Construction of minimalistic pan-coronavirus vaccines devoid of adverse spike epitopes but with a safer LNP delivery system
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PROVIDER: PRJEB71450 | ENA |
REPOSITORIES: ENA
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Project description:The efficient activation of professional antigen-presenting cells-such as dendritic cells (DC)-in tumors and lymph nodes is critical for the design of next-generation cancer vaccines and may be able to provide anti-tumor effects by itself through immune stimulation. The challenge is to stimulate these cells without causing excessive toxicity. It is hypothesized that a multi-pronged combinatorial approach to DC stimulation would allow dose reductions of innate immune receptor-stimulating TLR3 agonists while enhancing drug efficacy. Here, a hybrid lipid nanoparticle (LNP) platform is developed and tested for double-stranded RNA (polyinosinic:polycytidylic acid for TLR3 agonism) and immune modulator (L-CANDI) delivery. This study shows that the ≈120 nm hybrid nanoparticles-in-nanoparticles effectively eradicate tumors by themselves and generate long-lasting, durable anti-tumor immunity in mouse models.
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Project description:BackgroundThe SARS-CoV-2 non-Spike (S) structural protein targets on nucleocapsid (N), membrane (M) and envelope (E), critical in the host cell interferon response and memory T-cell immunity, are grossly overlooked in COVID vaccine development. The current Spike-only vaccines bear an intrinsic shortfall for promotion of a fuller T cell immunity. Vaccines designed to target conserved epitopes could elicit strong cellular immune responses that would synergize with B cell responses and lead to long-term vaccine success. We pursue a universal (pan-SARS-CoV-2) vaccine against Delta, Omicrons and ever-emergent new mutants.Methods and findingsWe explored booster immunogenicity of UB-612, a multitope-vaccine that contains S1-RBD-sFc protein and sequence-conserved promiscuous Th and CTL epitope peptides on the Sarbecovirus N, M and S2 proteins. To a subpopulation (N = 1,478) of infection-free participants (aged 18-85 years) involved in a two-dose Phase-2 trial, a UB-612 booster (third dose) was administered 6-8 months after the second dose. The immunogenicity was evaluated at 14 days post-booster with overall safety monitored until the end of study. The booster induced high viral-neutralizing antibodies against live Wuhan WT (VNT50, 1,711) and Delta (VNT50, 1,282); and against pseudovirus WT (pVNT50, 11,167) vs. Omicron BA.1/BA.2/BA.5 variants (pVNT50, 2,314/1,890/854), respectively. The lower primary neutralizing antibodies in the elderly were uplifted upon boosting to approximately the same high level in young adults. UB-612 also induced potent, durable Th1-oriented (IFN-γ+-) responses (peak/pre-boost/post-boost SFU/106 PBMCs, 374/261/444) along with robust presence of cytotoxic CD8+ T cells (peak/pre-boost/post-boost CD107a+-Granzyme B+, 3.6%/1.8%/1.8%). This UB-612 booster vaccination is safe and well tolerated without SAEs.ConclusionsBy targeting conserved epitopes on viral S2, M and N proteins, UB-612 could provide potent, broad and long-lasting B-cell and T-cell memory immunity and offers the potential as a universal vaccine to fend off Omicrons and new VoCs without resorting to Omicron-specific immunogens.Trial registrationClinicalTrials.gov ID: NCT04773067; ClinicalTrials.gov ID: NCT05293665; ClinicalTrials.gov ID: NCT05541861.
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Project description:Extracellular vesicles (EVs) are tiny, lipid membrane-bound structures that are released by most cells. They play a vital role in facilitating intercellular communication by delivering bioactive cargoes to recipient cells and triggering cellular as well as biological responses. EVs have enormous potential for therapeutic applications as native or engineered exosomes. Native EVs are naturally released by cells without undergoing any modifications to either the exosomes or the cells that secrete them. In contrast, engineered EVs have been deliberately modified post-secretion or through genetic engineering of the secreting cells to alter their composition. Here we propose that engineered EVs displaying pathogen proteins could serve as promising alternatives to lipid nanoparticle (LNP)-mRNA vaccines. By leveraging their unique characteristics, these engineered EVs have the potential to overcome certain limitations associated with LNP-mRNA vaccines.
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Project description:The development of clinically useful peptide-based vaccines remains a long-standing goal. This review highlights that intrinsically disordered protein antigens, which lack an ordered three-dimensional structure, represent excellent starting points for the development of such vaccines. Disordered proteins represent an important class of antigen in a wide range of human pathogens, and, contrary to widespread belief, they are frequently targets of protective antibody responses. Importantly, disordered epitopes appear invariably to be linear epitopes, rendering them ideally suited to incorporation into a peptide vaccine. Nonetheless, the conformational properties of disordered antigens, and hence their recognition by antibodies, frequently depend on the interactions they make and the context in which they are presented to the immune system. These effects must be considered in the design of an effective vaccine. Here we discuss these issues and propose design principles that may facilitate the development of peptide vaccines targeting disordered antigens.
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Project description:Dengue virus (DENV) infection is a major global public health concern, and there is no effective vaccine for it. In this study, we describe the design and characterization of three nucleotide-modified mRNA vaccines (prME-mRNA, E80-mRNA, and NS1-mRNA) for DENV-2. Our results showed that vaccination with E80-mRNA alone or a combination of E80-mRNA and NS1-mRNA can induce high levels of neutralizing antibodies and antigen-specific T cell responses; furthermore, these vaccines confer complete protection against DENV-2 challenge in immunocompetent mice. These data provide foundations for further development of a tetravalent DENV vaccine based on nucleotide-modified mRNA.
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Project description:Currently, there are over 230 different COVID-19 vaccines under development around the world. At least three decades of scientific development in RNA biology, immunology, structural biology, genetic engineering, chemical modification, and nanoparticle technologies allowed the accelerated development of fully synthetic messenger RNA (mRNA)-based vaccines within less than a year since the first report of a SARS-CoV-2 infection. mRNA-based vaccines have been shown to elicit broadly protective immune responses, with the added advantage of being amenable to rapid and flexible manufacturing processes. This review recapitulates current advances in engineering the first two SARS-CoV-2-spike-encoding nucleoside-modified mRNA vaccines, highlighting the strategies followed to potentiate their effectiveness and safety, thus facilitating an agile response to the current COVID-19 pandemic.
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Project description:LY6E is an antiviral restriction factor that inhibits coronavirus spike-mediated fusion, but the cell types in vivo that require LY6E for protection from respiratory coronavirus infection are unknown. Here, we used a panel of seven conditional Ly6e knockout mice to define which Ly6e-expressing cells confer control of airway infection by murine coronavirus and SARS-CoV-2. Loss of Ly6e in Lyz2-expressing cells, radioresistant Vav1-expressing cells, and non-hematopoietic cells increased susceptibility to murine coronavirus. Global conditional loss of Ly6e expression resulted in clinical disease and higher viral burden after SARS-CoV-2 infection, but little evidence of immunopathology. We show that Ly6e expression protected secretory club and ciliated cells from SARS-CoV-2 infection and prevented virus-induced loss of an epithelial cell transcriptomic signature in the lung. Our study demonstrates that lineage confined rather than broad expression of Ly6e sufficiently confers resistance to disease caused by murine and human coronaviruses.
2023-06-21 | GSE209974 | GEO
Project description:Gene therapy is now an effective approach to treat many forms of retinal degeneration. Delivery agents that are cell-specific, allow for multiple dosing regimens, and have low immunogenicity are needed to expand the utility of gene therapy for the retina. We generated eight novel lipid nanoparticles (LNPs) ranging in size from 50 nm to 150 nm by changing the PEG content from 5% to 0.5%, respectively. Subretinal injections of LNP-mRNA encoding luciferase revealed that 0.5% PEG content within nanoparticles elicits the highest expression. Similar injections of LNP delivered cre mRNA into Ai9 mice revealed cell-specific protein expression in the retinal pigment epithelium (RPE), confirmed by fundus photography and immunohistochemistry of whole globe cross-sections. To investigate mechanisms of LNP delivery to the eye, we injected mCherry mRNA using the subretinal approach in apoE-/- and Mertk-/- mice. RPE transfection was observed in both mouse models suggesting that LNP intracellular delivery is not solely dependent on apolipoprotein adsorption or phagocytosis. To investigate LNP penetration, particles were delivered to the vitreous chamber via an intravitreal injection. The 0.5% PEG particles mediated the highest luciferase activity and expression was observed in the Müller glia, the optic nerve head and the trabecular meshwork, but failed to reach the RPE. Overall, particles containing less PEG (~150 nm in size) mediated the highest expression in the eye. Thus far, these particles successfully transfect RPE, Müller cells, the optic nerve head and the trabecular meshwork based on route of administration which can expand the utility of LNP-mediated gene therapies for the eye.
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Project description:MicroRNAs (miRNAs) are endogenous small noncoding RNAs that negatively regulate gene expression by interfering with the translation or stability of target transcripts. Some tumor-suppressive miRNAs can concurrently target multiple cancer-promoting genes and may be useful as therapeutic anticancer agents. However, the development of drug delivery systems is critical for the implementation of miRNA-based therapeutics. We have previously demonstrated that the enforced expression of miR-634 effectively induces apoptosis by concurrently and directly targeting genes associated with mitochondrial homeostasis, antiapoptosis signaling, antioxidant ability, and autophagy in cancer cells. In the current study, we validated the therapeutic potential of lipid nanoparticle (LNP)-mediated delivery of miR-634 for cancer therapy. We confirmed the ability of enforced expression of miR-634 to induce apoptosis in various cancer cell lines, including pancreatic cancer cells. Intravenous administration of LNPs harboring miR-634 significantly reduced the xenograft tumor growth of BxPC-3 pancreatic cancer cells in mice. These findings suggest that LNP-mediated delivery of miR-634 can potentially be used for cancer therapy.
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