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Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, Mastomys rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of the Lassa virus's glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we used pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affected cell entry and antibody neutralization. Our experiments defined functional constraints throughout GPC. We quantified how GPC mutations affected neutralization with a panel of monoclonal antibodies. All antibodies tested were escaped by mutations that existed among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid the design of therapeutics and vaccines. [Display omitted] • Non-replicative pseudovirus deep mutational scanning of Lassa virus GPC • Effects of nearly all GPC mutations on cell entry and antibody escape were mapped • We identified natural Lassa GPC sequences with antibody-escape mutations Lassa fever causes thousands of deaths annually and lacks effective vaccines or therapies. Carr et al. use a non-replicative pseudovirus deep mutational scanning platform to determine how Lassa virus surface protein mutations affect cell entry and antibody neutralization. They also identify antibody-escape mutations in natural Lassa sequences. [ABSTRACT FROM AUTHOR]

Zoonotic spillovers of viruses have occurred through the animal trade worldwide. The start of the COVID-19 pandemic was traced epidemiologically to the Huanan Seafood Wholesale Market. Here, we analyze environmental qPCR and sequencing data collected in the Huanan market in early 2020. We demonstrate that market-linked severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic diversity is consistent with market emergence and find increased SARS-CoV-2 positivity near and within a wildlife stall. We identify wildlife DNA in all SARS-CoV-2-positive samples from this stall, including species such as civets, bamboo rats, and raccoon dogs, previously identified as possible intermediate hosts. We also detect animal viruses that infect raccoon dogs, civets, and bamboo rats. Combining metagenomic and phylogenetic approaches, we recover genotypes of market animals and compare them with those from farms and other markets. This analysis provides the genetic basis for a shortlist of potential intermediate hosts of SARS-CoV-2 to prioritize for serological and viral sampling., Competing Interests: Declaration of interests J.O.W. and N.M. receive funding from the Centers for Disease Control and Prevention (CDC) through contracts to J.O.W.’s institution unrelated to this research. M.A.S. receives contracts from the US Food & Drug Administration, US Department of Veterans Affairs, and Janssen Research & Development, all outside the scope of this work. R.F.G. is a cofounder of Zalgen Labs, a biotechnology company developing countermeasures for emerging viruses. A.C.-C. is an employee of Cultivarium, a nonprofit organization studying environmental microbes, unrelated to the scope of this work. M.W., A.L.R., J.E.P., A.R., M.A.S., E.C.H., S.A.G., J.O.W., and K.G.A. have received consulting fees and/or provided compensated expert testimony on SARS-CoV-2 and the COVID-19 pandemic. M.P.G.K. was involved in the WHO-convened SARS-CoV-2 origins mission., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex meaning of "local" when investigating connected epidemics and emphasize the importance of collaborative interventions for pandemic prevention and mitigation., Competing Interests: Declaration of interests K.G.A. has received consulting fees on SARS-CoV-2 and the COVID-19 pandemic., (Copyright © 2023 Elsevier Inc. All rights reserved.)