A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants

Jiang, Linglei; Lowman, Maggie; Jong, Wouter S. P.; Saparoea, H. van den Berg van Bart; Dhakal, Santosh; Zhou, Ruifeng; Caputo, Christopher; Littlefield, Kirsten; Sitaris, Ioannis; Chen, Mingfei W; Lima, Gabriela Trzewikoswki de; Гололобова, Олеся; Smith, Barbara J.; Mahairaki, Vasiliki; Lane, Andrew P.; Klein, Sabra L.; Pekosz, Andrew; Brayton, Cory; Luirink, Joen; Villano, Jason; Witwer, Kenneth W.

doi:10.1101/2021.06.28.450181

Cited by 18 publications

(13 citation statements)

References 43 publications

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“…The hamster model allowed us to avoid the significant limitations of autopsy tissue, including an often prolonged and severe disease course and tissue degradation during the postmortem interval. We utilized a higher viral inoculum (1×10 7 TCID50) to generate more uniform infections that would allow us to identify variation across age groups 30 . As expected, we observed the vast majority of NP + cells were apical sustentacular cells 31 in WA1 infected hamsters (Extended Data Fig.1a,b) at 4 dpi.…”

Section: Resultsmentioning

confidence: 99%

Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants

Chen

Pekosz

Villano

et al. 2022

Preprint

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SARS-CoV-2 infection in the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variants revealed that SARS-CoV-2 WA1 or Delta infects a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possesses broader cellular invasion capacity into the submucosa, while Omicron displays longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon is more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa is accompanied by a decline of phagocytosis related genes. Furthermore, robust basal stem cell activation contributes to neuroepithelial regeneration and restores ACE2 expression post-infection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration post infection. The shifting characteristics of viral infection at the airway portal provides insight into the variability of COVID-19 clinical features and may suggest differing strategies for early local intervention.

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Section: Resultsmentioning

confidence: 99%

Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants

Chen

Pekosz

Villano

et al. 2022

Preprint

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“…Intranasal immunization of mice with Bordetella pertussis OMVs induced mucosal IgA and Th17-mediated responses which prevented colonization of the nasal cavity and the lungs 53 . OMVs derived from Salmonella typhimurium and Escherichia coli have recently also been used to present respectively the Spike RBD or peptides derived from it, and in both cases intranasal immunization provided a protective response in animal models 54,55 . In our OMV-based COVID-19 vaccine the full length spike protein is included.…”

Section: And Meningococcalmentioning

confidence: 99%

An intranasal OMV-based vaccine induces high mucosal and systemic protecting immunity against a SARS-CoV-2 infection

Ley

Zariri

Riet

et al. 2021

Preprint

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The development of more effective, accessible and easy to administer COVID-19 vaccines next to the currently marketed mRNA, viral vector and whole inactivated vaccines, is essential to curtain the SARS-CoV-2 pandemic. A major concern is reduced vaccine-induced immune protection to emerging variants, and therefore booster vaccinations to broaden and strengthen the immune response might be required. Currently, all registered COVID-19 vaccines and the majority of COVID-19 vaccines in development are intramuscularly administered, targeting the induction of systemic immunity. Intranasal vaccines have the capacity to induce local mucosal immunity as well, thereby targeting the primary route of viral entry of SARS-CoV-2 with the potential of blocking transmission. Furthermore, intranasal vaccines offer greater practicality in terms of cost and ease of administration. Currently, only eight out of 112 vaccines in clinical development are administered intranasally. We developed an intranasal COVID-19 subunit vaccine, based on a recombinant, six proline stabilized, D614G spike protein (mC-Spike) of SARS-CoV-2 linked via the LPS-binding peptide sequence mCramp (mC) to Outer Membrane Vesicles (OMVs) from Neisseria meningitidis. The spike protein was produced in CHO cells and after linking to the OMVs, the OMV-mC-Spike vaccine was administered to mice and Syrian hamsters via intranasal or intramuscular prime-boost vaccinations. In all animals that received OMV-mC-Spike, serum neutralizing antibodies were induced upon vaccination. Importantly, high levels of spike-binding immunoglobulin G (IgG) and A (IgA) antibodies in the nose and lungs were only detected in intranasally vaccinated animals, whereas intramuscular vaccination only induced an IgG response in the serum. Two weeks after their second vaccination hamsters challenged with SARS-CoV-2 were protected from weight loss and viral replication in the lungs compared to the control groups vaccinated with OMV or spike alone. Histopathology showed no lesions in lungs seven days after challenge in OMV-mC-Spike vaccinated hamsters, whereas the control groups did show pathological lesions in the lung. The OMV-mC-Spike candidate vaccine data are very promising and support further development of this novel non-replicating, needle-free, subunit vaccine concept for clinical testing.

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“… 37 For example, EVs presenting the coronavirus S protein or its RBD were proposed as potential vaccines already in the mid-2000s for SARS-CoV 38 as well as for the current SARS-CoV-2 pandemic. 36 , 39 , 40 Moreover, they showed efficiency as decoys for neutralizing antibodies 41 and as systems for targeted delivery of antiviral agents. 42 In addition, the ease at which EVs can be genetically engineered makes these formulations ideal for rapid studies of emerging viral mutations as they appear.…”

Section: Introductionmentioning

confidence: 99%

Genetically Engineered MRI-Trackable Extracellular Vesicles as SARS-CoV-2 Mimetics for Mapping ACE2 Binding In Vivo

et al. 2022

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The elucidation of viral-receptor interactions and an understanding of virus-spreading mechanisms are of great importance, particularly in the era of a pandemic. Indeed, advances in computational chemistry, synthetic biology, and protein engineering have allowed precise prediction and characterization of such interactions. Nevertheless, the hazards of the infectiousness of viruses, their rapid mutagenesis, and the need to study viral-receptor interactions in a complex in vivo setup call for further developments. Here, we show the development of biocompatible genetically engineered extracellular vesicles (EVs) that display the receptor binding domain (RBD) of SARS-CoV-2 on their surface as coronavirus mimetics (EVs RBD ). Loading EVs RBD with iron oxide nanoparticles makes them MRI-visible and, thus, allows mapping of the binding of RBD to ACE2 receptors noninvasively in live subjects. Moreover, we show that EVs RBD can be modified to display mutants of the RBD of SARS-CoV-2, allowing rapid screening of currently raised or predicted variants of the virus. The proposed platform thus shows relevance and cruciality in the examination of quickly evolving pathogenic viruses in an adjustable, fast, and safe manner. Relying on MRI for visualization, the presented approach could be considered in the future to map ligand-receptor binding events in deep tissues, which are not accessible to luminescence-based imaging.

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A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants

Cited by 18 publications

References 43 publications

Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants

Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants

An intranasal OMV-based vaccine induces high mucosal and systemic protecting immunity against a SARS-CoV-2 infection

Genetically Engineered MRI-Trackable Extracellular Vesicles as SARS-CoV-2 Mimetics for Mapping ACE2 Binding In Vivo

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