The coronavirus disease 2019 (COVID-19) outbreak was first reported in Wuhan, China, in late 2019 and, at the time of writing this article, has since spread to 216 countries and territories 1. It has brought the world to a standstill. The respiratory viral pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected at least 20.1 million individuals and killed more than 737,000 people globally, and counting 1. Although physical-distancing a n d o t h er t r a n s m i ss i o n-m i tigation s t r a t e g ies i m p l e m e nted in most countries during the current pandemic have prevented most citizens from being infected, these strategies will paradoxically leave them without immunity to SARS-CoV-2 and thus susceptible to additional waves of infection. Health-care workers, seniors and those with underlying health conditions are at particularly high risk 2-4. It is widely accepted that the world will not return to its prepandemic normalcy until safe and effective vaccines become available and a global vaccination programme is successfully implemented 5. As COVID-19 is new to humankind and the nature of protective immune responses is poorly understood, it is unclear which vaccine strategies will be most successful. Therefore, it is imperative to develop various vaccine platforms and strategies in parallel. Indeed, since the outbreak began, researchers around the world have been racing to develop COVID-19 vaccines, with at least 166 vaccine candidates currently in preclinical and clinical development 5 (Fig. 1). To meet the urgent need for a vaccine, a new pandemic vaccine development paradigm has been proposed that compresses the development timeline from 10-15 years to 1-2 years 6. However, there remains a lack of clarity as to what may

Innate immune memory is an emerging area of research. However, innate immune memory at major mucosal sites remains poorly understood. Here, we show that respiratory viral infection induces longlasting memory alveolar macrophages (AMs). Memory AMs are programed to express high MHC II, a defense-ready gene signature, and increased glycolytic metabolism, and produce, upon re-stimulation, neutrophil chemokines. Using a multitude of approaches, we reveal that the priming, but not maintenance, of memory AMs requires the help from effector CD8 T cells. T cells jump-start this process via IFN-g production. We further find that formation and maintenance of memory AMs are independent of monocytes or bone marrow progenitors. Finally, we demonstrate that memory AMs are poised for robust trained immunity against bacterial infection in the lung via rapid induction of chemokines and neutrophilia. Our study thus establishes a new paradigm of immunological memory formation whereby adaptive T-lymphocytes render innate memory of mucosal-associated macrophages.

The emerging SARS-CoV-2 variants of concern (VOC) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.

Adenoviruses represent the most widely used viral-vectored platform for vaccine design, showing a great potential in the fight against intracellular infectious diseases to which either there is a lack of effective vaccines or the traditional vaccination strategy is suboptimal. The extensive understanding of the molecular biology of adenoviruses has made the new technologies and reagents available to efficient generation of adenoviral-vectored vaccines for both preclinical and clinical evaluation. The novel adenoviral vectors including nonhuman adenoviral vectors have emerged to be the further improved vectors for vaccine design. In this review, we discuss the latest adenoviral technologies and their utilization in vaccine development. We particularly focus on the application of adenoviral-vectored vaccines in mucosal immunization strategies against mucosal pathogens including Mycobacterium tuberculosis, flu virus, and human immunodeficiency virus.