Mycobacteria are extremely diverse, with many species recently only discovered or reclassified with use of new molecular identification techniques [1][2][3] . As outlined by Runyon and others, mycobacteria can be separated into two broad categories 4,5 : tuberculosis-causing mycobacteria and non-tuberculous mycobacteria (NTM). In addi tion, Mycobacterium leprae, which is genetically and phenotypically distinct from all other identified mycobacterium species owing to its evolutionary genome reduction, is often represented in a distinct genetic clade 6 . Mycobacteria can be further classified according to their growth rate, with most NTM belonging to the rapidly growing mycobacteria (RGM) 7 and fewer belonging to the slowly growing mycobacteria. Of the approximately 200 NTM species identified to date 2 , 95% are environmental bacteria, with most being saprophytes or non-pathogenic to humans and animals, particularly in the RGM group (Box 1). Typically, NTM are highly abundant in environmental niches such as soil and natural and drinking water sources, often leading to high rates of human-pathogen contact 8 . In addition, several host factors, such as the increasing age of the global population, lung diseases (including cystic fibrosis and bronchiectasis) 9,10 , immunosuppression 11,12 and broadspectrum antibiotic therapy 9,13 , contribute to the rise of NTM infections, which frequently surpass the global incidence of new tuberculosis infections in developed countries 8,[14][15][16] .Lung disease is the most common clinical manifestation of NTM infection. However, NTM infections are phenotypically diverse, manifesting themselves as a large

COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.

Global control of COVID-19 requires broadly accessible vaccines that are effective against SARS-CoV-2 variants. In this report, we exploit the immunostimulatory properties of bacille Calmette-Guérin (BCG), the existing tuberculosis vaccine, to deliver a vaccination regimen with potent SARS-CoV-2-specific protective immunity. Combination of BCG with a stabilised, trimeric form of SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the blood of vaccinated mice, that was further augmented by the addition of alum. This vaccine formulation, BCG:CoVac, induced high-titre SARS-CoV-2 neutralising antibodies (NAbs) and Th1-biased cytokine release by vaccine-specific T cells, which correlated with the early emergence of T follicular helper cells in local lymph nodes and heightened levels of antigen-specific plasma B cells after vaccination. Vaccination of K18-hACE2 mice with a single dose of BCG:CoVac almost completely abrogated disease after SARS-CoV-2 challenge, with minimal inflammation and no detectable virus in the lungs of infected animals. Boosting BCG:CoVac-primed mice with a heterologous vaccine further increased SARS-CoV-2-specific antibody responses, which effectively neutralised B.1.1.7 and B.1.351 SARS-CoV-2 variants of concern. These findings demonstrate the potential for BCG-based vaccination to protect against major SARS-CoV-2 variants circulating globally.