Science papers on COVID-19
Neutralization of SARS-CoV-2 Variants B.1.429 and B.1.351 —New England Journal of Medicine (4/7/21)
An analysis of cross-reactive viral binding and neutralization of emerging SARS-CoV-2 variants suggests that the mRNA-1273 and NVX-CoV2373 vaccines elicit immune responses that are effective at neutralizing the B.1.429 variant but less effective in recognizing the B.1.351 variant.
Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus —Cell 182
B Korber, WM Fischer, S Gnanakaran, H Yoon, J Theiler, W Abfalterer, ...
A SARS-CoV-2 variant carrying the Spike protein amino acid change D614G has become the most prevalent form in the global pandemic. Dynamic tracking of variant frequencies revealed a recurrent pattern of G614 increase at multiple geographic levels: national, regional, and municipal. The shift occurred even in local epidemics where the original D614 form was well established prior to introduction of the G614 variant. The consistency of this pattern was highly statistically significant, suggesting that the G614 variant may have a fitness advantage. We found that the G614 variant grows to a higher titer as pseudotyped virions. In infected individuals, G614 is associated with lower RT-PCR cycle thresholds, suggestive of higher upper respiratory tract viral loads, but not with increased disease severity.
Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2 —BioRxiv
B Korber, W Fischer, SG Gnanakaran, H Yoon, J Theiler, W Abfalterer, ...
We have developed an analysis pipeline to facilitate real-time mutation tracking in SARS-CoV-2, focusing initially on the Spike (S) protein because it mediates infection of human cells and is the target of most vaccine strategies and antibody-based therapeutics. To date we have identified thirteen mutations in Spike that are accumulating. Mutations are considered in a broader phylogenetic context, geographically, and over time, to provide an early warning system to reveal mutations that may confer selective advantages in transmission or resistance to interventions. Each one is evaluated for evidence of positive selection, and the implications of the mutation are explored through structural modeling. The mutation Spike D614G is of urgent concern; it began spreading in Europe in early February, and when introduced to new regions it rapidly becomes the dominant form. Also, we present evidence of recombination between locally circulating strains, indicative of multiple strain infections. These finding have important implications for SARS-CoV-2 transmission, pathogenesis and immune interventions.
The D614G mutation in Spike: increased infectivity and neutralizing Ab sensitivity and the underlying mechanism —Los Alamos National Laboratory (LANL) technical presentation
Korber at al. present evidence that there are now more SARS-CoV-2 virused circulating in the human population globally that have the G614 form of the Spike protein versus the D614 form that was originally identified from the first human cases in Wuhan, China. Patients with G614 shed more viral nucleic acid compared with those with D614 and G614 bearing viruses show significantly higher infectious titers in vitro than their D614 counterparts.
Emergence of SARS-CoV-2 through recombination and strong purifying selection —Science Advances 6 (27), eabb9153
X Li, EE Giorgi, MH Marichannegowda, B Foley, C Xiao, XP Kong, Y Chen, ...
Understanding the origins of SARS-CoV-2 is critical for deterring future zoonosis, discovering new drugs, and developing a vaccine. We show evidence of strong purifying selection around the receptor binding motif (RBM) in the spike and other genes among bat, pangolin, and human coronaviruses, suggesting similar evolutionary constraints in different host species. We also demonstrate that SARS-CoV-2’s entire RBM was introduced through recombination with coronaviruses from pangolins, possibly a critical step in the evolution of SARS-CoV-2’s ability to infect humans. Similar purifying selection in different host species, together with frequent recombination among coronaviruses, suggests a common evolutionary mechanism that could lead to new emerging human coronaviruses.
The SARS-CoV-2 spike variant D614G favors an open conformational state —Science Advances 7 (16), eabf3671
RA Mansbach, S Chakraborty, K Nguyen, DC Montefiori, B Korber, ...
The COVID-19 (coronavirus disease 2019) 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 is associated with increased viral loads in the upper airways. To gain insight into the molecular-level underpinnings of these characteristics, we used microsecond all-atom simulations. We show that changes in the protein energetics favor a higher population of infection-capable states in the G-form through release of asymmetry present in the D-form inter-protomer interactions. 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 owing to enhanced exposure of the receptor binding domain, a key target region.
SARS-CoV-2 variant B. 1.1. 7 is susceptible to neutralizing antibodies elicited by ancestral Spike vaccines —Cell Host & Microbe
X Shen, H Tang, C McDanal, K Wagh, W Fischer, J Theiler, H Yoon, D Li, ...
All current vaccines for COVID-19 utilize ancestral SARS-CoV-2 spike with the goal of generating protective neutralizing antibodies. The recent emergence and rapid spread of several SARS-CoV-2 variants carrying multiple spike mutations raise concerns about possible immune escape. One variant, first identified in the United Kingdom (B.1.1.7, also called 20I/501Y.V1), contains eight spike mutations with potential to impact antibody therapy, vaccine efficacy, and risk of reinfection. Here, we show that B.1.1.7 remains sensitive to neutralization, albeit at moderately reduced levels (∼sim;2-fold), by serum samples from convalescent individuals and recipients of an mRNA vaccine (mRNA-1273, Moderna) and a protein nanoparticle vaccine (NVX-CoV2373, Novavax). A subset of monoclonal antibodies to the receptor binding domain (RBD) of spike are less effective against the variant, while others are largely unaffected.
D614G spike mutation increases SARS CoV-2 susceptibility to neutralization —Cell Host & Microbe 29 (1), 23-31. e4
D Weissman, MG Alameh, T de Silva, P Collini, H Hornsby, R Brown, ...
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.
Recombination and low-diversity confound homoplasy-based methods to detect the effect of SARS-CoV-2 mutations on viral transmissibility —BioRxiv
EE Giorgi, T Bhattacharya, WM Fischer, H Yoon, W Abfalterer, B Korber
The SARS-CoV-2 variant carrying the Spike protein mutation G614 was first detected in late January 2020 and within a few months became the dominant form globally. In the months that followed, many studies, both in vitro and in animal models, showed that variants carrying this mutation were more infectious and more readily transmitted than the ancestral Wuhan form. Here we investigate why a recently published study by van Dorp et al. failed to detect such higher transmissibility of the G614 variant using homoplasy-based methods. We show that both low diversity and recombination confound the methods utilized by van Dorp et al. and significantly decrease their sensitivity. Furthermore, though they claim no evidence of recombination in their dataset, we and several other studies identify a subset of the sequences as recombinants, possibly enough to affect their statistic adversely.
Exploring the role of glycans in the interaction of SARS-CoV-2 RBD and human receptor ACE2 —BioRxiv
K Nguyen, S Chakraborty, R Mansbach, B Korber, S Gnanakaran
During viral infection, the Spike RBD of SARS-CoV-2 binds the human host cell receptor ACE2, enabling the virus to enter the host cell. Both the Spike and ACE2 are densely glycosylated, and it is unclear how distinctive glycan types may modulate the interaction of RBD and ACE2. Detailed understanding of these determinants is key for the development of novel therapeutic strategies. To this end, we perform extensive all-atom simulations of the (i) RBD-ACE2 complex without glycans, (ii) RBD-ACE2 with oligomannose MAN9 glycans in ACE2, and (iii) RBD-ACE2 with complex FA2 glycans in ACE2.
Machine Intelligent Survival Models of Patient–Ventilation Interaction for COVID-19 —Technical report, Los Alamos National Lab.(LANL), Los Alamos, NM (United States)
AT Mohan, CD Shelley, JD Riglin, JD Bernardin, SY Del Valle
Challenges in Mechanical Ventilation system, like ventilator-induced lung injury, arise from a lack of detailed understanding of internal air flow through lungs. - Air pressure, mechanical stresses on alveoli, impact of mucus on internal air flow, etc. have not been studied rigorously or adopted for ventilator design -- developing complex computational modeling and data analytics/AI techniques for predicting *system* impact on lung health.
Mathematical Modeling of COVID-19: Understanding the Impact of School Reopening —Technical report, Los Alamos National Lab.(LANL), Los Alamos, NM (United States)
CA Manore, CD Shelley, SY Del Valle
Conclusions • School reopening is possible in a “no to low” infections scenario. • School can be protective for a community and reduce the number of total infected individuals. • School removes a subgroup of students from the general population. • The length of school days attended in a full cohort scenario appears to have little effect in further amplifying this effect. • School can instead by very detrimental to the community by speeding up the outbreak if the initially infected case is a student. • This is because we assume higher rates of transmission within schools.
COVID-19 reopening strategies at the county level in the face of uncertainty: Multiple Models for Outbreak Decision Support —MedRxiv
K Shea, RK Borchering, WJM Probert, E Howerton, TL Bogich, S Li, ...
Policymakers make decisions about COVID-19 management in the face of considerable uncertainty. We convened multiple modeling teams to evaluate reopening strategies for a mid-sized county in the United States, in a novel process designed to fully express scientific uncertainty while reducing linguistic uncertainty and cognitive biases. For the scenarios considered, the consensus from 17 distinct models was that a second outbreak will occur within 6 months of reopening, unless schools and non-essential workplaces remain closed. Up to half the population could be infected with full workplace reopening; non-essential business closures reduced median cumulative infections by 82%. Intermediate reopening interventions identified no win-win situations; there was a trade-off between public health outcomes and duration of workplace closures. Aggregate results captured twice the uncertainty of individual models, providing a more complete expression of risk for decision-making purposes.
Safely Reopening K-12 Schools During the COVID-19 Pandemic —MedRxiv
CD Shelley, PS Chadwick, C Manore, SY Del Valle
Early school closures were a consistent, nationwide response to the COVID-19 pandemic in mid-March due to the role that children play in spreading influenza. This left us with limited understanding of COVID-19 transmission in children until several states reopened schools for the 2020-2021 school year. While early school closures were likely beneficial in protecting children in the initial stages of the pandemic in the U.S., long-term closures pose significant cumulative effects in children who rely on schools for instruction and additional social services, and for parents who need to balance work and childcare obligations. Reopening schools safely is a high priority for many interested stakeholders. Proposed in-person school reopening plans include traditional, 100% school capacity, five days per week instruction, hybrid scenarios with reduced in-person instruction and virtual learning, and various reduced school capacity schedules with non-pharmaceutical interventions in place. To assess the potential impacts of different reopening plans, we created a modified SIR-type transmission model that captures multiple known pathways of COVID-19 transmission in a 100,000-person community. Our results show that plans that utilize consecutive days in school and divide students into separated smaller cohorts who attend school together, as well as plans that emphasize distance learning, are better able to suppress disease spread and reduce risk from an introduced infective into the community. Plans with more consecutive school days are protective for both the schoolchildren and surrounding community by acting to separate the larger intermixing.
Using an Agent-Based Model to Assess K-12 School Re-openings Under Different COVID-19 Spread Scenarios-United States, School Year 2020/21 —MedRxiv
Timothy C Germann, Manhong Z Smith, Lori Dauelsberg, Geoffrey Fairchild, Terece Turton, Morgan E Gorris, Chrysm Watson Ross, James P Ahrens, Daniel D Hemphill, Carrie Manore, Sara Y Del Valle
School-age children play a key role in the spread of airborne viruses like influenza due to the prolonged and close contacts they have in school settings. As a result, school closures and other non-pharmaceutical interventions were recommended as the first line of defense in response to the novel coronavirus pandemic (COVID-19). Assessing school reopening scenarios is a priority for states, administrators, parents, and children in order to balance educational disparities and negative population impacts of COVID-19. To address this challenge, we used an agent-based model that simulates communities across the United States including daycares, primary, and secondary schools to quantify the relative health outcomes of reopening schools. We explored different reopening scenarios including remote learning, in-person school, and several hybrid options that stratify the student population into cohorts (i.e., split cohort) in order to reduce exposure and disease spread. In addition, we assessed the combined impact of reduced in-person attendance in workplaces (e.g., through differing degrees of reliance on telework and/or temporary workplace closings) and school reopening scenarios to quantify the potential impact of additional transmission pathways contributing to COVID-19 spread. Scenarios where split cohorts of students return to school in non-overlapping formats resulted in significant decreases in the clinical attack rate (i.e., the percentage of symptomatic individuals), potentially by as much as 75% . These split cohort scenarios have impacts which are only modestly lesser than the most impactful 100% distance learning scenario.
The Novel Coronavirus, 2019-nCoV, is Highly Contagious and More Infectious Than Initially Estimated —MedRxiv
Steven Sanche, Yen Ting Lin, Chonggang Xu, Ethan Romero-Severson, Nick Hengartner, Ruian Ke doi:https://doi.org/10.1101/2020.02.07.20021154
The novel coronavirus (2019-nCoV) is a recently emerged human pathogen that has spread widely since January 2020. Initially, the basic reproductive number, R0, was estimated to be 2.2 to 2.7. Here we provide a new estimate of this quantity. We collected extensive individual case reports and estimated key epidemiology parameters, including the incubation period. Integrating these estimates and high-resolution real-time human travel and infection data with mathematical models, we estimated that the number of infected individuals during early epidemic double every 2.4 days, and the R0 value is likely to be between 4.7 and 6.6. We further show that quarantine and contact tracing of symptomatic individuals alone may not be effective and early, strong control measures are needed to stop transmission of the virus.
Fast spread of COVID-19 in Europe and the US and its implications: even modest public health goals require comprehensive intervention —MedRxiv
Ruian Ke, Steven Sanche, Ethan Romero-Severson, Nick Hengartner
We developed an inference approach using a mathematical model to control for these confounding factors. We fitted the model to both infection incidence and death count data collected from eight European countries and the US. Public health implications of empirical estimates were examined using simulations.
Fast spread of COVID-19 in Europe and the US and its implications: even modest public health goals require comprehensive intervention
Ruian Ke, PhD, Steven Sanche, PhD, Ethan Romero-Severson, PhD, Nick Hengartner, PhD
medRxiv, doi: https://www.medrxiv.org/content/10.1101/2020.04.04.20050427v1.full.pdf
Findings: In all countries, the early epidemic period was characterized by exponential growth with rates between 0.19-.29/day (epidemic doubling times between 2.4-3.7 days). However, the proportion of cases that had been detected was low ... With such high epidemic growth rates, moderate intervention efforts will have little impact on the public health outcome; high levels of efforts to achieve greater than 77-86<% reduction in transmission are needed, no matter whether the goal is to slow down the growth to protect a large fraction of population from infection within 18 months, or to reverse the growth all together.
Interpretation: The extremely fast spread of COVID-19 in Europe and the US suggest a highly infectious virus with a high R0. Early, strong and comprehensive intervention efforts are necessary, whether the aim is mitigation or containment.
High Contagiousness and Rapid Spread of Severe Acute Respiratory Syndrome Coronavirus 2
Steven Sanche, Yen Ting Lin, Chonggang Xu, Ethan Romero-Severson, Nick Hengartner, Ruian Ke
EID Journal: https://wwwnc.cdc.gov/eid/article/26/7/20-0282_article
Severe acute respiratory syndrome coronavirus 2 is the causative agent of the 2019 novel coronavirus disease pandemic. Initial estimates of the early dynamics of the outbreak in Wuhan, China, suggested a doubling time of the number of infected persons of 6–7 days and a basic reproductive number (R0) of 2.2–2.7. We collected extensive individual case reports across China and estimated key epidemiologic parameters, including the incubation period. We then designed 2 mathematical modeling approaches to infer the outbreak dynamics in Wuhan by using high-resolution domestic travel and infection data. Results show that the doubling time early in the epidemic in Wuhan was 2.3–3.3 days. Assuming a serial interval of 6–9 days, we calculated a median R0 value of 5.7 (95% CI 3.8–8.9). We further show that active surveillance, contact tracing, quarantine, and early strong social distancing efforts are needed to stop transmission of the virus.
Emergence of SARS-CoV-2 through Recombination and Strong Purifying Selection
Xiaojun Li, Elena E. Giorgi, Manukumar Honnayakanahalli Marichann, Brian Foley, Chuan Xiao, Xiang-peng Kong, Yue Chen, Bette Korber, Feng Gao
bioRxiv, doi: https://doi.org/10.1101/2020.03.20.000885
Our team demonstrated, by looking at the genetic sequence of the virus and comparing it to other known coronaviruses, that it originated from animals. More specifically, it most likely came from a family of bat viruses that acquired the ability to infect human cells from another family of coronaviruses found in pangolins.
School dismissal as a pandemic influenza response: When, where and for how long
Timothy C. Germann, Hongjiang Gao, Manoj Gambhir, Andrew Plummer, Matthew Biggerstaff, Carrie Reed, Amra Uzicanin
Epidemics, 2019 – Elsevier
We used individual-based computer simulation models at community, regional and national levels to evaluate the likely impact of coordinated pre-emptive school dismissal policies during an influenza pandemic. Such policies involve three key decisions: when, over what geographical scale, and how long to keep schools closed. Our evaluation includes uncertainty and sensitivity analyses, as well as model output uncertainties arising from variability in serial intervals and presumed modifications of social contacts during school dismissal periods.
