies. SpyCatcher003 conjugation enables nanodisplay of diverse symmetries towards generation of potent vaccines.

Automated summary

The challenge of matching symmetry at interfaces in molecular assembly is overcome by coupling virus-like particles (VLPs) to diverse antigen symmetries using SpyCatcher003. This approach enables efficient VLP conjugation and extreme thermal resilience, allowing for the display of antigens with varying symmetries. The nanodisplay of different symmetries through SpyCatcher003 conjugation shows promise for the generation of potent vaccines.