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Abstract SARS-CoV-2 main protease, Mpro , is responsible for processing the viral polyproteins into individual proteins, including the protease itself. Mpro is a key target of anti-COVID-19 therapeutics such as nirmatrelvir (the active component of Paxlovid). Resistance mutants identified clinically and in viral passage assays contain a combination of active site mutations (e.g., E166V, E166A, L167F), which reduce inhibitor binding and enzymatic activity, and non-active site mutations (e.g., P252L, T21I, L50F), which restore the fitness of viral replication. To probe the role of the non-active site mutations in fitness rescue, here we use an Mpro triple mutant (L50F/E166A/L167F) that confers nirmatrelvir drug resistance with a viral fitness level similar to the wild-type. By comparing peptide and full-length Mpro protein as substrates, we demonstrate that the binding of Mpro substrate involves more than residues in the active site. Particularly, L50F and other non-active site mutations...

Abstract Background The International Health Regulations (2005) (IHR), requires that States Parties develop their capacities to detect, assess, and respond to public health threats and report to the World Health Assembly through the States Parties Annual Report (SPAR). The National Pandemic Preparedness and Response Plans (PPRP) contribute to countries capacities however there are some discrepancies between both tools. To identify gaps and define priority actions to strengthen pandemic plans, we assessed the concordance between national pandemic preparedness and response plans for respiratory pathogens against the pandemic checklist published in 2023 and the SPAR. Methods In this retrospective, semi-quantitative study , conducted in August 2024, we reviewed the most recent respiratory pandemic plans for 35 PAHO member states and assessed their concordance with (1) actionable guidelines in the World Health Organization pandemic checklist and (2) IHR (2005) core capacities using the late...

Abstract H1N1 influenza viruses are responsible for both seasonal and pandemic influenza . The continual antigenic shift and drift of these viruses highlight the urgent need for a universal influenza vaccine to elicit broadly neutralizing antibodies (bnAbs). Identification and characterization of bnAbs elicited in natural infection and immunization to influenza virus hemagglutinin (HA) can provide insights for development of a universal influenza vaccine. Here, we structurally and biophysically characterize four antibodies that bind to a conserved region on the HA membrane-proximal region known as the anchor epitope. Despite some diversity in their VH and VK genes, the antibodies interact with the HA through germline-encoded residues in HCDR2 and LCDR3. Somatic mutations on HCDR3 also contribute hydrophobic interactions with the conserved HA epitope. This convergent binding mode provides extensive neutralization breadth against H1N1 viruses and suggests possible countermeasures against...