scholarly journals A Novel CRISPR-Engineered, Stem Cell-Derived Cellular Vaccine

2021 ◽  
Author(s):  
Krishnendu Chakraborty ◽  
Abishek Chandrashekar ◽  
Adam Sidaway ◽  
Elizabeth Latta ◽  
Jingyou Yu ◽  
...  
Keyword(s):  
Viral Antigen ◽  
Large Scale ◽  
Neutralizing Antibody ◽  
Clinical Translation ◽  
Host Cells ◽  
Universal Vaccine ◽  
Mhc I ◽  
Global Pandemic ◽  
Heterologous Challenge ◽  
Induced Pluripotent

COVID-19 has forced rapid clinical translation of novel vaccine technologies, principally mRNA vaccines, that have resulted in meaningful efficacy and adequate safety in response to the global pandemic. Notwithstanding this success, there remains an opportunity for innovation in vaccine technology to address current limitations and meet the challenges of inevitable future pandemics. We describe a universal vaccine cell (UVC) rationally designed to mimic the natural physiologic immunity induced post viral infection of host cells. Induced pluripotent stem cells were CRISPR engineered to delete MHC-I expression and simultaneously overexpress a NK Ligand adjuvant to increase rapid cellular apoptosis which was hypothesized to enhance viral antigen presentation in the resulting immune microenvironment leading to a protective immune response. Cells were further engineered to express the parental variant WA1/2020 SARS-CoV-2 spike protein as a representative viral antigen prior to irradiation and cryopreservation. The cellular vaccine was then used to immunize non-human primates in a standard 2-dose, IM injected prime + boost vaccination with 1e8 cells per 1 ml dose resulting in robust neutralizing antibody responses (1e3 nAb titers) with decreasing levels at 6 months duration. Similar titers generated in this established NHP model have translated into protective human neutralizing antibody levels in SARS-Cov-2 vaccinated individuals. Animals vaccinated with WA1/2020 spike antigens were subsequently challenged with 1.0 x 105 TCID50 infectious Delta (B.1.617.2) SARS-CoV-2 in a heterologous challenge which resulted in an approximately 3-log order decrease in viral RNA load in the lungs. These heterologous viral challenge results reflect the ongoing real-world experience of original variant WA1/2020 spike antigen vaccinated populations exposed to rapidly emerging variants like Delta and now Omicron. This cellular vaccine is designed to be a rapidly scalable cell line with a modular poly-antigenic payload to allow for practical, large-scale clinical manufacturing and use in an evolving viral variant environment. Human clinical translation of the UVC is being actively explored for this and potential future pandemics.

scholarly journals Emerging antibody-based therapeutics against SARS-CoV-2 during the global pandemic

2020 ◽  
Vol 3 (4) ◽  
pp. 246-256
Author(s):  
Yaping Sun ◽  
Mitchell Ho
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Host Cells ◽  
Spike Protein ◽  
Inhaled Drugs ◽  
Viral Attachment ◽  
Global Pandemic ◽  
Attachment Sites ◽  
Antibody Discovery

Abstract SARS-CoV-2 antibody therapeutics are being evaluated in clinical and preclinical stages. As of 11 October 2020, 13 human monoclonal antibodies targeting the SARS-CoV-2 spike protein have entered clinical trials with three (REGN-COV2, LY3819253/LY-CoV555, and VIR-7831/VIR-7832) in phase 3. On 9 November 2020, the US Food and Drug Administration issued an emergency use authorization for bamlanivimab (LY3819253/LY-CoV555) for the treatment of mild-to-moderate COVID-19. This review outlines the development of neutralizing antibodies against SARS-CoV-2, with a focus on discussing various antibody discovery strategies (animal immunization, phage display and B cell cloning), describing binding epitopes and comparing neutralizing activities. Broad-neutralizing antibodies targeting the spike proteins of SARS-CoV-2 and SARS-CoV might be helpful for treating COVID-19 and future infections. VIR-7831/7832 based on S309 is the only antibody in late clinical development, which can neutralize both SARS-CoV-2 and SARS-CoV although it does not directly block virus receptor binding. Thus far, the only cross-neutralizing antibody that is also a receptor binding blocker is nanobody VHH-72. The feasibility of developing nanobodies as inhaled drugs for treating COVID-19 and other respiratory diseases is an attractive idea that is worth exploring and testing. A cocktail strategy such as REGN-COV2, or engineered multivalent and multispecific molecules, combining two or more antibodies might improve the efficacy and protect against resistance due to virus escape mutants. Besides the receptor-binding domain, other viral antigens such as the S2 subunit of the spike protein and the viral attachment sites such as heparan sulfate proteoglycans that are on the host cells are worth investigating.

scholarly journals Molecular Mechanism of the N501Y Mutation for Enhanced Binding between SARS-CoV-2’s Spike Protein and Human ACE2 Receptor

2021 ◽  
Author(s):  
Binquan Luan ◽  
Haoran Wang ◽  
Tien Huynh
Keyword(s):  
Molecular Mechanism ◽  
Hydrophobic Interactions ◽  
Neutralizing Antibody ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Global Pandemic ◽  
Dynamics Simulations ◽  
Antibody Cocktail

AbstractCoronavirus disease 2019 (COVID-19) has been an ongoing global pandemic for over a year. Recently, an emergent SARS-CoV-2 variant (B.1.1.7) with an unusually large number of mutations had become highly contagious and wide-spreading in United Kingdom. From genome analysis, the N501Y mutation within the receptor binding domain (RBD) of the SARS-CoV-2’s spike protein might have enhanced the viral protein’s binding with the human angiotensin converting enzyme 2 (hACE2). The latter is the prelude for the virus’ entry into host cells. So far, the molecular mechanism of this enhanced binding is still elusive, which prevents us from assessing its effects on existing therapeutic antibodies. Using all atom molecular dynamics simulations, we demonstrated that Y501 in mutated RBD can be well coordinated by Y41 and K353 in hACE2 through hydrophobic interactions, increasing the overall binding affinity between RBD and hACE2 by about 0.81 kcal/mol. We further explored how the N501Y mutation might affect the binding between a neutralizing antibody (CB6) and RBD. We expect that our work can help researchers design proper measures responding to this urgent virus mutation, such as adding a modified/new neutralizing antibody specifically targeting at this variant in the therapeutic antibody cocktail.Abstract Figure

scholarly journals A Neutralizing Antibody-Conjugated Photothermal Nanoparticle Captures and Inactivates SARS-CoV-2

2020 ◽  
Author(s):  
Xiaolei Cai ◽  
Aleksander Prominski ◽  
Yiliang Lin ◽  
Nicholas Ankenbruck ◽  
Jillian Rosenberg ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Host Cells ◽  
Photothermal Effect ◽  
Semiconducting Polymer ◽  
Global Pandemic ◽  
Multiple Strains ◽  
Novel Therapeutic

ABSTRACTThe outbreak of 2019 coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic. Despite intensive research including several clinical trials, currently there are no completely safe or effective therapeutics to cure the disease. Here we report a strategy incorporating neutralizing antibodies conjugated on the surface of a photothermal nanoparticle to actively capture and inactivate SARS-CoV-2. The photothermal nanoparticle is comprised of a semiconducting polymer core and a biocompatible polyethylene glycol surface decorated with neutralizing antibodies. Such nanoparticles displayed efficient capture of SARS-CoV-2 pseudoviruses, excellent photothermal effect, and complete inhibition of viral entry into ACE2-expressing host cells via simultaneous blocking and inactivating of the virus. This photothermal nanoparticle is a flexible platform that can be readily adapted to other SARS-CoV-2 antibodies and extended to novel therapeutic proteins, thus providing a broad range of protection against multiple strains of SARS-CoV-2.

Even if politicians deal, Lebanon faces a bleak future

2021 ◽  
Keyword(s):  
Foreign Aid ◽  
Rural Areas ◽  
Large Scale ◽  
Economic Reforms ◽  
Financial Strain ◽  
Economic Conditions ◽  
Medium Term ◽  
Content Type ◽  
Global Pandemic ◽  
Food Shortages

Significance The audit and wider structural economic reforms are preconditions for urgently needed foreign aid. Economic conditions in Lebanon are still worsening, with power cuts, food shortages and rising poverty. Impacts A new government would allow reform planning to resume and temporarily stall the decline of the currency. The easing of the global pandemic will somewhat reduce the financial strain, as Lebanon reopens its economy. Soaring poverty rates could provoke large-scale ‘bread riots’ in the coming months. Further devaluation of the currency will make poor Lebanese more dependent on sectarian protection and strengthen patronage. If the situation worsens, sectarian rural areas could revert to warlordism in the medium term.

scholarly journals Atomistic simulations indicate the functional loop-to-coiled-coil transition in influenza hemagglutinin is not downhill

2018 ◽  
Vol 115 (34) ◽  
pp. E7905-E7913 ◽  
Author(s):  
Xingcheng Lin ◽  
Jeffrey K. Noel ◽  
Qinghua Wang ◽  
Jianpeng Ma ◽  
José N. Onuchic
Keyword(s):  
Viral Entry ◽  
Large Scale ◽  
Coiled Coil ◽  
Structural Rearrangement ◽  
Structural Heterogeneity ◽  
Host Cells ◽  
Fusion Peptides ◽  
Influenza Hemagglutinin ◽  
Loop Region ◽  
Coil Transition

Influenza hemagglutinin (HA) mediates viral entry into host cells through a large-scale conformational rearrangement at low pH that leads to fusion of the viral and endosomal membranes. Crystallographic and biochemical data suggest that a loop-to-coiled-coil transition of the B-loop region of HA is important for driving this structural rearrangement. However, the microscopic picture for this proposed “spring-loaded” movement is missing. In this study, we focus on understanding the transition of the B loop and perform a set of all-atom molecular dynamics simulations of the full B-loop trimeric structure with the CHARMM36 force field. The free-energy profile constructed from our simulations describes a B loop that stably folds half of the postfusion coiled coil in tens of microseconds, but the full coiled coil is unfavorable. A buried hydrophilic residue, Thr59, is implicated in destabilizing the coiled coil. Interestingly, this conserved threonine is the only residue in the B loop that strictly differentiates between the group 1 and 2 HA molecules. Microsecond-scale constant temperature simulations revealed that kinetic traps in the structural switch of the B loop can be caused by nonnative, intramonomer, or intermonomer β-sheets. The addition of the A helix stabilized the postfusion state of the B loop, but introduced the possibility for further β-sheet structures. Overall, our results do not support a description of the B loop in group 2 HAs as a stiff spring, but, rather, it allows for more structural heterogeneity in the placement of the fusion peptides during the fusion process.

scholarly journals Structural models of SARS-CoV-2 Omicron variant in complex with ACE2 receptor or antibodies suggest altered binding interfaces

2021 ◽  
Author(s):  
Joseph H. Lubin ◽  
Christopher Markosian ◽  
D. Balamurugan ◽  
Renata Pasqualini ◽  
Wadih Arap ◽  
...  
Keyword(s):  
Structural Information ◽  
Structural Models ◽  
Interaction Network ◽  
Neutralizing Antibody ◽  
Data Bank ◽  
Binding Interface ◽  
Global Pandemic ◽  
Residue Interaction ◽  
Protein Interfaces ◽  
Class 1

There is enormous ongoing interest in characterizing the binding properties of the SARS-CoV-2 Omicron Variant of Concern (VOC) (B.1.1.529), which continues to spread towards potential dominance worldwide. To aid these studies, based on the wealth of available structural information about several SARS-CoV-2 variants in the Protein Data Bank (PDB) and a modeling pipeline we have previously developed for tracking the ongoing global evolution of SARS-CoV-2 proteins, we provide a set of computed structural models (henceforth models) of the Omicron VOC receptor-binding domain (omRBD) bound to its corresponding receptor Angiotensin-Converting Enzyme (ACE2) and a variety of therapeutic entities, including neutralizing and therapeutic antibodies targeting previously-detected viral strains. We generated bound omRBD models using both experimentally-determined structures in the PDB as well as machine learning-based structure predictions as starting points. Examination of ACE2-bound omRBD models reveals an interdigitated multi-residue interaction network formed by omRBD-specific substituted residues (R493, S496, Y501, R498) and ACE2 residues at the interface, which was not present in the original Wuhan-Hu-1 RBD-ACE2 complex. Emergence of this interaction network suggests optimization of a key region of the binding interface, and positive cooperativity among various sites of residue substitutions in omRBD mediating ACE2 binding. Examination of neutralizing antibody complexes for Barnes Class 1 and Class 2 antibodies modeled with omRBD highlights an overall loss of interfacial interactions (with gain of new interactions in rare cases) mediated by substituted residues. Many of these substitutions have previously been found to independently dampen or even ablate antibody binding, and perhaps mediate antibody-mediated neutralization escape (e.g., K417N). We observe little compensation of corresponding interaction loss at interfaces when potential escape substitutions occur in combination. A few selected antibodies (e.g., Barnes Class 3 S309), however, feature largely unaltered or modestly affected protein-protein interfaces. While we stress that only qualitative insights can be obtained directly from our models at this time, we anticipate that they can provide starting points for more detailed and quantitative computational characterization, and, if needed, redesign of monoclonal antibodies for targeting the Omicron VOC Spike protein. In the broader context, the computational pipeline we developed provides a framework for rapidly and efficiently generating retrospective and prospective models for other novel variants of SARS-CoV-2 bound to entities of virological and therapeutic interest, in the setting of a global pandemic.

scholarly journals Recent update on COVID-19 in India: Is locking down the country enough?

2020 ◽  
Author(s):  
Jitender Singh Virk ◽  
Syed Azmal Ali ◽  
Gurjeet Kaur
Keyword(s):  
Growth Factor ◽  
Large Scale ◽  
Inflection Point ◽  
Indian Population ◽  
Lasso Regression ◽  
Logistic Curve ◽  
Global Pandemic ◽  
Care Facilities ◽  
The World ◽  
The Usa

AbstractBackgroundIndia is the second-largest population in the world, and it is not well equipped, hitherto, in the scenario of the global pandemic, SARS-CoV-2 could impart a devastating impact on the Indian population. Only way to respond against this critical condition is by practicing large-scale social distancing. India lock down for 21 days, however, till 7 April 2020, SARS- CoV-2 positive cases were growing exponentially, which raises the concerns if the number of reported and actual cases are similar.MethodsWe use Lasso Regression with α = 0.12 and Polynomial features of degree 2 to predict the growth factor. Also, we predicted Logistic curve using the Prophet Python. Further, using the growth rate to logistic, and carrying capacity is 20000 allowed us to calculate the maximum cases and new cases per day.ResultsWe found the predicted growth factor with a standard deviation of 0.3443 for the upcoming days. When the growth factor becomes 1.0, which is known as Inflection point, it will be safe to state that the rate is no longer exponential. The estimated time to reach the inflection point is between 15-20 April. At that time, the estimated number of total positive cases will be over 12500, if lockdown remains continue.ConclusionsOur analysis suggests that there is an urgent need to take action to extend the period of lockdown and allocate enough resources, including personnel, beds, and intensive care facilities, to manage the situation in the next few days and weeks. Otherwise, the outbreak in India can reach the level of the USA or Italy or could be worse than these countries within a few days or weeks, given the size of the population and lack of resources.

scholarly journals Covidom, a Telesurveillance Solution for Home Monitoring Patients With COVID-19 (Preprint)

2020 ◽  
Author(s):  
Youri Yordanov ◽  
Agnes Dechartres ◽  
Xavier Lescure ◽  
Caroline Apra ◽  
Pascaline Villie ◽  
...  
Keyword(s):  
Health Care Professionals ◽  
Web Application ◽  
Large Scale ◽  
Home Monitoring ◽  
Control Center ◽  
Regional Control ◽  
Global Pandemic ◽  
Number Of Patients ◽  
Paris Area ◽  
Innovative Solution

UNSTRUCTURED In a matter of months, COVID-19 has escalated from a cluster of cases in Wuhan, China, to a global pandemic. As the number of patients with COVID-19 grew, solutions for the home monitoring of infected patients became critical. This viewpoint presents a telesurveillance solution—Covidom—deployed in the greater Paris area to monitor patients with COVID-19 in their homes. The system was rapidly developed and is being used on a large scale with more than 65,000 registered patients to date. The Covidom solution combines an easy-to-use and free web application for patients (through which patients fill out short questionnaires on their health status) with a regional control center that monitors and manages alerts (triggered by questionnaire responses) from patients whose health may be deteriorating. This innovative solution could alleviate the burden of health care professionals and systems while allowing for rapid response when patients trigger an alert.

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