Synthetic biology for bioengineering virus-like particle vaccines

Abstract

Vaccination is the most effective method of disease prevention and control. Many viruses and bacteria that once caused catastrophic pandemics (e.g., smallpox, poliomyelitis, measles, and diphtheria) are either eradicated or effectively controlled through routine vaccination programs. Nonetheless, vaccine manufacturing remains incredibly challenging. Viruses exhibiting high antigenic diversity and high mutation rates cannot be fairly contested using traditional vaccine production methods and complexities surrounding the manufacturing processes, which impose significant limitations. Virus-like particles (VLPs) are recombinantly produced viral structures that exhibit immunoprotective traits of native viruses but are noninfectious. Several VLPs that compositionally match a given natural virus have been developed and licensed as vaccines. Expansively, a plethora of studies now confirms that VLPs can be designed to safely present heterologous antigens from a variety of pathogens unrelated to the chosen carrier VLPs. Owing to this design versatility, VLPs offer technological opportunities to modernize vaccine supply and disease response through rational bioengineering. These opportunities are greatly enhanced with the application of synthetic biology, the redesign and construction of novel biological entities. This review outlines how synthetic biology is currently applied to engineer VLP functions and manufacturing process. Current and developing technologies for the identification of novel target-specific antigens and their usefulness for rational engineering of VLP functions (e.g., presentation of structurally diverse antigens, enhanced antigen immunogenicity, and improved vaccine stability) are described. When applied to manufacturing processes, synthetic biology approaches can also overcome specific challenges in VLP vaccine production. Finally, we address several challenges and benefits associated with the translation of VLP vaccine development into the industry.

Keywords: capsomere; computational; omics technologies; synthetic biology; vaccine; virus-like particle.

Figure 1

Design tools for VLP vaccine engineering. Multitude of tools and recent advances in synthetic biology enable screening for pathogen‐specific antigens with high immunogenic potential and engineering of VLP function. (1) Omics technologies enable rapid identification and discovery of novel/potential vaccine antigens. (2) Structural biology and (3) system immunology assist rational reconfiguration and engineering of epitopes/VLPs for enhanced immunogenicity. (4) Bioinformatics and computational biology accelerate data analysis and translation into applicable knowledge. (a) Engineering VLP function on different types of VLP. While nonenveloped VLPs are commonly engineered using genetic engineering or chemical conjugation, enveloped VLPs rely on pseudotyping for function engineering. (b) VLPs can be engineered to offer broader immunogenicity, improved immunogenicity, or enhanced stability. Broadly immunogenic VLPs can be obtained by displaying multiple antigenically distinct epitopes (Pushko et al., 2011; Schwartzman et al., 2015), highly conserved epitopes (Krammer, 2015; Wiersma et al., 2015), or computationally optimized epitopes (Carter et al., 2016) within a single VLP. Improving VLP immunogenicity can be achieved by incorporating immunomodulatory agents, such as dendritic cells targeting antibodies into particles structure (Rosenthal et al., 2014). VLP stability can be enhanced by modulating particles formulation (Collins et al., 2017; Lua et al., 2014). VLP: virus‐like particle [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Application of synthetic biology to VLP vaccine platforms. (1) Enhanced immunogenicity of peptides is achieved through their insertion into exposed loops of viral capsid proteins (Murata et al., 2009; Slupetzky et al., 2007; Ye et al., 2014). (2) The structural properties of complex peptides are maintained through the incorporation of epitope scaffolds into exposed loops (Schneemann et al., 2012). (3) Large antigens are modularized onto VLP vaccine platforms using long flexible linkers to maintain structural separation between the viral capsid protein and the antigen (Kratz et al., 1999); or onto preformed VLPs using plug and play technologies, such as SpyCatcher/SpyTag (Brune et al., 2016) and AviTag (Thrane et al., 2015). (4) Dual expression of modified and unmodified viral capsid proteins reduces steric hindrance and permits VLP assembly (Tekewe et al., 2017). (5) The SplitCore system permits modularization of antigens with an extended structure through the coexpression of modified and unmodified HBcAg core fragments (Walker, Skamel, and Nassal, 2011). (a) Synthetic production of capsomeres minimizes host cell contaminants reducing required bioprocessing steps (Chuan et al., 2010). (b) Synthetic engineering of baculovirus vectors can increase VLP expression yield (Gómez‐Sebastián et al., 2014; Y. K. Liu et al., 2015; Y. V. Liu et al., 2015). VLP: virus‐like particle [Color figure can be viewed at wileyonlinelibrary.com]