Spike proteins and receptor-binding domains (RBDs) are regarded as promising antigens for many recombinant-proteinbased COVID-19 vaccine candidates; [2] these vaccines can be easily adapted to scale-up manufacturing for rapid development, guaranteeing fast access to the public. [3] However, such strategies seldom offer effective immunogenicity. [4] Under these circumstances, a rationally designed COVID-19 adjuvant is also urgently needed, and is expected to conform to the requisite safety profile and rapid assembly procedures to enable large-scale deployment in a short time. In addition to the robust secretion of antigenspecific antibodies, lessons learned from severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) vaccines indicate that T-cell-mediated cellular responses are imperative to combat coronaviruses; they induce CD8+ T cells and can confer CD4+ T helper 1 (Th1)-type immunity to orchestrate both humoral and cellular immunity to enhance anti-viral effects and immune memory. [5] To date, aluminum hydroxide microgels (termed as "alums") have been used as the sole licensed adjuvants in most developing countries; [6] they facilitate antigen-specific antibody secretion in For rapid response against the prevailing COVID-19 (coronavirus disease 19), it is a global imperative to exploit the immunogenicity of existing formulations for safe and efficient vaccines. As the most accessible adjuvant, aluminum hydroxide (alum) is still the sole employed adjuvant in most countries. However, alum tends to attach on the membrane rather than entering the dendritic cells (DCs), leading to the absence of intracellular transfer and process of the antigens, and thus limits T-cell-mediated immunity. To address this, alum is packed on the squalene/water interphase is packed, forming an alum-stabilized Pickering emulsion (PAPE). "Inheriting" from alum and squalene, PAPE demonstrates a good biosafety profile. Intriguingly, with the dense array of alum on the oil/water interphase, PAPE not only adsorbs large quantities of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antigens, but also harbors a higher affinity for DC uptake, which provokes the uptake and cross-presentation of the delivered antigens. Compared with alum-treated groups, more than six times higher antigen-specific antibody titer and threefold more IFN-γ-secreting T cells are induced, indicating the potent humoral and cellular immune activations. Collectively, the data suggest that PAPE may provide potential insights toward a safe and efficient adjuvant platform for the enhanced COVID-19 vaccinations. Since the outbreak of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the world has suffered more than 8 million infections, 400 000 deaths, and billions of dollars in economic losses in more than 160 countries. [1] It is a global imperative challenge to develop safe and effective vaccines against the spreading

For enhanced COVID‐19 vaccines, in article number 2004210, Yufei Xia, Guanghui Ma, and co‐workers pack licensed alum on a squalene/water interphase. Thereby, this century‐old adjuvant “travels through time” in a new form of alum‐stabilized Pickering emulsion (PAPE), which not only inherits the clinically acknowledged biosafety, but also demonstrates enhanced cellular uptake and cross‐presentation of antigens for potent humoral and cellular responses.

Current attempts in vaccine delivery systems concentrate on replicating the natural dissemination of live pathogens, but neglect that pathogens evolve to evade the immune system rather than to provoke it. In the case of enveloped RNA viruses, it is the natural dissemination of nucleocapsid protein (NP, core antigen) and surface antigen that delays NP exposure to immune surveillance. Here, we report a multi-layered aluminum hydroxide-stabilized emulsion (MASE) to dictate the delivery sequence of the antigens. In this manner, the receptor-binding domain (RBD, surface antigen) of the spike protein was trapped inside the nanocavity, while NP was absorbed on the outside of the droplets, enabling the burst release of NP before RBD. Compared with the natural packaging strategy, the inside-out strategy induced potent type I interferon-mediated innate immune responses and triggered an immune-potentiated environment in advance, which subsequently boosted CD40+ DC activations and the engagement of the lymph nodes. In both H1N1 influenza and SARS-CoV-2 vaccines, rMASE significantly increased antigen-specific antibody secretion, memory T cell engagement, and Th1-biased immune response, which diminished viral loads after lethal challenge. By simply reversing the delivery sequence of the surface antigen and core antigen, the inside-out strategy may offer major implications for enhanced vaccinations against the enveloped RNA virus.