How to Build a Synthetic Virus without a Living Host for Vaccination

There are 1.6 million mammalian and waterfowl viruses (Bull.WHO, 2018; 96:292). Even though only a miniscule set of these are known to infect humans, the potential that additional zoonotic viruses exist is high. Moreover, the natural evolution of viruses is rapid and hard to predict. Our best defense against viral illness is to train our immune system to recognize a threat before we are exposed to it. While vaccines address this need, we are largely ill-prepared to design, manufacture, and distribute vaccines rapidly during a pandemic outbreak. To stay abreast of viral threats, we must transform our approach to vaccine science and engineering. mRNA vaccines are one approach, as are “virus-like particle (VLP) vaccines. Our team takes another approach; we use synthetic biology and engineering to build a proteo-lipid nanoparticle vaccine that is easy to synthesize, tunable in antigen(s) presentation, nonvirulent, and eliminates cell production currently required to generate both VLP vaccines or the expression of the antigen from mRNA lipoparticles. We have achieved the successful cell-free synthesis of Nipah virus viral coat proteins embedded into lipid vesicles using our synthetic biology approach and show that the nanoparticles we created elicit neutralizing antibodies in mice. We have also successfully synthesized into lipid vesicles the full transmembrane Spike protein from coronavirus and hemagglutinin from influenza into lipid nanoparticles using cell-free approaches. This synthetic approach enables molecular-level modification that can be guided by computational and data-driven design approaches, leading to a modular approach to vaccine optimization. New insights into fundamental mechanisms of immune response will be enabled by unprecedented homogeneity of the particle structure possible with this approach.