Austria plans vaccine drive in area hit by SA virus variant

Austria plans vaccine drive in area hit by SA virus variant

Austrian officials said Wednesday that they plan to offer vaccinations to most residents in a district that has seen significant numbers of infections with the South African coronavirus variant.

Tyrol province’s Schwaz district, east of the provincial capital of Innsbruck and home to about 84,000 people, has been a source of concern for weeks.

Schwaz accounts for 66 of 88 currently active confirmed cases of the more transmissible variant in the province, the Austria Press Agency reported.

The plan announced Wednesday calls for a vaccination drive starting next week. Health Minister Rudolf Anschober said the rollout will see vaccinations offered to all aged 16 and over.

APA reported that from around March 10, coinciding with the start of the drive and until it is complete, people will be required to get a negative coronavirus test before they could leave the Schwaz district.

The plan “is our opportunity to eliminate the variant in the Schwaz district,” Chancellor Sebastian Kurz said. He said numbers of active cases have already fallen.

The variant first identified in South Africa is a source of particular concern because of doubts over whether all vaccines currently available are fully effective against it.

Austrian officials said they have been able to bring forward the delivery of 100,000 doses of the Pfizer-BioNTech vaccine for Tyrol in cooperation with the European Union’s executive Committee and the manufacturers.

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Comparative analysis of SARS-CoV-2 antivirals leads to new potential treatment for COVID-19

A rapid spread of the virus that caused symptoms similar to severe pneumonia was first reported in Wuhan, China, in December 2019. Scientists found that this novel virus belonged to the family Coronaviridae and was later named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Worldwide, researchers are developing various vaccines, medicines, facemasks, and many other means to contain the SARS-CoV-2 infection.

Among various antiviral drugs, remdesivir has been approved for the treatment of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection. Remdesivir is a nucleoside analog that inhibits the SARS-CoV-2 RNA-dependent RNA-polymerase (RdRp). It is a virus polymerase inhibitor that involves the termination of both the viral transcript and newly synthesized viral genomes. However, there are some limitations that have escalated the need to develop other potential antiviral drugs that have minimal side effects and maximum efficacy.

Study: A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19. Image Credit: Ekaterina Bondaretc / Shutterstock

Researchers have discovered an alternate target site of SARS-CoV-2: the 3CLpro (Mpro), main protease. This protease plays a key role in the life cycle of the virus. After the virus enters into the host cell, the positive-stranded RNA genome of the virus gets rapidly translated into two polyproteins. These polyproteins are processed into functional protein by PL2 pro and 3CLpro viral protease. Two of the main functions of 3CLpro are governing proper assembly and folding of polymerase subunits required to develop into a properly functional polymerase complex. Thereby, inhibition of 3CLpro would effectively stop the viral life cycle. Further, the unique substrate preference of 3CLpro also makes it an effective target site.

To date, PF -07304814 is the only 3CLpro inhibitor that has reached the clinical trials. It is a ketone-based covalent cysteine protease inhibitor administered as a phosphate prodrug, thereby converting to its active form, PF-90 00835231. In 2003, PF-00835231 was developed in response to the previous coronavirus epidemic as an inhibitor for the 3CLpro. However, due to the rapid decline in the infection rate, it was not brought to clinical trials, and further study about its efficacy was stopped.

Scientists believe that PF-00835231 would be effective against the novel SARS-CoV-2. This is because of a 96% similarity at the amino acid level and 100% similarity within the catalytic pocket of the 3CLpro present in both SARS-CoV and SARS-CoV-2. A recent study demonstrated the effectiveness of PF-00835231 at high micromolar levels.

In a forthcoming paper in the Journal of Virology, scientists compared the in vitro efficacy and cytotoxicity profiles of PF-00835231 and remdesivir in two human model systems for SARS-CoV-2 infection; namely, A549+ACE2 cells and polarized human airway epithelial cultures. After the initial characterization of A549+ACE2 cells to study SARS-CoV-2, an in vitro study was carried out to evaluate the efficacy and cytotoxicity of PF-00835231, GC-376 (protease inhibitor at the preclinical stage), and remdesivir in A549+ACE2 cells.

The team also conducted time-of-drug-addition assays in A549+ACE2 cells to define and compare the action time of the antiviral drugs within the SARS-CoV-2 life cycle. The role of efflux transporter Multi-Drug Resistance Protein 1 (MDR1) on the antiviral efficacy of PF-00835231 was also studied. The main focus of the study was to provide in vitro evidence of the potential PF-00835231 as an effective antiviral drug for SARS-CoV-2 and also highlight its negative effects based on prior studies.

This research has shown that both PF-00835231 and remdesivir are similarly potent in studying a model of polarized human airway epithelial cultures (HAEC). However, in A549+ACE2 cell assay, PF-00835231 revealed better activity than the preclinical GC-376 and similar or marginally effect as remdesivir.

The optimal time to start antiviral drug treatment is the first week after the onset of symptoms, i.e. when the virus replication is actively ongoing. In the case of patients who are severely affected by COVID-19, the active replication of SARS-CoV-2 can be prolonged. This study revealed that intravenous treatment of PF-00835231 would remain effective for severely infected patients. Intravenous remdesivir treatment was also found to be effective against SARS-CoV-2.

Cell composition of polarized human airway epithelial cultures (HAEC), and cytotoxicity of PF-00835231 and remdesivir. a. Schematic representation of a transwell containing a polarized HAEC in air-liquid interface. Dark blue, cycling basal cells; light blue, basal cells; red, suprabasal cells; purple, secretory cells; yellow, microfold cells; green, ciliated cells; grey, mucus. To test for cytotoxicity, drugs were added to the media in the basolateral chamber. b. Clustered UMAP of single cells determined by single-cell RNA sequencing from n=3 uninfected HAEC. Clusters were determined by markers from the literature(37, 38) and by differentially expressed marker genes for each cluster determined by Wilcox test. c., d. Representative cross-sections of uninfected HAEC, 72 h post treatment with 10 µM PF-00835231 or 10 µM remdesivir. H&E (c.) or PAS-Alcian blue staining (d.). e. Trans-epithelial resistance (TEER) in drug1205 treated, uninfected HAEC over time as a measure of epithelial integrity. Means ? SEM from n=3 independent experiments. f. CellTiter-glo assay on undifferentiated, basal-like Bci-NS1.1 precursor cells. Means ? SEM from n=3 independent experiments.

The current research has also demonstrated a significant synergistic effect between PF-00835231 and remdesivir in inhibiting SARS-CoV-2. Researchers believe that the use of multiple antiviral drugs with different modes of action or target sites would efficiently circumvent cross-resistance caused by mutations. Hence, the development of antiviral treatments using multiple antiviral drugs would significantly improve antiviral therapy in COVID -19.

To summarize, the team's research reveals the significance of the novel antiviral drug, PF–00835231, against SARS-CoV-2 with the help of 3D in vitro models of human airway epithelium. This would help to decrease the mortality rate of COVID-19 and also pave the way to explore new treatment methods for other harmful viruses.

Journal reference:
  • Maren de Vries, Adil S. Mohamed, Rachel A. Prescott, Ana M. Valero Jimenez, Ludovic Desvignes, Rebecca O'Connor, Claire Steppan, Joseph C. Devlin, Ellie Ivanova, Alberto Herrera, Austin Schinlever, Paige Loose, Kelly Ruggles, Sergei B. Koralov, Annaliesa S. Anderson, Joseph Binder, Meike Dittmann. A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19, Journal of Virology Feb 2021, JVI.01819-20; DOI: 10.1128/JVI.01819-20 https://jvi.asm.org/content/early/2021/02/19/JVI.01819-20

Posted in: Medical Science News | Medical Research News | Disease/Infection News | Healthcare News | Pharmaceutical News

Tags: ACE2, Amino Acid, Antiviral Drug, Assay, Cell, Coronavirus, Coronavirus Disease COVID-19, Cysteine, Cytotoxicity, Drug Repurposing, Drugs, Efficacy, Genome, in vitro, Mortality, Nucleoside, Pneumonia, Polymerase, Preclinical, Protein, Remdesivir, Research, Respiratory, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Virology, Virus

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Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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FDA issues EUA for third COVID-19 vaccine

Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for the third vaccine for the prevention of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The EUA allows the Janssen COVID-19 Vaccine to be distributed in the U.S for use in individuals 18 years of age and older.

"The authorization of this vaccine expands the availability of vaccines, the best medical prevention method for COVID-19, to help us in the fight against this pandemic, which has claimed over half a million lives in the United States," said Acting FDA Commissioner Janet Woodcock, M.D.

"The FDA, through our open and transparent scientific review process, has now authorized three COVID-19 vaccines with the urgency called for during this pandemic, using the agency's rigorous standards for safety, effectiveness, and manufacturing quality needed to support emergency use authorization."

The FDA has determined that the Janssen COVID-19 Vaccine has met the statutory criteria for issuance of an EUA. The totality of the available data provides clear evidence that the Janssen COVID-19 Vaccine may be effective in preventing COVID-19. The data also show that the vaccine's known and potential benefits outweigh its known and potential risks, supporting the company's request for the vaccine's use in people 18 years of age and older. In making this determination, the FDA can assure the public and the medical community that it has conducted a thorough evaluation of the available safety, effectiveness, and manufacturing quality information.

The Janssen COVID-19 Vaccine is manufactured using a specific type of virus called adenovirus type 26 (Ad26). The vaccine uses Ad26 to deliver a piece of the DNA, or genetic material, that is used to make the distinctive "spike" protein of the SARS-CoV-2 virus.

While adenoviruses are a group of viruses that are relatively common, Ad26, which can cause cold symptoms and pink eye, has been modified for the vaccine so that it cannot replicate in the human body to cause illness.

After a person receives this vaccine, the body can temporarily make the spike protein, which does not cause disease but triggers the immune system to learn to react defensively, producing an immune response against SARS-CoV-2.

After a thorough analysis of the data, the FDA's scientists and physicians have determined that the vaccine meets the FDA's expectations for safety and effectiveness appropriate for the authorization of a vaccine for emergency use. With today's authorization, we are adding another vaccine in our medical toolbox to fight this virus. At the same time, the American people can be assured of the FDA's unwavering commitment to public health through our comprehensive and rigorous evaluation of the data submitted for vaccines to prevent COVID-19."

Peter Marks, MD, PhD, Director of the Center for Biologics Evaluation and Research, Food and Drug Administration

FDA evaluation of available safety data

The Janssen COVID-19 Vaccine is administered as a single dose. The available safety data to support the EUA include an analysis of 43,783 participants enrolled in an ongoing randomized, placebo-controlled study being conducted in South Africa, certain countries in South America, Mexico, and the U.S.

The participants, 21,895 of who received the vaccine and 21,888 of whom received saline placebo, were followed for a median of eight weeks after vaccination. The most commonly reported side effects were pain at the injection site, headache, fatigue, muscle aches, and nausea. Most of these side effects were mild to moderate in severity and lasted 1-2 days.

As part of the authorization, the FDA notes that it is mandatory for Janssen Biotech Inc. and vaccination providers to report the following to the Vaccine Adverse Event Reporting System (VAERS) for Janssen COVID-19 Vaccine: serious adverse events, cases of Multisystem Inflammatory Syndrome and cases of COVID-19 that result in hospitalization or death.

It is also mandatory for vaccination providers to report all vaccine administration errors to VAERS for which they become aware and for Janssen Biotech Inc. to include a summary and analysis of all identified vaccine administration errors in monthly safety reports submitted to the FDA.

FDA evaluation of available effectiveness data

The effectiveness data to support the EUA include an analysis of 39,321 participants in the ongoing randomized, placebo-controlled study being conducted in South Africa, certain countries in South America, Mexico, and the U.S. who did not have evidence of SARS-CoV-2 infection prior to receiving the vaccine.

Among these participants, 19,630 received the vaccine and 19,691 received a saline placebo. Overall, the vaccine was approximately 67% effective in preventing moderate to severe/critical COVID-19 occurring at least 14 days after vaccination and 66% effective in preventing moderate to severe/critical COVID-19 occurring at least 28 days after vaccination.

Additionally, the vaccine was approximately 77% effective in preventing severe/critical COVID-19 occurring at least 14 days after vaccination and 85% effective in preventing severe/critical COVID-19 occurring at least 28 days after vaccination.

There were 116 cases of COVID-19 in the vaccine group that occurred at least 14 days after vaccination, and 348 cases of COVID-19 in the placebo group during this time period. There were 66 cases of COVID-19 in the vaccine group that occurred at least 28 days after vaccination and 193 cases of COVID-19 in the placebo group during this time period.

Starting 14 days after vaccination, there were 14 severe/critical cases in the vaccinated group versus 60 in the placebo group, and starting 28 days after vaccination, there were 5 severe/critical in the vaccine group versus 34 cases in the placebo group.

At this time, data are not available to determine how long the vaccine will provide protection, nor is there evidence that the vaccine prevents transmission of SARS-CoV-2 from person to person.

The EUA process

On the basis of the determination by the Secretary of the Department of Health and Human Services on Feb. 4, 2020, that there is a public health emergency that has a significant potential to affect national security or the health and security of United States citizens living abroad, and issued declarations that circumstances exist justifying the authorization of emergency use of unapproved products, the FDA may issue a EUA to allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent COVID-19 when there are no adequate, approved, and available alternatives.

The issuance of a EUA is different than an FDA approval (licensure) of a vaccine, in that a vaccine available under a EUA is not approved.

In determining whether to issue a EUA for a product, the FDA evaluates the available evidence to determine whether the product may be effective and also assesses any known or potential risks and any known or potential benefits If the product meets the effectiveness standard and the benefit-risk assessment is favorable, the product is made available during the emergency.

Once a manufacturer submits a EUA request for a COVID-19 vaccine to the FDA, the agency then evaluates the request and determines whether the relevant statutory criteria are met, taking into account the totality of the scientific evidence about the vaccine that is available to the FDA.

The EUA also requires that fact sheets that provide important information, including dosing instructions, and information about the benefits and risks of the Janssen COVID-19 Vaccine, be made available to vaccination providers and vaccine recipients.

Janssen Biotech Inc. has submitted a pharmacovigilance plan to the FDA describing its commitment to monitor the safety of the Janssen COVID-19 Vaccine. The pharmacovigilance plan includes a plan to complete longer-term safety follow-up for participants enrolled in ongoing clinical trials.

The pharmacovigilance plan also includes other activities aimed at monitoring the safety profile of the Janssen COVID-19 Vaccine and ensuring that any safety concerns are identified and evaluated in a timely manner.

The FDA also expects manufacturers whose COVID-19 vaccines are authorized under a EUA to continue their clinical trials to obtain additional safety and effectiveness information and pursue approval (licensure).

The EUA for the Janssen COVID-19 Vaccine was issued to Janssen Biotech Inc., a Janssen Pharmaceutical Company of Johnson & Johnson. The authorization will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biologics for prevention and treatment of COVID-19 is terminated.

The EUA for Janssen COVID-19 Vaccine may be revised or revoked if it is determined the EUA no longer meets the statutory criteria for issuance.

Source:

Food and Drug Administration

Posted in: Disease/Infection News | Healthcare News | Pharmaceutical News

Tags: Adenovirus, Cold, Coronavirus, Coronavirus Disease COVID-19, DNA, Drugs, Eye, Fatigue, Genetic, Headache, Health and Human Services, Immune Response, Immune System, Manufacturing, Muscle, Nausea, Pain, Pandemic, pH, Pink Eye, Placebo, Protein, Public Health, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Vaccine, Virus

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Retroviruses invading the koala germline contribute to high cancer rates

Koalas are facing multiple environmental and health issues which threaten their survival. Along with habitat loss – accelerated by last year’s devastating bush fires – domestic dog attacks and road accidents, they suffer from deadly chlamydial infections and extremely high frequency of cancer.

An international team of scientists led by the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) now demonstrate that a retrovirus invading the koala germline explains the high frequency of koala cancer. The results are reported in the journal Nature Communications.

The koala retrovirus (KoRV) is a virus that, like other retroviruses such as HIV, inserts itself into the DNA of an infected cell. At some point in the past 50,000 years, KoRV has infected the egg or sperm cells of koalas, leading to offspring that carry the retrovirus in every cell in their body.

The entire koala population of Queensland and New South Wales in Australia now carry copies of KoRV in their genome. All animals, including humans, have gone through similar "germline" infections by retroviruses at some point in their evolutionary history and contain many ancient retroviruses in their genomes.

These retroviruses have, over millions of years, mutated into degraded, inactive forms that are no longer harmful to the host. Since in most animal species this process occurred millions of years ago, the immediate health effects on the host at that time are unknown but it has been suspected for some time that the invasion of a genome by a retrovirus may have considerable detrimental health effects.

The koala is at a very early stage of this process when the retrovirus is still active and these health effects can be studied.

Since retroviruses can cause cancer, it was thought that there is a link between KoRV and the high frequency of lymphoma, leukaemia and other cancers in koalas from northern Australia. To investigate this link, scientists at the Leibniz-IZW sequenced DNA from wild koalas suffering from cancer.

This allowed them to accurately detect the number of copies of KoRV in the koala genomes and identify the precise locations where the retrovirus had inserted its DNA. By comparing this information between healthy and tumour tissues in single koalas, and by comparing insertion sites between koala individuals, they found multiple links between KoRV and genes known to be involved in the kind of cancers to which koalas are prone.

"Each koala carries around 80 – 100 inherited copies of KoRV in its genome. The genomic locations of most of these are not shared between koalas, indicating a rapid expansion and accumulation of KoRV copies in the population. Each time a retrovirus copies and re-inserts itself into the genome, it causes a mutation, potentially disrupting gene expression, which could be detrimental to the host," says Prof Alex Greenwood, Head of Department of Wildlife Diseases at the Leibniz-IZW.

This means that by frequently copying itself to new locations in the genome, KoRV is currently conferring a high mutational load on the koala population. Tumour tissues contain many new copies of KoRV, indicating that KoRV is more active in tumour cells.

These copies generally were located close to genes associated with cancer. New KoRV insertions in tumour tissues affected the expression of genes in their vicinity. Such changes in gene expression associated with cancer can cause increased cell growth and proliferation, which leads to tumours.

Although other factors may also contribute to cancer in koalas, the mutational burden from KoRV likely increases the frequency of cells becoming cancerous and may shorten the time for cancer to develop.

In one koala, a copy of KoRV was found that had incorporated an entire cancer-related gene from the koala genome into its DNA sequence. This greatly increased the expression of this gene and most likely caused cancer in this particular koala.

If this mutated virus is transmissible, it would be of grave concern for koala conservation efforts. Comparing the genomic location of KoRVs between koalas also suggests that KoRV may predispose related koalas to particular tumours, with koalas sharing KoRV insertions in specific cancer-related genes suffering from similar types of cancer which they can pass on to their offspring.

Across all koalas studied, there were "hot spots" in the genome where KoRV frequently inserts itself. These hot spots were also located in proximity to genes associated with cancer.

In summary then, we find multiple links at the genomic level between cancer-related genes and KoRV, revealing ways in which KoRV underlies the high frequency of cancer in koalas."

Gayle McEwen, Scientist, Leibniz Institute for Zoo and Wildlife Research (IZW)

The results highlight the detrimental health consequences that wildlife species can suffer following germline infection by retroviruses.

Germline invasions have been repeatedly experienced during vertebrate evolution and have shaped vertebrate genomes, including the lineage leading to modern humans. These were most likely associated with severe detrimental health effects, which must be endured and overcome to ensure species survival.

The scientists at the Leibniz-IZW have previously shown that old retroviruses present in the koala genome aid the rapid degradation of KoRV. The koala finds itself in a race to survive the effects of KoRV long enough for the virus to be degraded. Considering the many threats to koalas, it is a race they need to win.

Source:

Leibniz Institute for Zoo and Wildlife Research (IZW)

Journal reference:

McEwen, G. K., et al. (2021) Retroviral integrations contribute to elevated host cancer rates during germline invasion. Nature Communications. doi.org/10.1038/s41467-021-21612-7.

Posted in: Genomics | Life Sciences News

Tags: Cancer, Cell, DNA, Evolution, Frequency, Gene, Gene Expression, Genes, Genome, Genomic, Germline, HIV, Leukemia, Lymphoma, Mutation, Proliferation, Research, Retrovirus, Sperm, Virus

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CRISPR screen identifies clinically approved immunosuppressants that could treat coronavirus infections

Researchers in Switzerland and Germany have identified host cell factors required for coronavirus replication that could serve as targets for treatment with clinically-approved drugs.

The team found that several autophagy-related genes were common host defense factors required for the replication of both endemic and emerging coronaviruses.

These coronaviruses include the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic.

Autophagy – cellular response to stressors such as hypoxia or infection – involves the recycling of proteins and organelles to maintain homeostasis. Various trafficking pathways enable the transportation of cytoplasmic material to the lysosome, where it is destroyed.

Among the autophagy-related genes were three immunophilins – high affinity-receptor proteins that specifically bind to certain immunosuppressive agents.

Furthermore, inhibition of the immunophilins with the clinically-approved drugs Cyclosporin A and Alisporivir resulted in dose-dependent reduction of coronavirus replication in primary human nasal epithelial cells.

The study was conducted by a team from the Institute of Virology and Immunology in Bern and Mittelhäusern, Switzerland and Ruhr-Universität Bochum in Germany

“Overall, we identified host factors that are crucial for coronavirus replication and demonstrate that these factors constitute potential targets for therapeutic intervention by clinically approved drugs,” writes Volker Thiel and the team.

A pre-print version of the paper is available on the bioRxiv* server, while the article undergoes peer review.

Study: A genome-wide CRISPR screen identifies interactors of the autophagy pathway as conserved coronavirus targets. Image Credit: Meletios Verras / Shutterstock

Three highly pathogenic coronaviruses have emerged over the last two decades

The last two decades have seen the emergence of three highly pathogenic coronaviruses, including the SARS-CoV virus responsible for the 2002-2004 SARS outbreaks, the Middle Eastern respiratory syndrome coronavirus (MERS-CoV) that emerged in 2012 and, most recently, the SARS-CoV-2 virus that causes COVID-19.

The severe risk these outbreaks have posed to human health over a relatively short period has highlighted the importance of developing effective approaches to treating both current coronavirus infections and those that could emerge in the future.

Coronaviruses rely on host dependency factors

Coronaviruses rely on cellular host factors – termed host dependency factors (HDFs) – for viral entry, replication and survival.

“The identification of HDFs is therefore important for understanding essential host-virus interactions required for successful viral replication and providing a framework to guide the development of new pharmacological strategies for the treatment of coronavirus infections,” says Thiel and colleagues.

One hallmark process that occurs during coronavirus replication is extensive virus-induced remodeling of host endomembranes to form double-membrane vesicles (DMVs) that are targeted by viral replication and transcription complexes.

“However, the host factors that are required for the formation of these structures remain elusive,” says the team.

What did the researchers do?

The researchers conducted two independent genome-wide loss-of-function CRISPR screens to identify HDFs required for the replication of both endemic and emerging coronaviruses.

The knockout screens were performed in Huh7 cells infected with the highly pathogenic MERS-CoV and with human coronavirus 229E (HCoV-229E) – a less pathogenic endemic coronavirus that generally only causes mild respiratory symptoms.

Enrichment analysis uncovers host biological networks crucial for CoV replication. (A) Enrichment map summarizing major host biological networks co-opted by CoVs during infection. Gene Ontology (GO) enrichment analysis was performed using hits from both MERS-CoV and HCoV-229E CRISPR screens and filtered to contain conserved representative GO terms and genes. Each node represents an individual GO term and nodes that are functionally related cluster together into a larger network. Node size reflects number of significantly enriched genes in the node and color indicates the CoV screen for which the node was significant.

What did the study find?

The team identified multiple virus-specific and conserved HDFs, including several that are required for replication of SARS-CoV-2.

The study revealed that several autophagy-related genes, including the immunophilins FK506 binding protein 8 (FKBP8), transmembrane protein 41B (TMEM41B), and membrane integral NOTCH2-associated receptor 1 (MINAR1) were common HDFs.

The researchers say that the interaction between autophagy components and coronaviruses in the context of replication has been considered for some time because parts of the autophagy process share similarities with the process of DMV formation.

However, “studies investigating the possible involvement of the early autophagy machinery in the conversion of host membranes into DMVs reached conflicting conclusions,” says Thiel and colleagues.

“Another possibility is that single components of the autophagic machinery may be hijacked by coronaviruses independently of their activity in autophagic processing,” they add.

The team says that irrespective of the precise underlying mechanism, the results suggest that FKBP8, TMEM41B, and MINAR1 represent potential therapeutic targets.

CoV HDFs are interactors of the autophagy pathway but do not depend on autophagy for replication. (A) Upon starvation, the mTORC1 complex is blocked and activation of the PI3K complex, as well as the ULK1 complex leads to the initiation of phagophore formation, as an initial step in the autophagy pathway. MERS-CoV and HCoV503 229E top scoring CRISPR knockout screen hits FKBP8, MINAR1, TMEM41B and VMP1 are involved in this early pathway. Furthermore, the ATG8 system containing among others LC3, which is recruited by VPM1 or FBKP8 is necessary for targeting cellular cargo to the autophagosome. PPP3R1 is upregulated and initiates TFEB translocalization to the nucleus, where it catalyzes transcription of ATGs. MERS-CoV or conserved host dependency factors (HDFs) are indicated in respective colors. Inhibitor intervention in this pathway is shown in red.

Targeting the immunophilins with clinically-approved drugs

Next, the researchers showed that inhibition of the immunophilin family with the clinically-approved and well-tolerated drugs Tacrolimus, Cyclosporin A and Alisporivir reduced the replication of MERS-CoV, SARS-CoV, and SARS-CoV-2 in a dose-dependent manner.  

However, the team noted that while Huh7 cells are valuable for studying coronaviruses, they are likely less effective at capturing important aspects of infection than primary human airway epithelial cells.

To address this limitation, the researchers also tested the drugs in primary human nasal epithelial cell cultures.

This revealed that Cyclosporin A and Alisporivir potently inhibited SARS-CoV-2 replication at concentrations known to be achievable and efficacious in patients.

“Overall, the genes and pathways identified in our coronavirus screens expand the current repertoire of essential HDFs required for replication that can be exploited to identify novel therapeutic targets for host-directed therapies against both existing and future emerging CoVs,” writes Thiel and colleagues.

“Together these findings depict a promising path towards the repurposing of Cyclosporin A and Alisporivir as COVID-19 treatment options,” concludes the team.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Thiel V, et al. A genome-wide CRISPR screen identifies interactors of the autophagy pathway as conserved coronavirus targets. bioRxiv, 2021. doi: https://doi.org/10.1101/2021.02.24.432634, https://www.biorxiv.org/content/10.1101/2021.02.24.432634v1

Posted in: Device / Technology News | Medical Research News | Disease/Infection News

Tags: Autophagy, Cell, Coronavirus, Coronavirus Disease COVID-19, CRISPR, Drugs, Gene, Genes, Genome, Hypoxia, Immunology, Knockout, MERS-CoV, Pandemic, Protein, Receptor, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Tacrolimus, Transcription, Virology, Virus

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Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.

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Lab study of South African SARS-CoV-2 variant and Moderna vaccine: reduced neutralization, but still protective

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic rages on, several virus variants have been emerging with mutations in the structural and non-structural proteins. The SARS-CoV-2 spike protein binds to the host angiotensin-converting enzyme 2 (ACE2) receptor, facilitating viral entry into the host cell. Studies have shown many different mutations in the spike protein over the last twelve months.

The first significant spike protein variant emerged with a mutation from aspartic acid (D) to glycine (G) at position 614, leading to increased viral fitness, replication, and binding to ACE2 and conformational changes within the protein. Several other variants have emerged over the past few months, raising concerns about changes to transmission, nature of the disease, and viral fitness.

When SARS-CoV-2 infects humans, our immune system rapidly responds against the viral spike protein. The receptor-binding motif in the spike protein interacts with the ACE2 receptor and is a key target of neutralization for antibodies. Longitudinal studies have found that the antibodies to the spike protein can remain in the body for at least a year following infection.

The mRNA-1273 vaccine encodes the SARS-CoV-2 spike protein and triggers a potent neutralizing antibody response to the virus that lasts for several months. The B.1.351 variant originated in South Africa has three mutations in the receptor-binding domain and many other mutations in the spike protein, all of which may influence viral binding to the ACE2 receptor and viral resistance to neutralization by antibodies.

Comparing antibody binding and viral neutralization against two different SARS-CoV-2 variants

Researchers from the US recently compared antibody binding and viral neutralization against 2 SARS-CoV-2 variants that emerged in different parts of the world. The researchers used sera from spike mRNA vaccinated and naturally infected individuals against a circulating B.1 variant and the emerging B.1.351 variant. The study is published on the preprint server bioRxiv*.

Study: Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant. Image Credit: NIAID

EHC-083E (the B.1 variant) belongs to the B.1 PANGO lineage and was isolated in March 2020 from a nasopharyngeal swab of a patient in Atlanta, GA. This variant has the D614G mutation in the viral spike protein. The B.1.351 variant was isolated in November 2020 from an oropharyngeal swab of a patient in KwaZulu-Natal, South Africa. This variant of the virus contains amino acid mutations (L18F, D80A, D215G) within the viral spike protein and deletion at positions 242-244 (L242del, A243del, and L244del), K417N, E484K, N501Y, and D614G.

Neutralizing antibodies for B.1.351 variant are produced early in the infection phase

The researchers observed decreased antibody binding to the B.1.351-derived receptor binding domain of the SARS-CoV-2 spike protein and neutralization power against the B.1.351 variant in sera from both infected and vaccinated individuals. Their longitudinal convalescent COVID-19 cohort assessed the impact on antibody binding to the receptor-binding domain and neutralization across the SARS-CoV-2 variants. Interestingly, most convalescent COVID-19 individuals showed less impact on neutralization against the B.1.351 variant at longer durations post-infection. This showed that neutralizing antibodies for the B.1.351 variant is produced early during infection and last for several months.

Most SARS-CoV-2-infected individuals showed binding and neutralizing titers against the B.1.351 variant in both acute and convalescent sera

According to the observations, most sera samples from acute and convalescent COVID-19 individuals showed antibody binding to the B.1.351-dervied receptor binding domain.  Most samples also showed a neutralizing capacity for the B.1.351 variant, and the effector functions of these neutralizing antibodies might contribute to SARS-CoV-2 infection control.

To summarize, although decreased by a few folds, most SARS-CoV-2 infected individuals showed binding and neutralizing titers against the B.1.351 variant in acute as well as convalescent sera. Moreover, all mRNA-1273 vaccinated individuals still maintained viral neutralization. These findings agree with previous notions that natural infection- and vaccine-induced immunity can offer protection against COVID-19 in the context of the SARS-CoV-2 B.1.351 variant.

“Our results show that despite few fold decrease, most infected individuals showed binding and neutralizing titers against the B.1.351 variant in acute and convalescent sera, and further, all mRNA-1273 vaccinated individuals still maintained neutralization.”

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant, Venkata Viswanadh Edara, Carson Norwood, Katharine Floyd, Lilin Lai, Meredith E. Davis-Gardner, William H. Hudson, Grace Mantus, Lindsay E. Nyhoff, Max W. Adelman, Rebecca Fineman, Shivan Patel, Rebecca Byram, Dumingu Nipuni Gomes, Garett Michael, Hayatu Abdullahi, Nour Beydoun, Bernadine Panganiban, Nina McNair, Kieffer Hellmeister, Jamila Pitts, Joy Winters, Jennifer Kleinhenz, Jacob Usher, James B. O’Keefe, Anne Piantadosi, Jesse J. Waggoner, Ahmed Babiker, David S. Stephens, Evan J. Anderson, Srilatha Edupuganti, Nadine Rouphael, Rafi Ahmed, Jens Wrammert, Mehul S. Suthar, bioRxiv, 2021.02.20.432046; doi: https://doi.org/10.1101/2021.02.20.432046, https://www.biorxiv.org/content/10.1101/2021.02.20.432046v1

Posted in: Medical Research News | Disease/Infection News

Tags: ACE2, Amino Acid, Angiotensin, Angiotensin-Converting Enzyme 2, Antibodies, Antibody, Aspartic Acid, Cell, Coronavirus, Coronavirus Disease COVID-19, Enzyme, Glycine, Immune System, Infection Control, Mutation, Pandemic, Protein, Receptor, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Vaccine, Virus

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Written by

Susha Cheriyedath

Susha has a Bachelor of Science (B.Sc.) degree in Chemistry and Master of Science (M.Sc) degree in Biochemistry from the University of Calicut, India. She always had a keen interest in medical and health science. As part of her masters degree, she specialized in Biochemistry, with an emphasis on Microbiology, Physiology, Biotechnology, and Nutrition. In her spare time, she loves to cook up a storm in the kitchen with her super-messy baking experiments.

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COVID-19 vaccine candidate shows potential against SARS-CoV-2 and potential future zoonotic coronaviruses

Over the last two decades, three major outbreaks of highly pathogenic coronaviruses have occurred. The third is the ongoing coronavirus disease 2019 (COVID-19) pandemic that has claimed well over 2.46 million human lives so far, in a little over a year from its onset. Without any targeted, safe and effective antivirals to prevent or treat the infection by the causative pathogen, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), population immunity via mass vaccination seems to be the only way out – as complex and expensive as the process is likely to be.

Study: SARS-CoV-2 vaccination induces neutralizing antibodies against pandemic and pre-emergent SARS-related coronaviruses in monkeys. Image Credit: Numstocker / Shutterstock

Pan-group 2b CoV vaccine

A new study, released on the bioRxiv* preprint server, sheds light on the threat posed by future zoonotic coronaviruses to make similar leaps across species barriers to infect human beings and cause other pandemics. The goal would appear to be a vaccine capable of inducing not limited immunity against SARS-CoV-2 alone, but one that can elicit broadly neutralizing antibody and cellular immune responses against a range of other betaCoVs.

This includes existing SARS-related coronaviruses (SARSr-CoVs) in humans, as well as those that are now circulating in animals.

The first evidence that this could be so came from the observation that SARS-CoV caused the production of cross-neutralizing antibodies against many betacoronaviruses (betaCoVs). This proof-of-concept drove the search for a vaccine that would induce neutralizing antibodies against multiple group 2b Sarbecoviruses.

Cross-neutralizing antibodies

Cross-neutralizing antibodies always target the viral receptor-binding domain (RBD) via a specific epitope. The RBD can be rendered more immunogenic by using a multimeric form. One way to achieve this is by using nanoparticles to mount arrays of RBD proteins, creating a virus-like particle (VLP).

Vaccines have been shown to successfully induce cross-neutralizing antibodies against pseudoviruses expressing CoV antigens in mouse studies. The current study describes a non-human primate (NHP) study that explores the cross-neutralizing ability of a SARS-CoV-2 vaccine based on multimeric SARS-CoV-2 RBD-bearing nanoparticles.

RBD-conjugated nanoparticle vaccine

The RBD-conjugated nanoparticle vaccine comprises 24 RBD protomers on a sortase-ferritin platform for the sake of versatility. This bound not only to the human host cell receptor, the angiotensin-converting enzyme 2 (ACE2), which is thought to be the SARS-CoV-2 entry receptor, but also to potent anti-RBD neutralizing antibodies. These include DH1041, DH1042, DH1043, DH1044, and DH1045.

All these antibodies bind to epitopes within the receptor-binding motif, within the RBD. However, antibodies that bound to epitopes outside the RBD were not able to bind the RBD-bearing nanoparticle. In contrast, it did show binding to the cross-neutralizing antibody DH1047.

This vaccine was assessed by a three-dose regimen, administered at four-week intervals, in a non-human primate (NHP) study. The vaccine was found to result in high plasma levels of antibodies to the SARS-CoV-2 RBD and to the stabilized spike protein.

The antibodies completely blocked the ACE2 binding site on the spike protein after two doses of vaccine and partially blocked the binding of the RBD antibody DH104.

SARS-CoV-2 receptor binding domain (RBD) sortase conjugated nanoparticles (scNPs) elicits extremely high titers of SARS-CoV-2 pseudovirus neutralizing antibodies. a. SARS-CoV-2 RBD nanoparticles were constructed by expressing RBD with a C-terminal sortase A donor sequence (blue and red) and a Helicobacter pylori ferritin nanoparticle with N737 terminal sortase A acceptor sequences (gray) on each subunit (top left). The RBD is shown in blue with the ACE2 binding site in red. The RBD was conjugated to nanoparticles by a sortase A (SrtA) enzyme conjugation reaction (top right). The resultant nanoparticle is modeled on the bottom left. Nine amino acid sortase linker is shown in orange. Two dimensional class averages of negative stain electron microscopy images of actual RBD nanoparticles are shown on the bottom right. b. Antigenicity of RBD nanoparticles determined by biolayer interferometry against a panel of SARS-CoV-2 antibodies and the ACE2 receptor. Antibodies are color-coded based on epitope and function. N-terminal domain (NTD), nonAbs IE, infection enhancing non-neutralizing antibody; nAb, neutralizing antibody; nonAb, non-neutralizing antibody. Mean and standard error from 3 independent experiments are shown. c. Cynomolgus macaque challenge study scheme. Blue arrows indicate 748 RBD-NP immunization timepoints. Intranasal/intratracheal SARS-CoV-2 challenge is indicated at week 10. d. Macaque serum IgG binding determined by ELISA to recombinant SARS-CoV-2 stabilized Spike ectodomain (S-2P), RBD, NTD, and Fusion peptide (FP). Binding titer is shown as area752under-the curve of the log10-transformed curve. Arrows indicate immunization timepoints. e. Plasma antibody blocking of SARS-CoV-2 S-2P binding to ACE2-Fc and RBD neutralizing antibody DH1041. Group mean and standard error are shown. f. Dose-dependent serum neutralization of SARS-COV-2 pseudotyped virus infection of ACE2- expressing 293T cells. Serum was collected after two immunizations. The SARS-CoV-2 pseudovirus spike has an aspartic acid to glycine change at position 614 (D614G). Each curve represents a single macaque. g. Heat map of serum neutralization ID50 and ID80 titers for SARS-COV-2 D614G pseudotyped virus after two immunizations. h. SARS-COV-2 D614G pseudotyped virus serum neutralization kinetics. Each curve represents a single macaque. i. Comparison of serum neutralization ID50 titers from cynomolgus macaques immunized with recombinant protein RBD nanoparticles (blue) or nucleoside-modified mRNA-LNP expressing S- 2P (burgundy) (**P<0.01, Two-tailed Exact Wilcoxon test n = 5). j. Comparison of serum neutralization titers obtained from RBD-scNP-vaccinated macaques (blue) and SARS-CoV-2 infected humans (shades of green). Human samples were stratified based on disease severity as asymptomatic (N=34), symptomatic (n=71), and hospitalized (N=60) (**P<0.01, Two-tailed Wilcoxon test n = 5).

Competitive with the Moderna/Pfizer vaccine for neutralizing antibody titer

When tested against the currently dominant D614G strain of SARS-CoV-2, the RBD-conjugated nanoparticle vaccine induced higher neutralizing antibody titers than another vaccine similar to the Moderna and Pfizer lipid-encapsulated nucleoside-modified mRNA (mRNA-LNP) vaccines that are now being used in the vaccination campaigns against COVID-19.

The measure of antibody titer used here showed an eight-fold increase with the former compared to the latter. The antibody response was also higher with the RBD-nanoparticle vaccine than with natural infection of all grades of severity.

Unaffected by emerging variants

It also showed potent neutralizing activity against the new SARS-CoV-2 variant B.1.1.7, which is rapidly spreading worldwide. This is not only more infective but may be resistant to many RBD-targeting antibodies, as well as more virulent.

While changes in binding affinity of anti-RBD antibody DH1041 to the ACE2 receptor and to the spike protein were observed with different mutations, such as those acquired during mink infection, or those found in the South African or Brazil or UK strains, the cross-neutralizing antibody DH1047 showed unchanged binding to the SARS-CoV-2.

“RBD-scNP (RBD sortase A conjugated nanoparticle) and mRNA-LNP-induced RBD binding antibodies were not sensitive to spike mutations present in neutralization-resistant UK, South Africa or Brazil SARS-CoV-2 variants.”

SARS-CoV-2 spike induces cross-neutralizing antibodies to pre-emergent betaCoVs

SARSr-CoVs still pose a danger of future pandemics to human beings. The researchers, therefore, explored the ability of this vaccine to neutralize other viruses. Similar to the LNP-mRNA vaccines based on the prefusion stabilized spike or the RBD, the RBD-scNP also elicited potent cross-neutralizing antibodies against SARS-CoV and SARSr-bat CoVs (batCoV-WIV-1, and batCoV-SHC014).

The neutralization was most potent against SARS-CoV-2, however. The highest neutralizing antibody titers were observed with RBD-scNP and the least with the RBD-expressing LNP-mRNA vaccine. The high titers may indicate that durable immunity is achieved.  

The RBD-scNP vaccine showed cross-neutralizing activity against batCoV-RaTG13 and pangolin CoV GXP4L spike antigens, in addition to SARS-CoV and SARS-CoV-2. Notably, sera obtained following vaccination with this formulation failed to neutralize the seasonal human CoVs or MERS-CoV, probably because of the difference in RBD among these CoVs, which belong to different groups.

The similarity between the RBD-scNP and DH1047 in terms of cross-neutralizing profile shows that not only do antibodies induced by the former bind near the epitope bound by the latter, but they are not specific to SARS-CoV-2 RBD. In fact, they also block batCoV-SHC01.

Notably, only a third of COVID-19 patients produce antibodies that block DH1047, indicating it is a sub-immunodominant epitope. As such, the RBD-scNP vaccine targets this epitope rather than the immunodominant ACE2 blocking epitope.

Protection against productive infection

The RBD-scNP vaccine was also protective for vaccinated monkeys when challenged with the SARS-CoV-2 virus via the respiratory tract. In all but one of the vaccinated macaques, “RBD-scNP-induced immunity prevented virus replication, and likely provided sterilizing immunity, in the upper and lower respiratory tract.”

What are the implications?

The RBD-scNP platform induced the highest cross-neutralizing antibody titer for group 2b CoVs, and as such, may serve as the basis for a reasonably effective initial broadly neutralizing vaccine against this group – both now, and in the future, if the further zoonotic transmission should occur.

The study also showed that the use of both RBD-scNP and the LNP-spike mRNA vaccines, the latter resembling those which have been recently rolled out, is capable of inducing cross-neutralizing antibodies to the dominant D614G variant and the newer variants of SARS-CoV-2, but at lower titers.

The findings indicate the ability of the SARS-CoV-2 Spike to be included in an RBD-scNP or LNP-mRNA formulation to induce cross-neutralizing antibodies against several SARSr-CoVs. Thus, even the currently used vaccines are likely to prevent future pandemics if immunization is successfully achieved.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Saunders, K. O. et al. (2021). SARS-CoV-2 vaccination induces neutralizing antibodies against pandemic and pre-emergent SARS-related coronaviruses in monkeys. bioRxiv preprint. doi: https://doi.org/10.1101/2021.02.17.431492. https://www.biorxiv.org/content/10.1101/2021.02.17.431492v1

Posted in: Medical Science News | Medical Research News | Disease/Infection News | Healthcare News

Tags: ACE2, Amino Acid, Angiotensin, Angiotensin-Converting Enzyme 2, Antibodies, Antibody, Aspartic Acid, binding affinity, Cell, Conjugation, Coronavirus, Coronavirus Disease COVID-19, Electron, Electron Microscopy, Enzyme, Glycine, heat, Helicobacter pylori, Immunization, MERS-CoV, Microscopy, Nanoparticle, Nanoparticles, Nucleoside, Pandemic, Pathogen, Protein, Pseudovirus, Receptor, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Vaccine, Virus

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Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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CovMT: Tracking virus mutations across the world

virus

A SARS-CoV-2 tracker uses publicly available sequencing data to show how the virus is changing and spreading over time. The tracker, called CovMT, was developed at KAUST and is expected to help researchers and policymakers understand the evolution of the virus’s mutations. This could have implications for vaccine development, patient treatment and the implementation of restrictions.

“As new variants of the SARS-CoV-2 virus emerge, authorities around the world need to know if these, or similar variants, have entered their countries,” says computational biologist, Intikhab Alam, who designed the CovMT system with a team in KAUST’s Computational Bioscience Research Center. “The World Health Organization is stressing to all countries to ramp up their sequencing efforts. With this increase in sequencing, we expect CovMT will help researchers, the public and policymakers to explore up-to-date country-specific information on sequencing efforts, evolving virus variants and disease severity.”

Each day, publicly available data is downloaded to CovMT from GISAID, an initiative that collates genetic sequences and the related clinical and epidemiological data about the SARS-CoV-2 virus from various parts of the world. The CovMT platform processes this data to detect mutations and mutation fingerprints and define clades.

CovMT thenprovides interactive graphics to help visualize the resultsin a user-friendly form.

For example, the tracker shows which SARS-CoV-2 clades are present in which continents. It also shows the countries that are providing SARS-CoV-2 sequencing data and the local and foreign mutational fingerprints of the virus present in each country.

The team devised the concept of “mutational fingerprints” to describe virus isolates that have the same set of virus mutations. This helps scientists to see where a virus with a mutational fingerprint was first detected and then to which countries it eventually spread. Since GISAID includes some patient data that correlates virus variants and mutations with disease severity, the tracker can also predict the disease severity of virus isolates that have similar mutational fingerprints but lack patient data.

The tracker shows that the B.1.1.7 variant, which acquired a specific mutation in its spike protein called N501Y to lead to a rapid rise of infections in the UK in the autumn and winter months of 2020, has also acquired the E484K mutation. This could have implications for vaccine effectiveness against this variant.

Also, the tracker shows that 510 virus isolates of the B.1.351 variant have three mutations in the receptor binding region of the spike protein. This region is of particular significance because mutations in it could make the virus more infectious. This triple RBD mutation variant is now found in South Africa, the UK and 22 other countries.

“CovMT can be adapted for other infectious diseases like MERS-CoV and the influenza virus in the future,” says molecular biologist, Takashi Gojobori, the acting director of KAUST’s Computational Bioscience Research Center. He formed the task force that developed CovMT.

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Vaccination programs combined with physical distancing could contain COVID-19 resurgence

A combination of robust vaccination programs and strict physical distancing rules could avoid recurring peaks of COVID-19 without the need to rely on stay-at-home restrictions, according to a new study by epidemiologists and demographers from WorldPop at the University of Southampton, in collaboration with The Chinese University of Hong Kong.

This research used anonymized mobile phone geolocation data with epidemiological and coronavirus case data from China to model the potential impact of vaccination and physical distancing on virus transmission. They predicted the effect of different combinations of interventions on low, medium and high density cities in the country.

The impact of physical distancing in containing future resurgences of COVID-19 depends greatly on the intensity of measures, population density, and the availability of vaccines across geographical areas and time. The researchers set out to gain a greater understanding of the relationship between these factors.

The findings are published in the journal Nature Human Behaviour.

The team predicts that in most cities, vaccination programmes and physical distancing combined will be enough to contain virus resurgence without the need to greatly restrict population mobility. Containment in this study was defined as maintaining a low transmission rate, or 'R' below one.

The researchers report cities with medium and high density populations will need both vaccination and distancing to prevent future intense waves of COVID-19, until herd immunity is reached. However, they suggest cities with low populations and effective vaccination could fully interrupt transmission without the need for physical distancing. In all cities, full 'stay-at-home' lockdowns would no longer be necessary.

The team's results also suggest strong physical distancing interventions implemented for short periods of time may be more effective than mild, longer term ones.

The author and spatial epidemiologist, Dr Shengjie Lai, Senior Research Fellow in Geography and Environmental Sciences at the University of Southampton comments: "Our research provides a framework and set of outputs that can be used by policy-makers and public health authorities to identify appropriate levels of intervention to keep COVID-19 outbreaks in check over time. Although our study was based on data from China, our methods and findings are applicable to cities worldwide with similar levels of population density and social contact patterns."

Director of WorldPop, Professor Andy Tatem, added: "Previous studies have assumed that when people reduce mobility, they proportionately reduce their social contacts, but this isn't necessarily the case and as more SARS-CoV-2 vaccines come online, there is an urgent need to understand the relationship between these factors, so we can adjust and tailor interventions and open up sections of society in a safer way."

The researchers recognize some limitations to their study, for example, the absence of data on the contribution of handwashing and face masks and challenges of vaccine supply, but emphasize that their approach can be quickly adapted to provide near real-time data to address emerging, time critical needs.

Source:

University of Southampton

Journal reference:

Huang, B., et al. (2021) Integrated vaccination and physical distancing interventions to prevent future COVID-19 waves in Chinese cities. Nature Human Behaviour. doi.org/10.1038/s41562-021-01063-2.

Posted in: Medical Research News | Disease/Infection News | Healthcare News

Tags: Coronavirus, Education, Public Health, Research, SARS, SARS-CoV-2, students, Vaccine, Virus

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Substrain of SARS-CoV-2 variant in UK may resist antibody neutralization

Researchers at the Polish Academy of Sciences in Warsaw have identified a substrain of the recently emerged B.1.1.7 variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may confer resistance to antibody neutralization.

The SARS-CoV-2 virus is the agent responsible for the coronavirus disease 2019 (COVID-19) pandemic that has now claimed the lives of more than 2.35 million people.

The substrain of the B.1.1.7 variant of concern (VOC) contains mutations that have previously been shown to compromise the binding of neutralizing antibodies.

Tomasz Lipniacki and colleagues say mutations in the receptor-binding domain (RBD) of the viral spike protein are of particular concern, especially those identified in the receptor-binding motif (RBM).

The spike protein is the surface structure the virus uses to bind to and infect cells by attaching to the host cell receptor angiotensin-converting enzyme 2 (ACE2).

The researchers say the mutations could eventually lead to “immune escape” strains that can reinfect convalescent individuals and reduce the efficacy of the vaccines currently being used in mass immunization efforts.

“Such mutants may hinder the efficiency of existing vaccines and expand in response to the increasing after‐infection or vaccine‐induced seroprevalence,” writes the team.

A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer review.

Study: L18F substrain of SARS-CoV-2 VOC-202012/01 is rapidly spreading in England. Image Credit: NIAID

The B.1.1.7 variant has spread rapidly since mid-October 2020

The B.1.1.7 variant has rapidly spread since mid-October 2020, and by January 2021, it constituted about 80% of all SARS-CoV-2 genomes sequenced in England.

The high transmissibility of this VOC may be expressed in terms of its replicative advantage – defined as the ratio of the VOC reproduction number to that of non-VOC strains.

To date, a number of studies have estimated the replicative advantage as lying somewhere between 1.47 and 2.24.

As is the case with all viral strains, the B.1.1.7 variant will continue to mutate, and given its significant replicative advantage, any mutations acquired are likely to spread globally.

“As this strain will likely spread globally towards fixation, it is important to monitor its molecular evolution,” say the researchers.

What did the current study involve?

Using the Global Initiative on Sharing Avian Influenza Data (GISAID) database, Lipniacki and colleagues estimated growth rates of the mutations that B.1.1.7 has acquired.

This revealed a substrain with an L18F substitution in the spike protein that is rapidly growing in the UK.

This leucine‐to‐phenylalanine substitution in residue 18 was first reported to have occurred in a VOC strain genome collected on December 4th, 2020.

As of February 5th, 2021, as many as 850 spikes L18F VOC genomes had been reported in England.

Based on data collected between December 7th, 2020 and January 17th, 2021, the researchers showed that the L18F substrain had spread exponentially in England. They estimated a replicative advantage of 1.70 relative to the remaining B.1.1.7 substrains.

RBM mutations are particularly concerning

Lipniacki and colleagues say that mutations in the RBD of the spike protein are particularly concerning, especially substitutions E484K and S494P found in the RBM.

Importantly, the LI8F mutation has expanded in the South African variant 501Y.V2 that contains the spike mutations E484K and N501Y. Studies have suggested that E484K may compromise the binding of class 2 neutralizing antibodies, while the A501V mutation compromises the binding of class 1 antibodies.

Furthermore, in a 2021 study published in Science, the S494P substitution was characterized as an escape mutation, along with six other escape residues in the RBM that included F490.

In the current study, Lipniacki and colleagues also identified F490S as a potential escape mutation.

What do the authors advise?

“These mutations may potentially lead to immune escape mutants, resulting in reinfection of convalescent individuals and lowering efficacy of current vaccines,” warn the researchers.

“Propagation of such mutations is facilitated by high replicative advantage of the VOC strain and potential selection due to the increasing number of convalescent or immunized individuals,” they add.

Correspondingly, a study published in 2021 showed that L18F substitution compromises the binding of neutralizing antibodies, suggesting that the replicative advantage of L18F mutants may be partly associated with the ability to infect seroprevalent individuals (who already have anti-SARS-CoV-2 antibodies).

“In turn, propagation of mutations in escape residues (L18, E484, F490S, or S494) on the VOC strain suggests an increasing selection pressure resulting from the growth of the seroprevalent fraction of the population of England,” says Lipniacki and colleagues.

“This trend can be enhanced by the ongoing English vaccination program, in which the relatively large time span between the first and second dose can be a contributing factor,” concludes the team.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Lipniacki T, et al. L18F substrain of SARS-CoV-2 VOC-202012/01 is rapidly spreading in England. medRxiv, 2021. doi: https://doi.org/10.1101/2021.02.07.21251262, https://www.medrxiv.org/content/10.1101/2021.02.07.21251262v1

Posted in: Medical Research News | Disease/Infection News

Tags: ACE2, Angiotensin, Angiotensin-Converting Enzyme 2, Antibodies, Antibody, Avian Influenza, Cell, Coronavirus, Coronavirus Disease COVID-19, Efficacy, Enzyme, Evolution, Genome, Immunization, Influenza, Leucine, Mutation, Pandemic, Phenylalanine, Propagation, Protein, Receptor, Reproduction, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Vaccine, Virus

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Written by

Sally Robertson

Sally has a Bachelor's Degree in Biomedical Sciences (B.Sc.). She is a specialist in reviewing and summarising the latest findings across all areas of medicine covered in major, high-impact, world-leading international medical journals, international press conferences and bulletins from governmental agencies and regulatory bodies. At News-Medical, Sally generates daily news features, life science articles and interview coverage.

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