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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]

We describe a small lipid nanoparticle (SLNP)‐based nanovaccine platform and a new combination treatment regimen. Tumor antigen‐displaying, CpG adjuvant‐embedded SLNPs (OVAPEP‐SLNP@CpG) were prepared from biocompatible phospholipids and a cationic cholesterol derivative. The resulting nanovaccine showed highly potent antitumor efficacy in both prophylactic and therapeutic E.G7 tumor models. However, this vaccine induced T cell exhaustion by elevating PD‐L1 expression, leading to tumor recurrence. Thus, the nanovaccine was combined with simultaneous anti‐PD‐1 antibody treatment, but the therapeutic efficacy of this regimen was comparable to that of the nanovaccine alone. Finally, mice that showed a good therapeutic response after the first cycle of immunization with the nanovaccine underwent a second cycle together with anti‐PD‐1 therapy, resulting in suppression of tumor relapse. This suggests that the antitumor efficacy of combinations of nanovaccines with immune checkpoint blockade therapy is dependent on treatment sequence and the timing of each modality. [ABSTRACT FROM AUTHOR]

We describe a small lipid nanoparticle (SLNP)‐based nanovaccine platform and a new combination treatment regimen. Tumor antigen‐displaying, CpG adjuvant‐embedded SLNPs (OVAPEP‐SLNP@CpG) were prepared from biocompatible phospholipids and a cationic cholesterol derivative. The resulting nanovaccine showed highly potent antitumor efficacy in both prophylactic and therapeutic E.G7 tumor models. However, this vaccine induced T cell exhaustion by elevating PD‐L1 expression, leading to tumor recurrence. Thus, the nanovaccine was combined with simultaneous anti‐PD‐1 antibody treatment, but the therapeutic efficacy of this regimen was comparable to that of the nanovaccine alone. Finally, mice that showed a good therapeutic response after the first cycle of immunization with the nanovaccine underwent a second cycle together with anti‐PD‐1 therapy, resulting in suppression of tumor relapse. This suggests that the antitumor efficacy of combinations of nanovaccines with immune checkpoint blockade therapy is dependent on treatment sequence and the timing of each modality. [ABSTRACT FROM AUTHOR]

Nanotechnologies are considered to be of growing importance to the vaccine field. Through decoration of immunogens on multivalent nanoparticles, designed nanovaccines can elicit improved humoral immunity. However, significant practical and monetary challenges in large‐scale production of nanovaccines have impeded their widespread clinical translation. Here, an alternative approach is illustrated integrating computational protein modeling and adaptive electroporation‐mediated synthetic DNA delivery, thus enabling direct in vivo production of nanovaccines. DNA‐launched nanoparticles are demonstrated displaying an HIV immunogen spontaneously self‐assembled in vivo. DNA‐launched nanovaccines induce stronger humoral responses than their monomeric counterparts in both mice and guinea pigs, and uniquely elicit CD8+ effector T‐cell immunity as compared to recombinant protein nanovaccines. Improvements in vaccine responses recapitulate when DNA‐launched nanovaccines with alternative scaffolds and decorated antigen are designed and evaluated. Finally, evaluation of functional immune responses induced by DLnanovaccines demonstrates that, in comparison to control mice or mice immunized with DNA‐encoded hemagglutinin monomer, mice immunized with a DNA‐launched hemagglutinin nanoparticle vaccine fully survive a lethal influenza challenge, and have substantially lower viral load, weight loss, and influenza‐induced lung pathology. Additional study of these next‐generation in vivo‐produced nanovaccines may offer advantages for immunization against multiple disease targets. [ABSTRACT FROM AUTHOR]

Although it has been shown that the size of nanoparticle-based vaccines is a key determining factor for the induction of immune responses, few studies have provided detailed analyses of thresholds or critical sizes of nanoparticle vaccines. Here we report effects of the size of gold nanoparticle (GNP)-based vaccines on their efficiency of delivery to lymph nodes (LNs) and induction of CD8 + T-cell responses. We further propose a threshold size of GNPs for use as an effective vaccine. To examine the effects of GNP size, we synthesized GNPs with diameters of 7, 14 and 28 nm, and then conjugated them with recombinant ovalbumin (OVA) as a model antigen. The resulting OVA-GNPs had hydrodynamic diameter (HD) of ~ 10, 22, and 33 nm for 7, 14 and 28 nm GNPs, respectively and exhibited a size-dependent increase in cellular uptake by dendritic cells (DCs) and subsequent T-cell cross-priming and activation. Upon injection into a mouse footpad, both 22- and 33-nm OVA-GNPs showed much higher delivery efficiency to draining LNs than did 10-nm OVA-GNPs. An ex vivo restimulation assay using OVA as an antigen revealed that frequencies of OVA-specific CD8 + T cells were higher in mice immunized with 22- and 33-nm OVA-GNPs than in those immunized with 10-nm OVA-GNPs; moreover, these cells were shown to be poly-functional. In a tumor-prevention study, 22-nm OVA-GNPs showed greater antitumor efficacy, and higher infiltration of CD8 + T-cells and greater tumor cell apoptosis and cell death than 10-nm OVA-GNPs. Taken together, our results suggest that the size threshold for induction of potent cellular responses and T-cell poly-functionality by GNPs lies between 10 nm and 22 nm, and highlight the importance of nanoparticle size as a critical parameter in designing and developing nanoparticle-based vaccines. [ABSTRACT FROM AUTHOR]

Abstract: Balancing immunogenicity with inflammation is a central tenet of vaccine design, especially for subunit vaccines that utilize traditional pro-inflammatory adjuvants. Here we report that by using a nanoparticulate peptide-based vaccine, immunogenicity and local inflammation could be decoupled. Self-assembled β-sheet-rich peptide nanofibers, previously shown to elicit potent antibody responses in mice, were found to be non-cytotoxic in vitro and, remarkably, elicited no measurable inflammation in vivo—with none of the swelling at the injection site, accumulation of inflammatory cells or cytokines, or production of allergic IgE that were elicited by an alum-adjuvanted vaccine. Nanofibers were internalized by dendritic cells and macrophages at the injection site, and only dendritic cells that acquired the material increased their expression of the activation markers CD80 and CD86. Immunization with epitope-bearing nanofibers elicited antigen-specific differentiation of T cells into T follicular helper cells and B cells into germinal center cells, as well as high-titer, high-affinity IgG that cross-reacted with the native protein antigen and was neutralizing in an in vitro influenza hemagglutination inhibition assay. These responses were superior to those induced by alum and comparable to those induced by complete Freund's adjuvant. Thus, nanoparticulate assemblies may provide a new route to non-inflammatory immunotherapies and vaccines. [Copyright &y& Elsevier]