Fast Evaluation of Viral Emerging Risks (FEVER): A computational tool for biosurveillance, diagnostics, and mutation typing of emerging viral pathogens

Viral pathogens can rapidly evolve, adapt to novel hosts, and evade human immunity. The early detection of emerging viral pathogens through biosurveillance coupled with rapid and accurate diagnostics are required to mitigate global pandemics. However, RNA viruses can mutate rapidly, hampering biosurveillance and diagnostic efforts. Here, we present a novel computational approach called FEVER (Fast Evaluation of Viral Emerging Risks) to design assays that simultaneously accomplish: 1) broad-coverage biosurveillance of an entire group of viruses, 2) accurate diagnosis of an outbreak strain, and 3) mutation typing to detect variants of public health importance. We demonstrate the application of FEVER to generate assays to simultaneously 1) detect sarbecoviruses for biosurveillance;2) diagnose infections specifically caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2);and 3) perform rapid mutation typing of the D614G SARS-CoV-2 spike variant associated with increased pathogen transmissibility. These FEVER assays had a high in silico recall (predicted positive) up to 99.7% of 525,708 SARS-CoV-2 sequences analyzed and displayed sensitivities and specificities as high as 92.4% and 100% respectively when validated in 100 clinical samples. The D614G SARS-CoV-2 spike mutation PCR test was able to identify the single nucleotide identity at position 23,403 in the viral genome of 96.6% SARS-CoV-2 positive samples without the need for sequencing. This study demonstrates the utility of FEVER to design assays for biosurveillance, diagnostics, and mutation typing to rapidly detect, track, and mitigate future outbreaks and pandemics caused by emerging viruses.

Fast Evaluation of Viral Emerging Risks (FEVER): A computational tool for biosurveillance, diagnostics, and mutation typing of emerging viral pathogens.

Viral pathogens can rapidly evolve, adapt to novel hosts, and evade human immunity. The early detection of emerging viral pathogens through biosurveillance coupled with rapid and accurate diagnostics are required to mitigate global pandemics. However, RNA viruses can mutate rapidly, hampering biosurveillance and diagnostic efforts. Here, we present a novel computational approach called FEVER (Fast Evaluation of Viral Emerging Risks) to design assays that simultaneously accomplish: 1) broad-coverage biosurveillance of an entire group of viruses, 2) accurate diagnosis of an outbreak strain, and 3) mutation typing to detect variants of public health importance. We demonstrate the application of FEVER to generate assays to simultaneously 1) detect sarbecoviruses for biosurveillance; 2) diagnose infections specifically caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); and 3) perform rapid mutation typing of the D614G SARS-CoV-2 spike variant associated with increased pathogen transmissibility. These FEVER assays had a high in silico recall (predicted positive) up to 99.7% of 525,708 SARS-CoV-2 sequences analyzed and displayed sensitivities and specificities as high as 92.4% and 100% respectively when validated in 100 clinical samples. The D614G SARS-CoV-2 spike mutation PCR test was able to identify the single nucleotide identity at position 23,403 in the viral genome of 96.6% SARS-CoV-2 positive samples without the need for sequencing. This study demonstrates the utility of FEVER to design assays for biosurveillance, diagnostics, and mutation typing to rapidly detect, track, and mitigate future outbreaks and pandemics caused by emerging viruses.

HIV-1 and SARS-CoV-2: Patterns in the evolution of two pandemic pathogens.

Humanity is currently facing the challenge of two devastating pandemics caused by two very different RNA viruses: HIV-1, which has been with us for decades, and SARS-CoV-2, which has swept the world in the course of a single year. The same evolutionary strategies that drive HIV-1 evolution are at play in SARS-CoV-2. Single nucleotide mutations, multi-base insertions and deletions, recombination, and variation in surface glycans all generate the variability that, guided by natural selection, enables both HIV-1's extraordinary diversity and SARS-CoV-2's slower pace of mutation accumulation. Even though SARS-CoV-2 diversity is more limited, recently emergent SARS-CoV-2 variants carry Spike mutations that have important phenotypic consequences in terms of both antibody resistance and enhanced infectivity. We review and compare how these mutational patterns manifest in these two distinct viruses to provide the variability that fuels their evolution by natural selection.

Evolutionary history, potential intermediate animal host, and cross-species analyses of SARS-CoV-2.

To investigate the evolutionary history of the recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China, a total of 70 genomes of virus strains from China and elsewhere with sampling dates between 24 December 2019 and 3 February 2020 were analyzed. To explore the potential intermediate animal host of the SARS-CoV-2 virus, we reanalyzed virome data sets from pangolins and representative SARS-related coronaviruses isolates from bats, with particular attention paid to the spike glycoprotein gene. We performed phylogenetic, split network, transmission network, likelihood-mapping, and comparative analyses of the genomes. Based on Bayesian time-scaled phylogenetic analysis using the tip-dating method, we estimated the time to the most recent common ancestor and evolutionary rate of SARS-CoV-2, which ranged from 22 to 24 November 2019 and 1.19 to 1.31 × 10-3 substitutions per site per year, respectively. Our results also revealed that the BetaCoV/bat/Yunnan/RaTG13/2013 virus was more similar to the SARS-CoV-2 virus than the coronavirus obtained from the two pangolin samples (SRR10168377 and SRR10168378). We also identified a unique peptide (PRRA) insertion in the human SARS-CoV-2 virus, which may be involved in the proteolytic cleavage of the spike protein by cellular proteases, and thus could impact host range and transmissibility. Interestingly, the coronavirus carried by pangolins did not have the RRAR motif. Therefore, we concluded that the human SARS-CoV-2 virus, which is responsible for the recent outbreak of COVID-19, did not come directly from pangolins.