Due to the high prevalence and long incubation periods often without symptoms, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected millions of individuals globally, causing the coronavirus disease 2019 (COVID-19) pandemic. Even with the recent approval of the anti-viral drug, remdesivir, and Emergency Use Authorization of monoclonal antibodies against S protein, bamlanivimab and casirimab/imdevimab, efficient and safe COVID-19 vaccines are still desperately demanded not only to prevent its spread but also to restore social and economic activities via generating mass immunization. Recent Emergency Use Authorization of Pfizer and BioNTech’s mRNA vaccine may provide a pathway forward, but monitoring of long-term immunity is still required, and diverse candidates are still under development. As the knowledge of SARS-CoV-2 pathogenesis and interactions with the immune system continues to evolve, a variety of drug candidates are under investigation and in clinical trials. Potential vaccines and therapeutics against COVID-19 include repurposed drugs, monoclonal antibodies, antiviral and antigenic proteins, peptides, and genetically engineered viruses. This paper reviews virology and immunology of SARS-CoV-2, alternative therapies for COVID-19 to vaccination, principles and design considerations in COVID-19 vaccine development, and the promises and roles of vaccine carriers in addressing the unique immunopathological challenges presented by the disease.

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Dendritic cells (DCs) are prime targets for vaccination and immunotherapy. However, limited control over antigen presentation at a desired maturation status in these plastic materials remains a fundamental challenge in efficiently orchestrating a controlled immune response. DC-derived extracellular vesicles (EVs) can overcome some of these issues, but have significant production challenges. Herein, this work employs a unique chemicallyinduced method for production of DC-derived extracellular blebs (DC-EBs) that overcome the barriers of DC and DC-derived EV vaccines. DC-EBs are molecular snapshots of DCs in time, cell-like particles with fixed stimulatory profiles for controlled immune signaling. DC-EBs are produced in an order of magnitude more quickly and efficiently than conventional EVs and display stable structural integrity and antigen presentation compared to live DCs. Multi-omic analysis confirmed DC-EBs are majorly pure plasma membrane vesicles that are homogeneous at the single-vesicle level, critical for safe and effective vaccination. Immature versus mature molecular profiles on DC-EBs exhibit molecularly modulated immune responses compared to live DCs, improving remission and survival of tumor-challenged mice via generation of antigen-specific T cells. For the first time, DC-EBs make their case for use in vaccines and for their potential in modulating other immune responses, potentially in combination with other immunotherapeutics.

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