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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

D614G Spike Mutation Increases SARS CoV-2 Susceptibility to Neutralization

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein acquired a D614G mutation early in the pandemic that confers greater infectivity and is now the globally dominant form. To determine whether D614G might also mediate neutralization escape that could compromise vaccine efficacy, sera from spike-immunized mice, nonhuman primates, and humans were evaluated for neutralization of pseudoviruses bearing either D614 or G614 spike. In all cases, the G614 pseudovirus was moderately more susceptible to neutralization. The G614 pseudovirus also was more susceptible to neutralization by receptor-binding domain (RBD) monoclonal antibodies and convalescent sera from people infected with either form of the virus. Here, negative stain electron microscopy revealed a higher percentage of the 1-RBD “up” conformation in the G614 spike, suggesting increased epitope exposure as a mechanism of enhanced vulnerability to neutralization. Based on these findings, the D614G mutation is not expected to be an obstacle for current vaccine development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

The SARS-CoV-2 Spike Variant D614G Favors an Open Conformational State

The COVID-19 pandemic underwent a rapid transition with the emergence of a dominant viral variant (from the “D-form” to the “G-form”) that carried an amino acid substitution D614G in its “Spike” protein. The G-form is more infectious in vitro and associated with increased viral loads. To gain insight into the molecular-level underpinnings of these characteristics, we employed microsecond all-atom simulations. Here we show that changes in the protein energetics favor a higher population of infection-capable (open) states through release of hydrogen bonds of an asymmetry present in the D-form but not the G-form. Thus, the increased infectivity of the G-form is likely due to a higher rate of profitable binding encounters with the host receptor. It is also predicted to be more neutralization sensitive due to enhanced exposure of the receptor binding domain, a key target region for neutralizing antibodies. These results are significant for vaccine design. The Molecular Dynamics Simulations datasets generated in this study, namely that of the soluble form SARS-CoV-2 Spike protein are made available here. Details of the trajectory and supporting files are given in the README.txt file.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

The D614G mutation in Spike: increased infectivity and neutralizing Ab sensitivity and the underlying mechanism [Slides]

Evidence is presented that there are now more SARS-CoV-2 viruses circulating in the human population globally that have the G614 form that was originally identified from the first human cases in Wuhan, China. Follow-up studies show that patients infected with G614 shed more viral nucleic avid compared with those with D614 and G614-bearing viruses show significantly higher infectious titers in vitro than their D614 counterparts.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

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.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Network analysis uncovers the communication structure of SARS-CoV-2 spike protein identifying sites for immunogen design

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered myriad efforts to understand the structure and dynamics of this complex pathogen. The spike glycoprotein of SARS-CoV-2 is a significant target for immunogens as it is the means by which the virus enters human cells, while simultaneously sporting mutations responsible for immune escape. These functional and escape processes are regulated by complex molecular-level interactions. Our study presents quantitative insights on domain and residue contributions to allosteric communication, immune evasion, and local- and global-level control of functions through the derivation of a weighted graph representation from all-atom MD simulations. Focusing on the ancestral form and the D614G-variant, we provide evidence of the utility of our approach by guiding the selection of a mutation that alters the spike’s stability. Taken together, the network approach serves as a valuable tool to evaluate communication “hot-spots” in proteins to guide design of stable immunogens.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Estimating the strength of selection for new SARS-CoV-2 variants

Abstract Controlling the SARS-CoV-2 pandemic becomes increasingly challenging as the virus adapts to human hosts through the continual emergence of more transmissible variants. Simply observing that a variant is increasing in frequency is relatively straightforward, but more sophisticated methodology is needed to determine whether a new variant is a global threat and the magnitude of its selective advantage. We present two models for quantifying the strength of selection for new and emerging variants of SARS-CoV-2 relative to the background of contemporaneous variants. These methods range from a detailed model of dynamics within one country to a broad analysis across all countries, and they include alternative explanations such as migration and drift. We find evidence for strong selection favoring the D614G spike mutation and B.1.1.7 (Alpha), weaker selection favoring B.1.351 (Beta), and no advantage of R.1 after it spreads beyond Japan. Cutting back data to earlier time horizons reveals that uncertainty is large very soon after emergence, but that estimates of selection stabilize after several weeks. Our results also show substantial heterogeneity among countries, demonstrating the need for a truly global perspective on the molecular epidemiology of SARS-CoV-2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Broadly neutralizing antibodies against sarbecoviruses generated by immunization of macaques with an AS03-adjuvanted COVID-19 vaccine

The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that evade immunity elicited by vaccination has placed an imperative on the development of countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent monoclonal antibodies (mAbs) that neutralized multiple sarbecoviruses from macaques vaccinated with AS03-adjuvanted monovalent subunit vaccines. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells (MBCs) for at least 1 year after primary vaccination. Antibodies generated from these antigen-specific MBCs at 5 to 12 months after vaccination displayed greater potency and breadth relative to those identified at 1.4 months. Fifteen of the 338 (about 4.4%) antibodies isolated at 1.4 to 6 months after the primary vaccination showed potency against SARS-CoV-2 BA.1, despite the absence of serum BA.1 neutralization. 25F9 and 20A7 neutralized authentic clade 1 sarbecoviruses (SARS-CoV, WIV-1, SHC014, SARS-CoV-2 D614G, BA.1, and Pangolin-GD) and vesicular stomatitis virus–pseudotyped clade 3 sarbecoviruses (BtKY72 and PRD-0038). 20A7 and 27A12 showed potent neutralization against all SARS-CoV-2 variants and multiple Omicron sublineages, including BA.1, BA.2, BA.3, BA.4/5, BQ.1, BQ.1.1, and XBB. Crystallography studies revealed the molecular basis of broad and potent neutralization through targeting conserved sites within the RBD. Prophylactic protection of 25F9, 20A7, and 27A12 was confirmed in mice, and administration of 25F9 particularly provided complete protection against SARS-CoV-2, BA.1, SARS-CoV, and SHC014 challenge. These data underscore the extremely potent and broad activity of these mAbs against sarbecoviruses.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

SARS-CoV-2 Infection Severity Is Linked to Superior Humoral Immunity against the Spike

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity of the antibody response mounted against this novel virus is not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection exhibit a larger antibody response against the spike and nucleocapsid protein and epitope spreading to subdominant viral antigens, such as open reading frame 8 and nonstructural proteins. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein. Additionally, we revealed that antibodies against the spike are still capable of binding the D614G spike mutant and cross-react with the SARS-CoV-1 receptor binding domain. Together, this study reveals that subjects with a more severe SARS-CoV-2 infection exhibit a greater overall antibody response to the spike and nucleocapsid protein and a larger memory B cell response against the spike.

60 APPLIED LIFE SCIENCES↗