Hallmarks of a Super-Spreader, Spike Pattern of the 1928 Pandemic, Airborne Transmission Model: COVID-19 Updates

February 12, 2021

February 12, 2021 | New machine learning framework estimates asymptomatic cases, helium microscope used to visualize SARS CoV-2, SARS CoV-2 mutations develop in single patient, and new vaccine platforms. Plus: clinicians at UCI Health develop successful system for monoclonal antibody delivery, New Yorkers are responding more favorably to the new COVID-19 vaccine, and old drugs may be repurposed as COVID-19 treatments.


Research News

Researchers at Tulane University, Harvard University, MIT and Massachusetts General Hospital have learned that obesity, age and COVID-19 infection correlate with a propensity to breathe out more respiratory droplets—key spreaders of SARS-CoV-2. Their findings were published in Proceedings of the National Academy of Sciences. Using data from an observational study of 194 healthy people and an experimental study of nonhuman primates with COVID-19, researchers found that exhaled aerosol particles vary greatly between subjects. Those who were older with higher body mass indexes (BMI) and an increasing degree of COVID-19 infection had three times the number of exhaled respiratory droplets as others in the study groups. Researchers found that 18% of the human subjects accounted for 80% of the exhaled particles of the group, reflecting a distribution of exhaled aerosol particles that follows the 20/80 rule seen in other infectious disease epidemics: 20% of infected individuals are responsible for 80% of transmissions. DOI: 10.1073/pnas.2021830118

Drawing on a longitudinal dataset of college students before and during the pandemic, we document dramatic changes in physical activity, sleep, time use, and mental health. We show that biometric and time-use data are critical for understanding the mental health impacts of COVID-19, as the pandemic has tightened the link between lifestyle behaviors and depression. Our findings also suggest a puzzle: Disruptions to physical activity and mental health are strongly associated, but restoration of physical activity through a short-term intervention does not help improve mental health. These results highlight the large impact of COVID-19 on both lifestyle and well-being and offer directions for interventions aimed at restoring mental health. The findings were published in PNAS. DOI: 10.1073/pnas.2016632118

The 1918 influenza pandemic provides a cautionary tale for what the future may hold for COVID-19, says a Michigan State University researcher. Siddharth Chandra has been studying the 1918 flu pandemic for a decade. Now, in the American Journal of Public Health he has identified four waves of excess mortality over a span of two years, including a severe one in early 1920. Michigan’s experience holds sobering lessons for those who wish to understand how immunologically naïve populations encounter novel viral pathogens, he argues. DOI: 10.2105/AJPH.2020.305969

A research team from the University of Minnesota have published findings in PLOS Pathogens that points to the effectiveness of remdesivir including: SARS-CoV-2 primarily infects two types of cells in the upper respiratory tract: ciliated cells and goblet cells; goblet cells are the main producer of pro-inflammatory responses, which are common in severe COVID-19 cases; remdesivir, however, is effective in blocking virus replication in all cell types in the upper respiratory tract; and SARS-CoV-2 is highly effective at evading initial detection by the innate immune system, but when detected, virus replication is efficiently blunted by antiviral responses. DOI: 10.1371/journal.ppat.1009292

Until now the African green monkey was the only nonhuman primate used to study airborne transmission of the SARS-CoV-2 virus. According to new research published online this week, three nonhuman primate species were evaluated as potential models and any of these species may be useful in the testing of vaccines and treatments for COVID-19. The research team at U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) exposed cynomolgus macaques, rhesus macaques, and African green monkeys to SARS-CoV-2 using a model system invented at USAMRIID that generates a controlled dosage of highly respirable airborne particles within a sealed chamber. The animals were monitored, and their cases documented. All three species developed disease that resembled mild acute respiratory disease in human patients. Identification of additional animal models allows for continuing evaluation of vaccine and therapeutic candidates and helps to facilitate a more rapid deployment of new medical products to mitigate the COVID-19 pandemic. Read about it in PLoS ONE. DOI: 10.1371/journal.pone.0246366 

Past exposure to seasonal coronaviruses (CoVs), which cause the common cold, does not result in the production of antibodies that protect against the novel coronavirus SARS-CoV-2, according to a study from researchers at the Perelman School of Medicine at the University of Pennsylvania. Prior studies have suggested that recent exposure to seasonal CoVs protects against SARS-CoV-2, the virus that causes COVID-19. However the new work, published in Cell, suggests that if there is such protection, it does not come from antibodies. They found that about 20% of the individuals tested possessed non-neutralizing antibodies that cross-reacted with SARS-CoV-2 spike and nucleocapsid proteins. These antibodies were not associated with protection against SARS-CoV-2 infections or hospitalizations, but they were boosted upon SARS-CoV-2 infection. DOI: 10.1016/j.cell.2021.02.010

Researchers believe a reduction in fatal coronavirus cases can be achieved without the social disruption seen in cities like New York. After running thousands of simulations with variations in social distancing behavior at home, in schools, at public facilities, and in the workplace researchers from City University of Hong Kong, the Chinese Academy of Sciences, and Rensselaer Polytechnic Institute found school closures were of little benefit for prevention of serious cases of COVID-19. Because New York City is so densely populated the effect of school closings is significantly smaller than the effect of general day-to-day interactions in public. Students are also generally the least vulnerable to the effects of severe COVID-19. Instead, researchers found that the focus needs to be on social distancing in public places, particularly among the much more vulnerable elderly population. By substituting the age and location parameters in the model, the results can extend to any city and may help in defining local control measures. However, the researchers caution that these results are specific to New York City, and what is good practice in one city may not translate to another. Greater detail can be found in ChaosDOI: 10.1063/5.0040560  

A new study, led by scientists from Duke-NUS Medical School, Singapore, and Chulalongkorn University, Thailand, reveals SARS-CoV-2-related coronaviruses (SC2r-CoVs) circulating in animals as far away as Thailand. High levels of SARS CoV-2 neutralizing antibodies were found in bats and pangolins in the area, and the study indicates that Southeast Asia, with its diverse bat population, is a likely site for the discovery of additional SC2r-CoVs. The research team conducted serological examinations of Rhinolophus bats in a Thai cave, detecting SARS-CoV-2 neutralizing antibodies in bats and a pangolin and extending the geographic distribution of genetically diverse SARS-CoV-2-related coronaviruses. Read about it in Nature Communications.  DOI: 10.1038/s41467-021-21240-1

An important metric to guide public health efforts is the size of the infected population at a given point in time. Because accurate figures have been a challenge to obtain due to undetected and subsequently unreported infections, a new machine learning (ML) framework has been developed to estimate the actual number of daily cases. Using published epidemiological parameters and publicly available real-time daily data the model found severe and universal undercounting of COVID-19 cases across the US and 50 of the most infected countries worldwide. In 25 out of the 50 countries, actual cases were estimated to be five to 20 times greater than reported. The framework may provide crucial information for future COVID-19 management strategies by determining the regional severity of COVID-19 and could also help inform contact-tracing and other public health efforts. Find out more in PLoS ONE DOI: 10.1371/journal.pone.0246772 

Prolonged illness in an immunocompromised patient can create the right conditions for the viral selection of specific variants coinciding with the presence of convalescent plasma. The documentation for this can be found in Nature where researchers report observing the mutation of SARS CoV-2 in a single patient. A male patient in his 70s with lymphoma was treated in hospital for 101 days with remdesivir and convalescent plasma. Where the early days of infection were rather static, the viral population shifted between days 66 and 82. Between days 86 and 89 new mutations were seen and the previously dominant mutation had dropped to 10% or less. Sequencing on day 93 revealed one mutation at almost 100% while another was barely discernible. At day 93 and 95, in a last attempt to control the virus, a third and final course of remdesivir and CP were administered, respectively, leading to a reemergence of an older mutation. These patterns in variance frequencies hint at competition between mutant populations. DOI: 10.1038/s41586-021-03291-y 

It has been proposed that a pangolin could have played a role in the COVID-19 pandemic. When researchers at the Francis Crick Institute analyzed the ACE2-binding properties and spike protein structure from a Pangolin coronavirus (CoV) closely related to the SARS CoV-2, they found structural similarities indicating that pangolin viruses may be able to infect humans. The bat coronavirus RaTG13 is currently the closest known relative of SARS CoV-2.  Based on the very low affinity the RaTG13 S protein showed for human ACE2 receptors it is unlikely this class of bat viruses could infect humans. Researchers were able to uncover the fine details of the pangolin CoV S protein with cryo-EM showing it has a fully-closed conformation that, aside from the RBD--which in sequence and structure is remarkably like that of the SARS CoV-2--resembles the S protein of RaTG13 more than SARS CoV-2. Findings are published in Nature Communications. DOI: 10.1038/s41467-021-21006-9  

Scientists at Bielefeld University's Faculty of Physics, in conjunction with Bielefeld University's Medical School OWL and Justus-Liebig-University Giessen, have visualized the interaction of the coronavirus and its host cell for the first time, courtesy of helium ion microscopy. While the helium ion microscope has been used more in materials science and engineering over the past decade, it is now being turned towards the examination of biological samples because of its unique ability to capture three-dimensional detail with its greater depth of field. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) have been used examine SARS CoV-2, but only HIM has allowed researchers the precision to identify the virus, see the interplay between the virus and the host cells, and even distinguish between the virus particles bound to the cell membrane from those lying on it. Read more in the Beilstein Journal of Nanotechnology. DOI: 10.3762/bjnano.12.13   

USC researchers propose an artificial intelligence (AI) based vaccine discovery framework to rapidly design a multi-epitope vaccine. Their approach replaces traditional and slower in silico methods of vaccine development that lack the ability to comprehensively analyze multiple predictions. Deep neural networks enabled the identification of 26 fragments in the SARS-CoV-2 spike protein as possible vaccine subunit candidates in less than a second. The team then identified the best 11 to create a multi-epitope vaccine against SARS CoV-2.  Vaccine quality could be evaluated, 3-D structure predicted, refined, and validated and the codon sequence optimized and inserted into a plasmid. In silico creation techniques like this may be key in dealing with viral mutations. Researchers were able to quickly determine that the effectiveness of their multi-epitope vaccine would be unaffected by the three most frequent structural changes induced by mutations. They were also able to quickly examine the mutated sequences for new vaccine subunits. Using this technique, a new multi-epitope vaccine could be constructed, and its quality validated within an hour. The findings appear in Nature Research's Scientific Reports. DOI: 10.1038/s41598-021-81749-9

Researchers at the Karolinska Institutet believe that DNA-launched RNA replicon vector (DREP) vaccines offer multiple benefits in the effort to control the COVID-19 pandemic. Because they can encode any area of interest these vaccines can be rapidly produced, they do not require a cold chain, are highly stable, safe, and potent. Two alpha-based DREP vaccine candidates were compared and found to induce immunogenicity in mice. While the antibody titer levels were lower in the DREP-Secto vaccine candidate, following a boost with a spike protein antibody, titer levels rose significantly. The researchers believe this translates into increased potency of the vaccine regimen and encourage the use of mixed modalities in the effort to control the pandemic. The details are published in Scientific Reports. DOI: 10.1038/s41598-021-82498-5 

Emory researchers at Yerkes National Primate Research Center have responded to the need for development of SARS CoV-2 vaccines using different platforms with a modified vaccinia Ankara (MVA) vaccine. This technique of vaccine development offers multiple advantages—safety, durability, stability, and ease of manufacturing—but because of its multiple delivery routes can be used to generate a mucosal antibody response. MVA vaccines may also better induce a robust CD8+ T cell response than currently available vaccine options. Their candidate vaccine is a MVA vector expressing membrane anchored pre-fusion stabilized spike (MVA/S) capable of inducing strong neutralizing antibody and T cell response in mice. When the vaccine was further tested in rhesus macaques it was shown to effectively prevent SARS CoV-2 replication in the lung as well as protect from infection induced inflammation, while inducing a strong neutralizing antibody and CD8+ T cell response. Learn more in Immunity. DOI: 10.1016/j.immuni.2021.02.001  


Industry News

Clinicians at UCI Health have seen success with a system for delivering monoclonal antibodies to COVID-19 positive patients that manages the challenges of allocating healthcare workers and finding the space through the creation of a closed loop system that sees patients through doctor referral. With six chairs and a dedicated staff in an infusion clinic, the COVID-19 positive patients are kept separate from other patients, and if the monoclonal antibodies are successful—only about three percent of the first 86 patients to receive monoclonal antibody treatment at UCI later had to be admitted to the emergency department—COVID patients never have to touch the emergency department or hospital setting, helping the community and preserving hospital beds. UCI has seen a significant improvement in COVID-19 hospitalizations with monoclonal antibodies. Press Release

New Yorkers' acceptance of the COVID-19 vaccine has increased significantly according to a survey conducted by the City University of New York Graduate School of Public Health and Health Policy (CUNY SPH). These are key findings from the most recent tracking survey of public perceptions and experiences in New York City during the COVID-19 pandemic. Last September, 55% of residents reported they would take the vaccine when it became available. This January, 64% reported they would take it, and this increase persists across racial and ethnic groups. However, more than half (54%) of New York City respondents believe the state is not doing a good job of managing the vaccine rollout. Press Release

A large international study is underway with hopes of identifying drugs that may be repurposed as treatments against the COVID-19 pandemic, especially in low and middle-income countries where the resources to continue admitting patients to hospital at the current rate simply do exist. McMaster University researchers are leading a large international study with research clinic Cardresearch and the Pontifical Catholic University of Minas Gerais in Brazil and the University of Stellenbosch in South Africa on an ongoing clinical trial funded in part by the Bill and Melinda Gates Foundation and Fastgrants. The Together COVID-19 trial will evaluate the effectiveness of ivermectin, metformin, and fluvoxamine on preventing COVID-19 disease progression. Ivermectin is typically used to treat parasitic infections. Metformin is better known as a treatment for diabetes. And fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) used to treat depression and anxiety disorders. In Brazil there is particular interest in ivermectin. Costing less than $5 per treatment, ivermectin is on the WHO’s list of essential medicines. Some small clinical trials have indicated a benefit for COVID-19 patients treated with ivermectin during the early stage. Press Release 

An NIH trial has begun enrolling participants for an international randomized, controlled Phase III clinical trial to evaluate the safety and efficacy of an investigational long-acting antibody combination for treating people hospitalized with COVID-19. This trial is part of a larger framework, ACTIV-3, and has an adaptive design that allows researchers to add additional sub-studies of new experimental agents. A new sub-study is evaluating AZD7442, an investigational long-acting antibody combination developed by AstraZeneca. In 2020, researchers at Vanderbilt University Medical Center isolated antibodies from two patients who had recovered from COVID-19, and these antibodies, licensed to AstraZeneca, formed the basis for the synthetic antibodies in AZD7442. The AZD7442 study will run concurrently with two other sub-studies, one to evaluate VIR-7831, a SARS-CoV-2 experimental monoclonal antibody and another evaluating a combination of BRII-196 and BRII-198, two investigational SARS-CoV-2 neutralizing monoclonal antibodies. Press Release

ProPhase Labs has begun saliva-based testing that integrates the Spectrum Solution saliva self-collection system with a new multiplex qPCR platform for simultaneous RNA detection of SARS CoV-2, as well as its mutations, and Influenza A and B. The SDNA Viral saliva-based testing combo features painless self-collection and a safer sample collection process. Emergency use authorization applications have been filed, and ProPhase has received confirmation of a formal review from the FDA device division. Press Release

Nanomix has submitted an Emergency Use Authorization request to the FDA for their eLab COVID-19 rapid antigen test. The assay, which runs on the portable Nanomix eLab analyzer, provides results in 15 minutes and can be used in a range of settings. This platform allows medical professionals, but also employers to test for SARS CoV-2 antigens with a nasal swab that can be self-administered. Press Release

The NIH is sponsoring a Stanford University School of Medicine study using the Fluidigm mass cytometry technology and the Maxpar Direct Immune Profiling Assay in a longitudinal study of approximately 250 pediatric patients infected with SARS CoV-2. With blood samples collected at 20 clinical sites and sent to Stanford, the study will compare data on immune system activity in SARS-CoV-2 positive children with asymptomatic infections, mild COVID-19 infections, and multisystem inflammatory syndrome (MIS-C). The potentially life-threatening MIS-C typically begins several weeks after SARS-CoV-2 exposure and little is known about the immunologic mechanisms. A principal goal of the study is to characterize the immunologic pathways associated with different disease presentations and outcomes. The study is expected to enroll about 250 SARS-CoV-2 infected patients under age 21 from diverse racial and ethnic backgrounds. Press Release

Thermo Fisher Scientific has announced the launch of its CE-IVD-Marked, Applied Biosystems TaqPath COVID–19 HT Kit. This high-throughput solution, compatible with the Amplitude platform, will enable clinical and public health laboratories to test up to 8,000 COVID-19 samples per day with fewer staff. The automated Amplitude platform is a molecular diagnostic platform combining real-time PCR with a supply agreement and monthly delivery of reagent to scale testing for COVID-19. The diagnostic assay also received Interim Order Authorization from Health Canada on January 21.  Press Release

A team of researchers at Wayne State University are developing an artificial intelligence (AI) model to help identify early warning signs of severe SARS CoV-2 infection in children. They are working to define and compare the salivary molecular host response in children with varying phenotypes of SARS-CoV-2 infections. From there they will develop and validate a sensitive and specific model to predict severe SARS-CoV-2 illness in children. They want to develop a portable, rapid device that quantifies salivary miRNAs for early recognition of severe SARS-CoV-2 infection in children using an efficient AI model with cloud and edge intelligence-integrating noninvasive biomarkers. The two-year project, Severity Predictors Integrating Salivary Transcriptomics and Proteomics with Multi Neural Network Intelligence in SARS-CoV2 Infection in Children (SPITS MISC), received $1,433,469 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Press Release