Protein-based antigen presentation platforms for nanoparticle vaccines

Abstract

Modern vaccine design has sought a minimalization approach, moving to the isolation of antigens from pathogens that invoke a strong neutralizing immune response. This approach has created safer vaccines but may limit vaccine efficacy due to poor immunogenicity. To combat global diseases such as COVID-19, malaria, and AIDS there is a clear urgency for more effective next-generation vaccines. One approach to improve the immunogenicity of vaccines is the use of nanoparticle platforms that present a repetitive array of antigen on its surface. This technology has been shown to improve antigen presenting cell uptake, lymph node trafficking, and B-cell activation through increased avidity and particle size. With a focus on design, we summarize natural platforms, methods of antigen attachment, and advancements in generating self-assembly that have led to new engineered platforms. We further examine critical parameters that will direct the usage and development of more effective platforms.

Fig. 1. The three categories of nanoparticle roles in vaccines as adjuvants, carriers, and platforms with the descriptions of the role below.

Gray circles represent nanoparticles while, green circular indented units represent antigens. Abbreviations PLA, PLGA, and PEG correspond to polylactic acid, polylactic-co-glycolic acid, and polyethylene glycol, respectively. Modified and adapted from Zhao et al..

Fig. 2. Advantages of protein nanoparticle vaccines.

Yellow icosahedrons represent a protein nanoparticle platform while green circular sectors represent a genetically fused antigen. a Beneficial effects of increased size by presenting antigen on a nanoparticle platform. One of these effects is improved binding of complement indicated by the rectangular orange shape, on the surface of the nanoparticle. The bound complement facilitates binding to complement receptors on APCs such as follicular dendritic cells and promotes retention of the opsonized nanoparticles in the lymph nodes. Another effect of increased size is enhanced uptake of nanoparticles by APCs, indicated by the circular cavity and direction of travel arrow into the APC, in light blue. b Enhanced B-cell activation through the interaction of multiple antigens with BCRs, which are embedded within the membrane of the B-cell.

Fig. 3. Methods of Antigen attachment to nanoparticle platform.

Protein sequences are indicated by rectangular boxes, arranged left to right from N to C terminals. Protein nanoparticle platforms are represented by a yellow icosahedron and antigens are represented as a green circular sector. a A typical chemical conjugation scheme for protein nanoparticles, which involves the chemical treatment of a reactive amino acid on either the nanoparticle or antigen to conjugate with a reactive amino acid on the other respective protein. In this case, the nanoparticle is chemically treated to bind with a reactive amino acid residue on the antigen. b Genetic fusion with the platform, indicated by a distinct black line between the antigen and nanoparticle. c An example of tag-coupling systems, where the genetic fusion of a protein receptor or protein catcher, represented as cyan colored squares with a cavity, to one component allows for binding to another component through a genetically fused tag, represented as a small pink rectangle.

Fig. 4. Summary of published engineered self-assembling nanoparticles and naturally assembling nanoparticles, sorted by symmetry type.

For the names of engineered nanoparticles, the first letter indicates symmetry of the design T, O, or I for tetrahedral, octahedral, icosahedral, respectively. The first number indicates the oligomeric state of the primary building block, while the second number represents the oligomeric state of the secondary building block, if present in the design. The abbreviation “CC” stands for a coiled-coil motif. A plus (+) between the first and second number indicates that self-assembly is generated by genetic fusion between two monomers of the primary and secondary building block, versus Interface design with Rosetta. As a visual aid, the primary building block (red) and secondary (cyan) are aligned to the vertices or faces of a polyhedra^, that resembles the geometry of the nanoparticle. Genetically fused building blocks are emphasized with a yellow-dashed box.

Fig. 5. Critical parameters of nanoparticle platforms and potential optimal ranges based on current research.

Gradient increases in intensity from less optimal to most optimal. a Parameters for optimal size of a nanoparticle with a trend as size increases for enhanced opsonization and APC uptake, but inhibited lymph node trafficking. b Trend for improved B-cell activation as antigen valency increases. c The ideal range between antigen in order to facilitate efficient B-cell activation, with potential steric constraints preventing efficient B-cell activation at distances below 28 nm.