The pandemic emergency has brought to light the need for a new generation of rapidly developed vaccines that induce longer-lasting, potent, and broader immune responses. While the mRNA vaccines played a critical role during the emergency in reducing SARS-CoV-2 hospitalization rates and deaths, more efficient approaches are needed.
Introduction
Peripheral nerves accommodate mechanical loads during joint movement. Hypothesized protective features include increased nerve compliance near joints and axonal undulation. How axons perceive nerve deformation is poorly understood. We tested whether nerves increase local axonal undulation in regions of high epineurial strain to protect nerve fibers from strain‐induced damage.
Methods
Regional epineurial strain was measured near the elbow in median and ulnar nerves of mice expressing axonal fluorescence before and after decompression. Regional axonal tortuosity was quantified under confocal microscopy.
Results
Nerves showed higher epineurial strain just distal to the medial epicondyle; these differences were eliminated after decompression. Axonal tortuosity also varied regionally; however, unlike in the epineurium, it was greater in proximal regions.
Discussion
In this study we have proposed a neuromechanical model whereby axons can unravel along their entire length due to looser mechanical coupling to the peri/epineurium. Our findings have major implications for understanding nerve biomechanics and dysfunction. Muscle Nerve 59:619–619, 2019
Exosome based vaccines represent an interesting opportunity in the pandemic time we live. Compared to the available vaccines, an exosome-based vaccine may answer to the need of efficacy and increased safety. Here, we used exosomes to deliver a "cocktail" protein-based vaccine, in which two independent viral proteins are delivered using the exosome membrane as carrier. Cells were engineered to express either SARS-CoV-2 Delta spike (StealthTM X-Spike, STX-S) or nucleocapsid (StealthTM X-Nucleocapsid, STX-N) protein on the surface and facilitate their trafficking to the exosomes. When administered as single product, both STX-S and STX-N induced a strong immunization with the production of a potent humoral and cellular immune response. Interestingly, these effects are obtained with administration of nanograms of protein and without adjuvant. Therefore, we developed a multivalent low dose vaccine, namely STX-S+N, using a teeter-toother dose approach of STX-S and STX-N. In two independent animal models (mouse and rabbit), administration of STX-S+N resulted in increased antibody production, potent neutralizing antibodies with cross-reactivity to other VOC and strong T-cell response. Importantly, no competition in immune response was observed. Our data show that our exosome platform has an enormous potential to revolutionize vaccinology by rapidly facilitating antigen presentation, and for therapeutics by enabling cell and tissue specific targeting.
Exosomes are emerging as potent and safe delivery carriers for use in vaccinology and therapeutics. A better vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to provide improved, broader, longer lasting neutralization of SARS-CoV-2, a more robust T cell response, enable widespread global usage, and further enhance the safety profile of vaccines given the likelihood of repeated booster vaccinations. Here, we use Capricor's StealthXTM platform to engineer exosomes to express native SARS-CoV-2 spike Delta variant (STX-S) protein on the surface for the delivery of a protein-based vaccine for immunization against SARS-CoV-2 infection. The STX-S vaccine induced a strong immunization with the production of a potent humoral immune response as demonstrated by high levels of neutralizing antibody not only against the delta SARS-CoV-2 virus but also two Omicron variants (BA.1 and BA.5), providing broader protection than current mRNA vaccines. Additionally, both CD4+ and CD8+ T cell responses were increased significantly after treatment. Quantification of spike protein by ELISA showed that only nanograms of protein were needed to induce a potent immune response. This is a significantly lower dose than traditional recombinant protein vaccines with no adjuvant required, which makes the StealthXTM exosome platform ideal for the development of multivalent vaccines with a better safety profile. Importantly, our exosome platform allows novel proteins, or variants in the case of SARS-CoV-2, to be engineered onto the surface of exosomes in a matter of weeks, comparable with mRNA vaccine technology, but without the cold storage requirements. The ability to utilize exosomes for cellular delivery of proteins, as demonstrated by STX-S, has enormous potential to revolutionize vaccinology by rapidly facilitating antigen presentation at an extremely low dose resulting in a potent, broad antibody response.
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