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<jats:title>Abstract</jats:title><jats:p>Emerging variants of concern (VOCs) are driving the COVID-19 pandemic<jats:sup>1,2</jats:sup>. Experimental assessments of replication and transmission of major VOCs and progenitors are needed to understand the mechanisms of replication and transmission of VOCs<jats:sup>3</jats:sup>. Here we show that the spike protein (S) from Alpha (also known as B.1.1.7) and Beta (B.1.351) VOCs had a greater affinity towards the human angiotensin-converting enzyme 2 (ACE2) receptor than that of the progenitor variant S(D614G) in vitro. Progenitor variant virus expressing S(D614G) (wt-S<jats:sup>614G</jats:sup>) and the Alpha variant showed similar replication kinetics in human nasal airway epithelial cultures, whereas the Beta variant was outcompeted by both. In vivo, competition experiments showed a clear fitness advantage of Alpha over wt-S<jats:sup>614G</jats:sup> in ferrets and two mouse models—the substitutions in S were major drivers of the fitness advantage. In hamsters, which support high viral replication levels, Alpha and wt-S<jats:sup>614G</jats:sup> showed similar fitness. By contrast, Beta was outcompeted by Alpha and wt-S<jats:sup>614G</jats:sup> in hamsters and in mice expressing human ACE2. Our study highlights the importance of using multiple models to characterize fitness of VOCs and demonstrates that Alpha is adapted for replication in the upper respiratory tract and shows enhanced transmission in vivo in restrictive models, whereas Beta does not overcome Alpha or wt-S<jats:sup>614G</jats:sup> in naive animals.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Broadly neutralizing antibodies that target epitopes of haemagglutinin on the influenza virus have the potential to provide near universal protection against influenza virus infection<jats:sup>1</jats:sup>. However, viral mutants that escape broadly neutralizing antibodies have been reported<jats:sup>2,3</jats:sup>. The identification of broadly neutralizing antibody classes that can neutralize viral escape mutants is critical for universal influenza virus vaccine design. Here we report a distinct class of broadly neutralizing antibodies that target a discrete membrane-proximal anchor epitope of the haemagglutinin stalk domain. Anchor epitope-targeting antibodies are broadly neutralizing across H1 viruses and can cross-react with H2 and H5 viruses that are a pandemic threat. Antibodies that target this anchor epitope utilize a highly restricted repertoire, which encodes two public binding motifs that make extensive contacts with conserved residues in the fusion peptide. Moreover, anchor epitope-targeting B cells are common in the human memory B cell repertoire and were recalled in humans by an oil-in-water adjuvanted chimeric haemagglutinin vaccine<jats:sup>4,5</jats:sup>, which is a potential universal influenza virus vaccine. To maximize protection against seasonal and pandemic influenza viruses, vaccines should aim to boost this previously untapped source of broadly neutralizing antibodies that are widespread in the human memory B cell pool.</jats:p>

<jats:title>Abstract</jats:title><jats:p>It is not fully understood why COVID-19 is typically milder in children<jats:sup>1–3</jats:sup>. Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total <jats:italic>n</jats:italic> = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.</jats:p>

<jats:title>Abstract</jats:title><jats:p>By catalysing the microbial formation of methane, methyl-coenzyme M reductase has a central role in the global levels of this greenhouse gas<jats:sup>1,2</jats:sup>. The activity of methyl-coenzyme M reductase is profoundly affected by several unique post-translational modifications<jats:sup>3–6</jats:sup>, such as  a unique <jats:italic>C</jats:italic>-methylation reaction catalysed by methanogenesis marker protein 10 (Mmp10), a radical <jats:italic>S-</jats:italic>adenosyl-<jats:sc>l</jats:sc>-methionine (SAM) enzyme<jats:sup>7,8</jats:sup>. Here we report the spectroscopic investigation and atomic resolution structure of Mmp10 from <jats:italic>Methanosarcina acetivorans</jats:italic>, a unique B<jats:sub>12</jats:sub> (cobalamin)-dependent radical SAM enzyme<jats:sup>9</jats:sup>. The structure of Mmp10 reveals a unique enzyme architecture with four metallic centres and critical structural features involved in the control of catalysis. In addition, the structure of the enzyme–substrate complex offers a glimpse into a B<jats:sub>12</jats:sub>-dependent radical SAM enzyme in a precatalytic state. By combining electron paramagnetic resonance spectroscopy, structural biology and biochemistry, our study illuminates the mechanism by which the emerging superfamily of B<jats:sub>12</jats:sub>-dependent radical SAM enzymes catalyse chemically challenging alkylation reactions and identifies distinctive active site rearrangements to provide a structural rationale for the dual use of the SAM cofactor for radical and nucleophilic chemistry.</jats:p>