Virus-Like Nanoparticles for Non-Capsid Antigen Delivery with Virus Structure/Functional Mimicry to Activate B Cell Immunity

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Various nanoparticles (NPs) have been used for delivery of small antigens, which have limited viral mimic features and are more efficacious than soluble antigens in stimulating B-cell immunity. However, these traditional NPs lack characteristics of virus “spiky capsid protein peplomer”, e.g. spiky antigen clusters on the peplomers, optimal distance between antigen clusters, and highly localized antigen density on the spike. It is unknown how the lack of virus-like features of traditional NPs affect B cell immunity and durable antibody responses. Although virus-like features of B cell vaccine for durable B cell immunity are clinically validated using virus-like particles (VLPs) of viral capsid proteins, VLPs are not suitable for delivery of non-capsid small antigens (such as bacterial toxins, small molecules, and oncogenic peptides) since these non-capsid small antigens are not able to self-assemble to VLPs. There is a need to develop virus-like nanoparticles for small antigens to activate B cell immunity against deadly bacterial toxins (Anthrax, Botulinum), small molecules, and oncogenic peptides. Three components of B cell immunity are critical for durable antibody response: (A) Efficient antigen delivery/retention and unique antigen distribution patterns for B cell acquisition in the draining lymph nodes (dLNs), (B) Activation of antigen-specific B cells through multivalent binding/crosslink with B cell receptor (BCR), (C) Activation of follicular T Helper cells (Tfh) that support Germinal Center (GC) B cells and their differentiation to long-lived plasma cells (LLPCs). However, it is unknown how the lack of virus-like features of NPs antigen delivery systems affect these three critical components of B cell immunity for durable antibody response. In this proposal, we will generate inorganic virus like nanoparticles (IVLNs) with three features of spiky peplomers of virus' using four types of small antigens (peptides of anthrax and botulinum toxins, small molecule 4-hydroxy- 3-nitrophenyl acetyl-hapten, HER2 peptides) to test our hypothesis. We hypothesize that: (A) Virus-like features of IVLNs enhance efficient delivery/retention with unique antigen distribution patterns for B cell acquisition in the lymph node, (B) Virus-like features of IVLNs enhance B cell activation via multivalent bind/crosslink with B cell receptor, promote follicular T (Tfh) cell-dependent B-cell activation, enhance formation of long-lived plasma cells (LLPCs) in the Germinal Center (GC), and generate antibodies with high specificity/affinity, (C) Virus-like features of IVLNs induce durable antibody response against bacterial toxins (anthrax and botulinum) and oncogenic antigens. Aim 1 Determine virus-like features of IVLNs to improve antigen delivery/retention with unique antigen distribution patterns for B cell acquisition in the lymph nodes vs. traditional NPs Aim 2 Identify the stages of B cell responses by the virus-like features of IVLNs vs. traditional NPs Aim 3 Investigate IVLNs-antigen immunizations to induce more durable antibody response against Anthrax and Botulinum toxins and oncogenic HER2 in animals vs. traditional NPs