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Nanoparticle vaccines are a diverse category of vaccines for the prophylaxis or treatment of various diseases. Several strategies have been employed for their optimization, especially to enhance vaccine immunogenicity and generate potent B‐cell responses. Two major modalities utilized for particulate antigen vaccines include using nanoscale structures for antigen delivery and nanoparticles that are themselves vaccines due to antigen display or scaffolding—the latter of which we will define as "nanovaccines." Multimeric antigen display has a variety of immunological benefits compared to monomeric vaccines mediated through potentiating antigen‐presenting cell presentation and enhancing antigen‐specific B‐cell responses through B‐cell activation. The majority of nanovaccine assembly is done in vitro using cell lines. However, in vivo assembly of scaffolded vaccines potentiated using nucleic acids or viral vectors is a burgeoning modality of nanovaccine delivery. Several advantages to in vivo assembly exist, including lower costs of production, fewer production barriers, as well as more rapid development of novel vaccine candidates for emerging diseases such as SARS‐CoV‐2. This review will characterize the methods for de novo assembly of nanovaccines in the host using methods of gene delivery including nucleic acid and viral vectored vaccines. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious DiseaseBiology‐Inspired Nanomaterials > Nucleic Acid‐Based StructuresBiology‐Inspired Nanomaterials > Protein and Virus‐Based StructuresTherapeutic Approaches and Drug Discovery > Emerging Technologies [ABSTRACT FROM AUTHOR]

Nanoparticle vaccines usually prime stronger immune responses than soluble antigens. Within this class of subunit vaccines, the recent development of computationally designed self-assembling two-component protein nanoparticle scaffolds provides a powerful and versatile platform for displaying multiple copies of one or more antigens. Here we report the generation of three different nanoparticle immunogens displaying 60 copies of p67C, an 80 amino acid polypeptide from a candidate vaccine antigen of Theileria parva, and their immunogenicity in cattle. p67C is a truncation of p67, the major surface protein of the sporozoite stage of T. parva, an apicomplexan parasite that causes anoftenfatal bovine disease called East Coast fever (ECF) in sub-Saharan Africa. Compared to I32-19 and I32-28, we found that I53-50 nanoparticle scaffolds displaying p67C had the best biophysical characteristics. p67C-I53-50 also outperformed the other two nanoparticles in stimulating p67C-specific IgG1 and IgG2 antibodies and CD4+ T-cell responses, as well as sporozoite neutralizing capacity. In experimental cattle vaccine trials, p67C-I53-50 induced significant immunity to ECF, suggesting that the I53-50 scaffold is a promising candidate for developing novel nanoparticle vaccines. To our knowledge this is the first application of computationally designed nanoparticles to the development of livestock vaccines. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has demonstrated great promise with several checkpoint inhibitors being approved as the first-line therapy for some types of cancer, and new engineered cytokines such as Neo2/15 now being evaluated in many studies. In this work, we designed antibody-cytokine chimera (ACC) scaffolding cytokine mimetics on a full-length tumor-specific antibody. We characterized the pharmacokinetic (PK) and pharmacodynamic (PD) properties of first-generation ACC TA99-Neo2/15, which synergized with DLnano-vaccines to suppress in vivo melanoma proliferation and induced significant systemic cytokine activation. A novel second-generation ACC TA99-HL2-KOA1, with retained IL-2Rβ/γ binding and attenuated but preserved IL-2Rα binding, induced lower systemic cytokine activation with non-inferior protection in murine tumor studies. Transcriptomic analyses demonstrated an upregulation of Type I interferon responsive genes, particularly ISG15, in dendritic cells, macrophages and monocytes following TA99-HL2-KOA1 treatment. Characterization of additional ACCs in combination with cancer vaccines will likely be an important area of research for treating melanoma and other types of cancer.

Nanoparticle vaccines usually prime stronger immune responses than soluble antigens. Within this class of subunit vaccines, the recent development of computationally designed self-assembling two-component protein nanoparticle scaffolds provides a powerful and versatile platform for displaying multiple copies of one or more antigens. Here we report the generation of three different nanoparticle immunogens displaying 60 copies of p67C, an 80 amino acid polypeptide from a candidate vaccine antigen of Theileria parva, and their immunogenicity in cattle. p67C is a truncation of p67, the major surface protein of the sporozoite stage of T. parva, an apicomplexan parasite that causes an often-fatal bovine disease called East Coast fever (ECF) in sub-Saharan Africa. Compared to I32-19 and I32-28, we found that I53-50 nanoparticle scaffolds displaying p67C had the best biophysical characteristics. p67C-I53-50 also outperformed the other two nanoparticles in stimulating p67C-specific IgG1 and IgG2 antibodies and CD4+ T-cell responses, as well as sporozoite neutralizing capacity. In experimental cattle vaccine trials, p67C-I53-50 induced significant immunity to ECF, suggesting that the I53-50 scaffold is a promising candidate for developing novel nanoparticle vaccines. To our knowledge this is the first application of computationally designed nanoparticles to the development of livestock vaccines.

Multivalent presentation of antigens using nanoparticles (NPs) as a platform is an effective strategy to enhance the immunogenicity of subunit vaccines and thus induce a high level of organismal immune response. Our previous results showed that pre-existing porcine circovirus type 2 (PCV2) antibodies could increase the antibody levels of nanoparticle vaccines carried in PCV2 VLPs. Here, we have established a generalized nanoantigen display platform, Cap-Cat virus-like particles (VLPs). By combining PCV2 VLPs with the modular linker element SpyTag003/SpyCatcher003 system, four porcine-derived viral protective antigens with different sizes and multimeric structures: the PRRSV B-cell epitope, the PEDV COE monomer, the CSFV E2 dimer, and the SIV HA trimer were efficiently demonstrated to elicit a strong immune response in mice. Crucially, the modification of antigens by the Cap-Cat VLPs platform enhanced the Th2 response and improved the Th1 response. The use of the platform demonstrates that HA antigen protects against lethal attacks by influenza viruses and reduces viral load in the lungs. We have demonstrated that the Cap-Cat VLPs platform demonstrates that antigens enhance the immune response by improving the processes of DC uptake, transport, lymph node (LN) localization, and immune cell activation. This "plug-and-display" assembly strategy facilitates the use of the Cap-Cat VLPs nanoantigen display platform for more applications and thus facilitates the development of more efficient, general-purpose porcine subunit vaccines.

The Fc-fused receptor binding domain (RBD-Fc) vaccine for SARS-CoV-2 has garnered significant attention for its capacity to provide effective and specific immune protection. However, its immunogenicity is limited, highlighting the need for improvement in clinical application. Nanoparticle delivery has been shown to be an effective method for enhancing antigen immunogenicity. In this study, we developed bivalent nanoparticle recombinant protein vaccines by assembling the RBD-Fc of SARS-CoV-2 and Fc-binding homo-oligomers o42.1 and i52.3 into octahedral and icosahedral nanoparticles. The formation of RBD-Fc nanoparticles was confirmed through structural characterization and cell binding experiments. Compared to RBD-Fc dimers, the nanoparticle vaccines induced more potent neutralizing antibodies (nAb) and stronger cellular immune responses. Therefore, using bivalent nanoparticle vaccines based on RBD-Fc presents a promising vaccination strategy against SARS-CoV-2 and offers a universal approach for enhancing the immunogenicity of Fc fusion protein vaccines. • RBD-Fc based nanoparticle vaccines are assembled using designed Fc-binding homo-oligomers. • RBD-Fc nanoparticle vaccines enhance the humoral and cellular immune response induced by RBD-Fc. • This study provides a feasible method for enhancing the immunogenicity of Fc fusion antigens. [ABSTRACT FROM AUTHOR]

• The importance of the animal-human interface in the history of vaccinology. • Online tools for the design and development of veterinary vaccines. • Landmark discoveries in veterinary vaccinology. • Platform technologies for accelerating veterinary vaccine development. • The One Health benefits of controlling animal diseases. The animal-human interface has played a central role in advances made in vaccinology for the past two centuries. Many traditional veterinary vaccines were developed by growing, attenuating, inactivating and fractioning the pathogen of interest. While such approaches have been very successful, we have reached a point where they have largely been exhausted and alternative approaches are required. Furthermore, although subunit vaccines have enhanced safety profiles and created opportunities for combined discrimination between vaccinated and infected animal (DIVA) approaches, their functionality has largely been limited to diseases that can be controlled by humoral immunity until very recently. We now have a new generation of adjuvants and delivery systems that can elicit CD4 + T cells and/or CD8 + T cell responses in addition to high-titre antibody responses. We review the current vaccine platform technologies, describe their roles in veterinary vaccinology and discuss how knowledge of their mode of action allows informed decisions on their deployment with wider benefits for One Health. [ABSTRACT FROM AUTHOR]

The SARS‐CoV‐2 Delta (B.1.617.2) strain is a variant of concern (VOC) that has become the dominant strain worldwide in 2021. Its transmission capacity is approximately twice that of the original strain, with a shorter incubation period and higher viral load during infection. Importantly, the breakthrough infections of the Delta variant have continued to emerge in the first‐generation vaccine recipients. There is thus an urgent need to develop a novel vaccine with SARS‐CoV‐2 variants as the major target. Here, receptor binding domain (RBD)‐conjugated nanoparticle vaccines targeting the Delta variant, as well as the early and Beta/Gamma strains, are developed. Under both a single‐dose and a prime‐boost strategy, these RBD‐conjugated nanoparticle vaccines induce the abundant neutralizing antibodies (NAbs) and significantly protect hACE2 mice from infection by the authentic SARS‐CoV‐2 Delta strain, as well as the early and Beta strains. Furthermore, the elicitation of the robust production of broader cross‐protective NAbs against almost all the notable SARS‐CoV‐2 variants including the Omicron variant in rhesus macaques by the third re‐boost with trivalent vaccines is found. These results suggest that RBD‐based monovalent or multivalent nanoparticle vaccines provide a promising second‐generation vaccine strategy for SARS‐CoV‐2 variants. [ABSTRACT FROM AUTHOR]

Abstract The SARS‐CoV‐2 Delta (B.1.617.2) strain is a variant of concern (VOC) that has become the dominant strain worldwide in 2021. Its transmission capacity is approximately twice that of the original strain, with a shorter incubation period and higher viral load during infection. Importantly, the breakthrough infections of the Delta variant have continued to emerge in the first‐generation vaccine recipients. There is thus an urgent need to develop a novel vaccine with SARS‐CoV‐2 variants as the major target. Here, receptor binding domain (RBD)‐conjugated nanoparticle vaccines targeting the Delta variant, as well as the early and Beta/Gamma strains, are developed. Under both a single‐dose and a prime‐boost strategy, these RBD‐conjugated nanoparticle vaccines induce the abundant neutralizing antibodies (NAbs) and significantly protect hACE2 mice from infection by the authentic SARS‐CoV‐2 Delta strain, as well as the early and Beta strains. Furthermore, the elicitation of the robust production of broader cross‐protective NAbs against almost all the notable SARS‐CoV‐2 variants including the Omicron variant in rhesus macaques by the third re‐boost with trivalent vaccines is found. These results suggest that RBD‐based monovalent or multivalent nanoparticle vaccines provide a promising second‐generation vaccine strategy for SARS‐CoV‐2 variants.

Nanoparticle vaccines are a diverse category of vaccines for the prophylaxis or treatment of various diseases. Several strategies have been employed for their optimization, especially to enhance vaccine immunogenicity and generate potent B-cell responses. Two major modalities utilized for particulate antigen vaccines include using nanoscale structures for antigen delivery and nanoparticles that are themselves vaccines due to antigen display or scaffolding-the latter of which we will define as "nanovaccines." Multimeric antigen display has a variety of immunological benefits compared to monomeric vaccines mediated through potentiating antigen-presenting cell presentation and enhancing antigen-specific B-cell responses through B-cell activation. The majority of nanovaccine assembly is done in vitro using cell lines. However, in vivo assembly of scaffolded vaccines potentiated using nucleic acids or viral vectors is a burgeoning modality of nanovaccine delivery. Several advantages to in vivo assembly exist, including lower costs of production, fewer production barriers, as well as more rapid development of novel vaccine candidates for emerging diseases such as SARS-CoV-2. This review will characterize the methods for de novo assembly of nanovaccines in the host using methods of gene delivery including nucleic acid and viral vectored vaccines. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures Biology-Inspired Nanomaterials > Protein and Virus-Based Structures Therapeutic Approaches and Drug Discovery > Emerging Technologies., (© 2023 Wiley Periodicals LLC.)

Cancer immunotherapy has demonstrated great promise with several checkpoint inhibitors being approved as the first-line therapy for some types of cancer, and new engineered cytokines such as Neo2/15 now being evaluated in many studies. In this work, we designed antibody-cytokine chimera (ACC) scaffolding cytokine mimetics on a full-length tumor-specific antibody. We characterized the pharmacokinetic (PK) and pharmacodynamic (PD) properties of first-generation ACC TA99-Neo2/15, which synergized with DLnano-vaccines to suppress in vivo melanoma proliferation and induced significant systemic cytokine activation. A novel second-generation ACC TA99-HL2-KOA1, with retained IL-2Rβ/γ binding and attenuated but preserved IL-2Rα binding, induced lower systemic cytokine activation with non-inferior protection in murine tumor studies. Transcriptomic analyses demonstrated an upregulation of Type I interferon responsive genes, particularly ISG15, in dendritic cells, macrophages and monocytes following TA99-HL2-KOA1 treatment. Characterization of additional ACCs in combination with cancer vaccines will likely be an important area of research for treating melanoma and other types of cancer., Competing Interests: ZX, DW and DK have a pending patent US.62784318. MW and TS are employees of Inovio Pharmaceuticals and as such receive salary and benefits including ownership of stock and stock options from the company. DW has received grant funding, participates in industry collaborations, has received speaking honoraria, and has received fees for consulting, including serving on scientific review committees. Remunerations received by DW. include direct payments and equity/options. DW also discloses the following associations with commercial partners: Geneos (consultant/advisory board), AstraZeneca (advisory board, speaker), Inovio (board of directors, consultant), Sanofi (advisory board), BBI (advisory board), Pfizer (advisory Board), Flagship (consultant), and Advaccine (consultant). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding in part by Inovio Pharmaceuticals, SRA 21-04 awarded to DW. The funder had the following involvement in the study: electroporation device used for animal experiments., (Copyright © 2023 Tursi, Xu, Helble, Walker, Liaw, Chokkalingam, Kannan, Wu, Tello-Ruiz, Park, Zhu, Wise, Smith, Majumdar, Kossenkov, Kulp and Weiner.)

The ongoing COVID-19 pandemic caused by SARS-CoV-2 has led to millions of deaths worldwide. Streptococcus pneumoniae (S. pneumoniae) remains a major cause of mortality in underdeveloped countries. A vaccine that prevents both SARS-CoV-2 and S. pneumoniae infection represents a long-sought "magic bullet". Herein, a nanoparticle vaccine, termed SCTV01B, is rationally developed by using the capsular polysaccharide of S. pneumoniae serotype 14 (PPS14) as the backbone to conjugate with the recombinant receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. The final formulation of conjugated nanoparticles in the network structure exhibits high thermal stability. Immunization with SCTV01B induces potent humoral and Type 1/Type 2 T helper cell (Th1/Th2) cellular immune responses in mice, rats, and rhesus macaques. In particular, SCTV01B-immunized serum not only broadly cross-neutralizes all SARS-CoV-2 variants of concern (VOCs), including the most recent Omicron variant, but also shows high opsonophagocytic activity (OPA) against S. pneumoniae serotype 14. Finally, SCTV01B vaccination confers protection against challenges with the SARS-CoV-2 mouse-adapted strain and the original strain in established murine models. Collectively, these promising preclinical results support further clinical evaluation of SCTV01B, highlighting the potency of polysaccharide-RBD-conjugated nanoparticle vaccine platforms for the development of vaccines for COVID-19 and other infectious diseases., (© 2022 Wiley-VCH GmbH.)