Germany to ease virus curbs for vaccinated people

COVID-19

People who have been fully vaccinated against COVID-19 will no longer have to abide by curfews and contact restrictions in Germany under a draft law agreed by the cabinet on Tuesday.

The law, which would also apply to people who have recovered from COVID-19, must still be signed off by parliament but could come into force as early as this week, Justice Minister Christine Lambrecht said.

There must be a “good reason” for any restrictions on public life, Lambrecht said. “As soon as this reason ceases to exist… these restrictions should then no longer be in place,” she said.

Under national measures introduced in April, areas of Germany with an incidence rate of more than 100 new infections per 100,000 people over the last seven days must introduce overnight curfews and people may only meet with one other person from another household during the day.

But people who have been vaccinated, or who have recovered from COVID and therefore have natural immunity, should in future be exempt from these rules, Lambrecht said.

The draft law seen by AFP would also exempt vaccinated and recovered people from quarantine rules for people returning from abroad, even from areas deemed high risk.

No more tests

Areas of Germany with incidence rates under 100 are currently allowed to open shops, restaurants, cinemas and other facilities, but only to people who can provide a negative test.

Under the new regulations, vaccinated and recovered people would also be exempt from this requirement.

Some German states, including Berlin and Bavaria, have already announced plans to scrap the negative test requirement for vaccinated people when they go shopping or visit the hairdresser.

The Bavarian cabinet on Tuesday also signed off a plan to allow hotels, holiday homes and campsites to open in regions with low incidence rates from May 21.

However, Bavaria’s iconic Oktoberfest beer festival, which usually attracts millions annually in September and October, will be cancelled this year for the second year running.

Germany has been in some form of virus shutdown since November, with numbers of new infections remaining consistently high amid an initially sluggish vaccination campaign.

But the campaign has since picked up pace, with more than a million jabs issued in one day last week, and new infection numbers have started to come down.

The Robert Koch Institute health agency recorded 7,534 new infections in the past 24 hours on Tuesday and 315 deaths, with a national incidence rate of 141.4.

But despite these successes, critics say it is too soon to be lifting restrictions.

Ute Teichert, the head of the Federal Association of German Public Health Officers, said it was “imperative that vaccinated people continue to be tested”.

“Without comprehensive testing, we will lose sight of the incidence of infections—especially with regard to virus variants,” she told the Funke media group on Tuesday.

MP and epidemiologist Karl Lauterbach said it was reasonable to lift some restrictions for vaccinated people, but restaurants, bars and other facilities should not be reopened just for them.

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Interdisciplinary project explores the phenomenon of so-called “superspreaders”

Scientists from the Departments of Physics, Biomedical Sciences and Process Engineering at Otto von Guericke University Magdeburg are in the process of analyzing the emergence and spread of infectious air bubbles in our breath, known as aerosols, using tissue cultivations and artificially-produced, virus-filled suspended particles.

The aim of the interdisciplinary project, which is funded by the German Research Foundation (DFG) to the tune of almost €900,000, is to find out why the phenomenon of so-called "superspreaders" exists.

The team of researchers is looking into the question of how the virus particles in the human body are packed into the tiny aerosols and which mechanisms lead to these aerosol particles adhering to the airways of other people, where they burst and leading to further infection. Process engineers are then developing simulation models to assist in making reliable predictions about the distribution and spread of the aerosols.

"The background to these scientific questions is that there is a considerable amount of knowledge already available about the biological processes involved in the actual infection process, so we already have an exact idea of how the virus reaches human cells and multiplies," explains biomedical scientist Professor Dr. rer. biol. hum.

Heike Walles from the Core Facility Tissue Engineering at Magdeburg University, where researchers are cultivating human cells on scaffolds to produce 3-dimensional biological models of human tissues.

However, what we do not know is how the viruses are then repackaged in the aerosols and how they exit our bodies in order to infect other people."

Heike Walles, Professor and Biomedical Scientist, Core Facility Tissue Engineering, Otto von Guericke University Magdeburg

Answering these questions requires the involvement of a wide variety of scientific disciplines within the university. "The great challenge in this exciting, interdisciplinary project lies in bringing together all of these individually extremely complicated technologies under sterile working conditions."

To this end, the team around physicist Professor Claus-Dieter Ohl from the Faculty of Natural Sciences will produce aerosols based on those found in nature and experimentally pack them with fluorescent proteins, and subsequently virus particles. Like the particles found in human lungs, a range of different sizes of particles are being produced.

The team around biomedical scientist Professor Heike Walles is cultivating artificial tissue models from the different regions of our airways in the laboratory and also tubular networks constructed from polymers, i.e. chemical molecules, in the geometries of our airways. These artificial respiratory tract models are coated with protein solutions to replicate mucus, in order to simulate the physical conditions in the airways.

Next, the way in which the aerosols are disseminated in the tubular networks after high-pressure application and the way that they adhere to biological surfaces and ultimately burst is also being tested. The movements of the aerosols is documented using high-speed cameras.

The team around Junior Professor Dr. Ing. Fabian Denner from the Chair for Mechanical Process Engineering in the Faculty of Process and Systems Engineering will populate simulation models with the multitude of data obtained from the experiments and so provide a basis of decision-making concerning which adjustments and changes are needed to the experimental approach.

"When we understand how the aerosols are produced, how they are disseminated and when and under what conditions they burst, it may, for example, be possible to to think about medications that affects and reduces the formation of aerosols in the airways or that fewer viruses end up in the aerosols," explains Professor Ohl. "This would make it possible to limit the spread of highly infectious viruses very effectively."

Biomedical scientist Professor Heike Walles adds: "If, as planned, we are able, to clarify the fundamental mechanisms of action, this established process could be transferred to the world-wide spread of a great number of infectious diseases, from Covid-19 to swine flu."

Source:

Otto-von-Guericke-Universität Magdeburg

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

Tags: Flu, Infectious Diseases, Laboratory, Lungs, Microscope, Polymers, Protein, Research, Respiratory, Swine Flu, Tissue Engineering, Virus

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UK virus variant associated with higher risk of hospital admission

UK virus variant associated with higher risk of hospital admission

The UK variant of the coronavirus is associated with a higher risk of being admitted to hospital, even among young adults, according to a new study from the Norwegian Institute of Public Health.

The UK variant is now the dominant variant of the SARS-CoV-2 virus in Norway. Researchers at the Norwegian Institute of Public Health have now investigated the association between the UK variant and admission to hospital with COVID-19 in Norway.

Young adults also have a higher risk of hospital admission

“We find that the UK variant is associated with a higher risk of a person with COVID-19 disease being admitted to hospital. This also applies to young adults,” says Line Vold at the Norwegian Institute of Public Health.

The UK variant has been identified as a specific variant.

“After adjusting for age, gender, country of birth, risk status, county and testing date, people infected with the UK variant had a 2.6-fold higher risk of being admitted to hospital with COVID-19 as the main reason for admission, compared with people infected with non-specific variants,” she explains.

The estimate has a 95 percent confidence interval of 1.9—3.6. The confidence interval represents the degree of uncertainty associated with the result of the study.

Among people infected with the UK variant, 255 were admitted to hospital. This corresponds to 4.3 percent. Among people infected with a non-specific variant, 106 people were admitted to hospital. This corresponds to 2.5 percent. The proportion who were admitted was higher for people infected with the UK variant than a non-specific variant in all age groups from 20 years and older.

Hospital admissions increased sharply in recent weeks

In the Norwegian Institute of Public Health’s weekly report for week 10, it was reported that approximately 72 percent of all cases were confirmed/ probably infected with the UK variant. The numbers vary between counties. The UK variant is more contagious than the variant that circulated earlier in the pandemic. Recent published studies suggest that it also increases the risk of severe disease course and death.

In Norway, the number of hospital admissions due to COVID-19 has increased sharply in recent weeks. In week 10, 165 new admissions were reported, which is the highest number in a week since the end of March 2020. A higher proportion of those infected are now admitted to hospital compared to earlier in the pandemic.

About the study

The NIPH study includes all new cases tested between 14 December and 7 March. A total of 32 374 cases were analyzed. Of these, 11 154 were examined for variants of concern. 54 percent were the UK variant, 38 percent were a non-specific variant, 8 percent were another specified variant and 0.5 percent were an unknown variant.

The study has not yet been peer-reviewed. It will be sent to a peer review journal.

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Japanese region seeks new virus emergency as Olympics near

coronavirus

Japan’s third most populated region will on Tuesday ask the central government to impose a state of emergency over the coronavirus as infections rise just three months before the country hosts the Olympics.

Osaka prefecture only lifted a state of emergency two months ago and restrictions are expected to be tougher this time, possibly involving store and shopping mall closures.

That would still fall short of the harsh lockdowns seen in many other parts of the world however.

Tokyo and several other areas are expected to follow suit, hoping to avoid the crisis now facing Osaka’s healthcare system, where beds for coronavirus patients in severe condition have run out.

Governor Hirofumi Yoshimura said he had already told the minister overseeing the coronavirus response, Yasutoshi Nishimura, that a state of emergency was needed as measures taken so far “are not enough”.

A formal request is expected to come later today, with official approval from the government following in the evening.

“I believe now is the time to take strong measures for a short period of time,” Yoshimura told reporters.

“The flow of people and the fast pace of the variant strains are causing surges,” he warned, calling for the closure of shopping malls, amusement parks and department stores.

He also urged people to move to teleworking, warning that otherwise “we won’t be able to curb the flow of people”.

Osaka is already under virus restrictions that mostly call for restaurants and bars to close by 8pm and urge residents to avoid unnecessary outings.

Those measures prompted the region to bar the Olympic torch relay from public roads, with the flame instead being carried by torchbearers on a closed track inside a park without spectators.

Nishimura earlier acknowledged the “extremely tough situation” in Osaka, saying the government was coordinating with authorities there “with a strong sense of crisis”.

According to local media, Tokyo also plans to request the government declare a state of emergency this week.

And at least two regions neighbouring Osaka are reportedly planning on requesting the measure.

The surge in cases comes with just over three months until the virus-postponed Tokyo Olympics, which organisers insist can be held safely.

Japan declared a virus state of emergency in early January for several areas, lifting it on March 1 in Osaka and three weeks later in Tokyo.

But infections have ticked back up, driven by more infectious variants, and vaccinations are moving slowly.

Only the Pfizer vaccine has been approved and so far it is being given only to medical workers and the elderly.

Just 25 percent of 4.8 million healthcare workers and slightly more than 13,000 elderly people have so far received a first vaccine dose.

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Japan expands virus alert in Tokyo area as surge spreads

Japan expands virus alert in Tokyo area as surge spreads

Japan is set to raise the coronavirus alert level in Tokyo’s three neighboring prefectures and a forth area in central Japan to allow tougher measures as a more contagious coronavirus variant spreads, along with doubts whether the Olympics can go ahead.

The move comes only four days after Tokyo was placed on alert while the vaccination campaign has covered less than 1% of the population.

The government is expected to official approve the alert status for Kanagawa, Saitama and Chiba and Aichi prefectures in central Japan at a meeting later Friday. It will allow heads of the prefectures to mandate shorter hours for bars and restaurants, along with punishments for violators and compensation for those who comply.

The measures are to begin Monday and continue through May 11.

Many of the cases have been linked to nightlife and dining spots, but they have recently spread to offices, elderly care facilities and schools.

Japan added some 4,300 cases on Wednesday for a total of about half a million with 9,500 deaths.

Prime Minister Yoshihide Suga said the measures cover the areas hit by rapid spikes fueled by a new virus variant first detected in the U.K.. “The government will respond firmly even during my U.S. trip,” he said before departing for Washington for talks with President Joe Biden.

Suga’s government has been criticized for being too slow in enacting anti-virus measures out of reluctance to further damage the economy.

The surge has also prompted concern among many Japanese about hosting the Tokyo Olympics July 23-Aug. 8. On Thursday, two top officials said there was a possibility the Games could be canceled or even if they proceed, it might be without fans.

The new alert comes with binding orders but only for businesses to close early while measures for residents are only requests, leading some experts to doubt their effectiveness.

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Updated Moderna vaccines neutralize South African SARS-CoV-2 variant in mice

Researchers in the United States have conducted a pre-clinical study demonstrating the efficacy of two updated versions of the Moderna mRNA-1273 vaccine against variants of severe acute respiratory syndrome coronavirus 2 – the agent that causes coronavirus disease 2019 (COVID-19).

Study: Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

The updated vaccine candidates include the monovalent mRNA-1273.351, which is designed to target the B.1.351 variant that emerged in South Africa, and the multivalent mRNA1273.211, which comprises a mixture of the original mRNA-1273 vaccine and mRNA-1273.351.

The vaccines were evaluated in mice as both a primary vaccination series and as a booster dose among animals that had previously been immunized with two doses of mRNA-1273.

The team reports that while the mRNA-1273.351 vaccine elicited high levels of neutralizing antibody titers against B.1.351, the multivalent mRNA-1273.211 was most effective at providing broad cross-variant neutralization.

In addition, a booster dose of mRNA-1273.351 dramatically increased neutralization titers against both wild-type SARS-CoV-2 and the B.1.351 variant.

“Both mRNA-1273.351 and mRNA-1273.211 are currently being evaluated in additional pre-clinical challenge models and in phase 1/2 clinical studies,” says the team from Moderna Inc and the National Institute of Allergy and Infectious Diseases.

Global surveillance for the emergence of further variants of concern (VOCs) is also ongoing, as are efforts to test the ability of mRNA-1273 to neutralize VOCs.

“If additional variants emerge that reduce the neutralization capacity of mRNA-1273 further, additional mRNA vaccine designs may be developed and evaluated,” writes Kai Wu and colleagues.

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

Model of S protein. mRNA-1273.351 encodes the B.1.351 lineage S variant. Surface representation of the trimeric S protein in the vertical view with the locations of surface-exposed mutated residues highlighted in red spheres and labeled on the grey monomer. The inset shows superimposition of ACE-2 receptor domain and the RBD. S protein structure, 6VSB. ACE2-RBD structure, 6M0J. ACE2, angiotensin converting enzyme 2; NTD, N-terminal domain; RBD, receptor-binding domain.

Variants increasingly pose a threat to vaccination

The emergence of SARS-CoV-2 variants has raised concerns that the virus may have evolved the ability to escape vaccine-induced immunity. Several variants have demonstrated resistance to neutralization by vaccinated sera, particularly the South African B.1.351 lineage that was first identified in December 2020.

The initial stage of the SARS-CoV-2 infection process is mediated by the viral spike protein, which attaches to the host cell receptor via its receptor-binding domain (RBD). This spike RBD is the primary target of the neutralizing antibodies that are generated following infection or vaccination. A neutralization “supersite” has also been identified in the N-terminal domain (NTD) of the spike protein.

Studies have shown that several recently emerged SARS-CoV-2 variants harbor mutations in the RBD and NTD of spike that may confer resistance to vaccine-induced neutralization activity.

“Importantly, mutations in the NTD domain, and specifically the neutralization supersite, are extensive in the B.1.351 lineage virus,” says Wu and colleagues.

Furthermore, “studies have demonstrated reduced neutralization titers against the full B.1.351 variant following mRNA-1273 vaccination,” they add.

What did the researchers do?

Now, Wu and colleagues have evaluated the efficacy of two updated vaccines.

The monovalent mRNA-1273.351 vaccine encodes the spike protein found in the B.1.351 lineage, while the multivalent mRNA-1273.211 comprises a 1:1 mix of mRNA-1273.351 and mRNA-1273.

The original mRNA-1273 vaccine targets the ancestral wild-type virus (Wuhan-Hu-1 variant) that contains a mutation called D614G.

The vaccines were administered in mice as a two-dose primary series and their immunogenicity against D614G and B.1.351 pseudoviruses was evaluated 2 weeks following the first and second immunizations.

The mRNA-1273.351 vaccine was also evaluated as a booster dose in animals that had previously received two doses of mRNA-1273.

What did the study find?

Vaccine mRNA-1273.351 elicited approximately 4-fold higher neutralization titers against B.1.351 than against D614G.

Vaccine mRNA-1273.211, on the other hand, elicited robust neutralization responses against both D614G and B.1.351, with no significant difference observed in neutralization titers.

“Thus, as a primary vaccination series, a multivalent approach appears most effective in broadening immune responses,” says the team.

Next, the researchers tested the ability of mRNA-1273.351 to serve as a booster shot for neutralization against both D614G and B.1.351.

Mice were injected with mRNA-1273 on days 1 and 22 and then evaluated for antibody responses over the course of 7 months before being vaccinated a third time with mRNA-1273.351.

Following this booster injection, neutralization titers against D614G increased 4.5-fold, while titers against B.1.351 increased 15-fold.

The mRNA-1273.351 vaccine is an “effective booster”

“mRNA-1273.351 is an effective third (booster) dose in animals previously vaccinated with a primary vaccination series of mRNA-1273,” says Wu and the team.

“Ongoing studies will evaluate the ability of mRNA-1273, mRNA-1273.351, and mRNA-1273.211 to effectively boost immunity driven by a primary vaccination series of mRNA-1273,” they add.

The team says the mRNA platform approach against SARS-CoV-2 VOCs has now been demonstrated in mice to effectively broaden neutralization across variants and boost antibody levels when applied as a third dose.

“The mRNA platform allows for rapid design of vaccine antigens that incorporate key mutations, allowing for rapid future development of alternative variant-matched vaccines should they be needed,” writes Wu and colleagues.

“Additional VOC designs can be rapidly developed and deployed in the future if needed to address the evolving SARS-CoV-2 virus,” they conclude.

*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:
  • Wu K, et al. Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice. bioRxiv, 2021. doi: https://doi.org/10.1101/2021.04.13.439482, https://www.biorxiv.org/content/10.1101/2021.04.13.439482v1

Posted in: Medical Research News | Disease/Infection News

Tags: ACE2, Allergy, Angiotensin, Antibodies, Antibody, Cell, Coronavirus, Coronavirus Disease COVID-19, Efficacy, Enzyme, Infectious Diseases, Mutation, Protein, Receptor, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Vaccine, Virus

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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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Recovered COVID-19 patients may develop blood clots due to overactive immune response

People who have recovered from COVID-19, especially those with pre-existing cardiovascular conditions, may be at risk of developing blood clots due to a lingering and overactive immune response, according to a study led by Nanyang Technological University, Singapore (NTU) scientists.

The team of researchers, led by NTU Assistant Professor Christine Cheung, investigated the possible link between COVID-19 and an increased risk of blood clot formation, shedding new light on "long-haul COVID" – the name given to the medium- and long-term health consequences of COVID-19.

The findings may help to explain why some people who have recovered from COVID-19 exhibit symptoms of blood clotting complications after their initial recovery. In some cases, they are at increased risk of heart attack, stroke or organ failure when blood clots block major arteries to vital organs.

The team, comprising researchers from NTU, Agency for Science, Technology and Research's (A*STAR) Singapore Immunology Network (SIgN), and the National Centre of Infectious Diseases, Singapore (NCID), collected and analysed blood samples from 30 COVID-19 patients a month after they had recovered from the infection and were discharged from hospital.

They found that all recovered COVID-19 patients had signs of blood vessel damage, possibly from a lingering immune response, which may trigger the formation of blood clots.

Their findings were published on 23 March in the peer-reviewed scientific journal eLife.

"With more people recovering from COVID-19, we started hearing from clinicians about patients returning with blood clotting issues after they had been discharged and cleared of the virus," said Asst Prof Christine Cheung from NTU's Lee Kong Chian School of Medicine. "This makes a strong case for the close monitoring of recovered COVID-19 patients, especially those with pre-existing cardiovascular conditions like hypertension and diabetes who have weakened blood vessels."

Blood vessel damage due to post-recovery overactive immune system

The team found that recovered COVID-19 patients had twice the normal number of circulating endothelial cells (CECs) that had been shed from damaged blood vessel walls. The elevated levels of CECs indicate that blood vessel injury is still apparent after recovering from viral infection.

The researchers also found that recovered COVID-19 patients continued to produce high levels of cytokines – proteins produced by immune cells that activate the immune response against pathogens – even in the absence of the virus.

Unusually high numbers of immune cells, known as T cells, that attack and destroy viruses were also present in the blood of recovered COVID-19 patients.

The presence of both cytokines and higher levels of immune cells suggest that the immune systems of recovered COVID-19 patients remained activated even once the virus was gone.

The researchers hypothesise that these persistently activated immune responses may attack the blood vessels of recovered COVID-19 patients, causing even more damage and increasing the risk of blood clot formation further.

While COVID-19 is mainly a respiratory infection, the virus may also attack the linings of blood vessels, causing inflammation and damage. Leakage from these damaged vessels triggers the formation of blood clots that may result in the sort of complications seen in the patients during hospitalisation."

Florence Chioh, Study First Author and Research Assistant, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

One of the co-authors of the paper, Professor Lisa Ng, Executive Director of A*STAR Infectious Diseases Labs and previously Senior Principal Investigator at SIgN, said: “We assessed the levels of immune mediators in these patients, which revealed several proinflammatory and activated T lymphocyte-associated cytokines sustained from infection to recovery phase. This correlated positively with CEC measure, implying cytokine-driven vessel damage. We found that COVID-19 patients with vascular complications have a higher frequency of T cells, which may in turn attack the blood vessels. Preventive therapy may be needed for these patients.”

Emphasising post- hospitalisation care for at-risk COVID-19 patients

The study's key findings can help inform guidelines for post-hospitalisation care of COVID-19 patients who might be susceptible to 'long-haul COVID' symptoms, said the research team.

In January this year, the World Health Organisation (WHO) released a recommendation in their revised clinical management guidelines, targeted at the risk of blood clot formation. For hospitalised patients, WHO recommended the use of low dose anticoagulants for preventing the blood clots forming in blood vessels.

Asst Prof Cheung added: "Those with cardiovascular conditions need to be more cautious since their underlying conditions already weaken their vascular systems. It's a double blow with COVID-19. As we gain greater understanding of complications COVID 'long-haulers' face, there is hope to encourage vaccine take-up rate to protect oneself from both the virus and its long-term complications."

Moving forward, the team is investigating the longer-term effects of COVID-19 in patients who have recovered from the infection for at least six months or longer.

Source:

Nanyang Technological University

Journal reference:

Chioh, F. W., et al. (2021) Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation. eLife. doi.org/10.7554/eLife.64909.

Posted in: Medical Research News | Disease/Infection News

Tags: Blood, Blood Clot, Blood Vessel, Blood Vessels, Cytokine, Cytokines, Diabetes, Frequency, Heart, Heart Attack, Hospital, Immune Response, Immune System, Immunology, Infectious Diseases, Inflammation, Lymphocyte, Medicine, Research, Respiratory, Stroke, Vaccine, Vascular, Virus

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Nanobody cocktails neutralize SARS-CoV-2 and variants

Researchers report a collection of nanobodies derived from llamas, some of which can work synergistically and work against newer virus variants.

Although several strategies have been implemented to combat the COVID-19 pandemic, it continues unabated. Despite several vaccines being approved and used, vaccination rates have been slow, and there have been challenges in the equitable distribution of vaccines. These, along with decreasing immunity in persons already infected and the emergence of new virus variants, make it difficult to contain the pandemic.

Several therapeutic strategies have used convalescent sera and human monoclonal antibodies. However, new variants have emerged, with mutations that can evade these therapeutics.

An alternative to monoclonal antibodies is nanobodies. These are smaller proteins derived from animals like llamas and alpacas. Their small size allows them to bind to regions that are generally not accessible to the larger monoclonal or polyclonal antibodies. They are also simpler to manufacture as they can be easily cloned and expressed in bacteria. They can also be delivered directly to the lungs via nebulization.

However, the nanobodies also recognize regions of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain (RBD), which can cause escape mutations, reducing their potency.

Pre-screening protocol to select llamas with naturally strong immune responses, as determined by activity against standard animal vaccines

Testing nanobody neutralization capability

In a study published in the bioRxiv* preprint server, researchers report a collection of a large number of nanobodies that could potentially be resistant to escape mutations.

To build their suite of nanobodies, the team refined and optimized their previous method. They chose llamas with a strong immune response to SARS-CoV-2 and selected 113 nanobodies for further testing. A large proportion of the antibodies bind to the RBD, while the other bind to the non-RBD portion of the S1 subunit of the spike protein and the rest to the S2 subunit.

To identify nanobodies that will be resistant to virus mutations, the team selected a large number of high RBD binding nanobodies and tested them against the B.1.1.7 variant. Of the seven nanobodies they tested, they found six showed strong binding to the variants. In addition, they also chose nanobodies that bind to the non-RBD regions of the spike protein.

The authors then categorized the antibodies depending on what parts of the RBD they bind to. Their analysis revealed the RBD-binding nanobodies could be classified into three distinct groups. Within each group, the nanobodies could be grouped into bins so that some bind to distinct epitopes and partially overlap, binding to other separate epitopes.

This suggests two or more nanobodies can bind to the RBD at the same time. Further analysis revealed at least three different nanobodies could bind to the RBD simultaneously, which will be important in designing nanobody cocktails for therapies.

The nanobodies were potent in neutralizing SARS-CoV-2 pseudoviruses, with 16 nanobodies neutralizing the pseudovirus at less than 20 nM concentration. Nanobodies that target the non-RBD regions and the S2 subunit also neutralized the virus but at higher concentrations. The authors write this is the first evidence of nanobody neutralization targeting regions outside the RBD.

Nanobody cocktails more potent against escape variants

The team also tested the best nanobodies against pseudoviruses carrying the spike protein of the B.1.351 variant. Some nanobodies showed no neutralization activity against this variant, while one showed similar neutralization as the wild-type virus. Two nanobodies, however, showed increased neutralization activity against the variant. The nanobodies that neutralized the pseudovirus also neutralized the real SARS-CoV-2 virus and human airway epithelial cells. The team also found some nanobody combinations can work synergistically and increase potency dramatically.

Using nanobody cocktails mixed with the SARS-CoV-2 virus and allowing multiple replications, the authors also identified mutations that resist neutralization. Some potent nanobodies caused mutations at the same location as generated by antibodies in human convalescent sera, such as E484K, indicating the ACE2 binding site is a point of vulnerability for neutralization.

However, nanobody cocktails also increased the genetic barrier for escape. Mixing two nanobodies required the virus to undergo two different amino acid substitutions, making it more difficult for it to escape neutralization. Carefully choosing mixtures with more nanobodies may further decrease escape mutations.

Thus, the escape experiments show that currently used or newer therapeutics may yet lose their potency with newer virus variants emerging, which is very likely as some of the mutations seen in the experiments have not been seen in human isolates so far. However, using a combination of nanobodies, which can work synergistically to improve neutralization potency, the large collection of nanobodies generated by the team may help develop more potent treatments.

*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:
  • Mast, F. D. et al. (2021) Nanobody Repertoires for Exposing Vulnerabilities of SARS-CoV-2. bioRxiv, https://doi.org/10.1101/2021.04.08.438911, ​https://www.biorxiv.org/content/10.1101/2021.04.08.438911v1

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

Tags: ACE2, Amino Acid, Antibodies, Bacteria, Coronavirus, Coronavirus Disease COVID-19, Genetic, Immune Response, Lungs, Nanobodies, Pandemic, Protein, Pseudovirus, Receptor, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Therapeutics, Virus

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Lakshmi Supriya

Lakshmi Supriya got her BSc in Industrial Chemistry from IIT Kharagpur (India) and a Ph.D. in Polymer Science and Engineering from Virginia Tech (USA).

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Researchers discover a new monoclonal antibody that is effective against SARS-CoV-2 variants

A new monoclonal antibody targets a particular region of the receptor-binding domain (RBD) on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This region is usually not accessible to immune cells,  which may be why it has broad neutralizing capabilities.

With the coronavirus disease 2019 (COVID-19) pandemic continuing around the globe, new mutants of SARS-CoV-2 are emerging. These new variants are likely more infectious and can better evade our immune response.

The SARS-CoV-2 spike protein, in particular the RBD, is key in binding to host receptors, mainly the angiotensin-converting enzyme 2 (ACE2) in humans. One highly conserved region of the RBD, called antigenic site II, can elicit neutralizing antibodies. However, this region is generally inaccessible because of the RBD conformation, and there is a low fraction of antibodies targeting this site in infected individuals.

Study: Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody. Image Credit: Design_Cells / Shutterstock

In a new study published in the bioRxiv* preprint server, researchers report a new monoclonal antibody that is targeted toward site II and has a broad neutralizing capability.

Testing potency of monoclonal antibody

The authors sorted spike protein-specific memory B cells from a convalescent individual 75 days after symptom onset. They found one monoclonal antibody, called S2X259, which reacted with 29 of 30 spike proteins of sarbecoviruses, including SARS-CoV-2 and its new variants. The antibody also reacted with bat sarbecoviruses, suggesting its broad neutralizing capability.

The antibody also bound strongly to 10 RBDs from different sarbecoviruses. The binding of this antibody was not affected by the different single-point RBD mutations seen in the new variants of SARS-CoV-2, including the United Kingdom, South African, Brazilian, and the B.1.427/B.1.429 variants.

Using pseudotyped virus systems, the team found that the antibody neutralized SARS-CoV-2 and did not lose its potency against the different variants or the N439K or Y453F mutation. The antibody not only neutralized a variety of sarbecoviruses that use the ACE2 receptor but also cross-reacts with sarbecoviruses that do not use ACE2 for infection.

To understand how this antibody has high neutralizing potency, the team imaged the complex formed between the spike protein and the antibody using cryo-electron microscopy. They found that the antibody recognizes a glycan-free site, which requires two RBDs to be in the open conformation. It forms contacts with residues 369-386, 404-411, and 499-508 in the RBD.

The epitope the antibody binds to is conserved in all the circulating SARS-CoV-2 variants. In addition, it does not target the 417 or 484 residues (mutations here are found in B.1.351 and P.1), and this could be why it is potent against the different variants.

The action of this antibody does not affect the neutralization effect of class 1 and class 3 antibodies. The majority of approved antibodies for clinical use belong to these classes. Hence, the new antibody can be used in combination with other antibodies to increase neutralization breadth.

The S2X259 broadly neutralizing sarbecovirus mAb recognizes RBD antigenic site II. a-b, CryoEM structure of the prefusion SARS-CoV-2 S ectodomain trimer with three S2X259 Fab fragments bound to three open RBDs viewed along two orthogonal orientations. c. The S2X259 binding pose involving contacts with multiple RBD regions. Residues corresponding to prevalent RBD mutations are shown as red spheres. d-e, Close-up views showing selected interactions formed between S2X259 and the SARS-CoV-2 RBD. In panels a-e, each SARS-CoV-2 S protomer is coloured distinctly (cyan, pink and gold) whereas the S2X259 light and heavy chain variable domains are coloured magenta and purple, respectively. N-linked glycans are rendered as blue spheres in panels a-c.

Potential use against a broad range of sarbecoviruses

Using computational analysis, the team determined what RBD mutations could escape the antibody from binding. They found only a few RBD mutations disrupt the binding of this antibody. The substitution of the residue at position 504 gave the most significant disruption in binding.

When they replicated a pseudotyped SARS-CoV-2 virus in the presence of the S2X259 antibody, the only mutation they found caused by selective pressure was G504D. This mutation has rarely been seen in human isolates so far.

The selection of a single escape mutation suggests the region targeted by the antibody might not tolerate amino acid substitutions without changing viral fitness. Hence it is conserved across different sarbecoviruses. Thus, there is a high barrier for the emergence of mutations against this antibody, suggesting it could become key in combating the pandemic.

When Syrian hamsters were challenged with SARS-CoV-2, with the antibody administered 48 hours before virus infection, the authors found more than two orders of magnitude decrease in virus in the lungs compared to hamsters that did not receive any treatment. In addition, the antibody also protected hamsters infected with the B.1.351 strain.

The detection of a large variety of sarbecoviruses in bats and other mammals, along with the increased human-animal interactions, makes it likely that more cross-species transmission of viruses can occur. With increasing evidence that antibodies targeting the RBD form a major proportion of neutralizing activity, RBD-based vaccines could elicit high levels of antibodies like S2X259 with high potency. Such strategies can help overcome the current COVID-19 pandemic and help prepare for future sarbecovirus infections.

*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:
  • Tortorici, M. A. et al. (2021) Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody. bioRxiv. https://doi.org/10.1101/2021.04.07.438818, https://www.biorxiv.org/content/10.1101/2021.04.07.438818v1

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

Tags: ACE2, Amino Acid, Angiotensin, Angiotensin-Converting Enzyme 2, Antibodies, Antibody, Coronavirus, Coronavirus Disease COVID-19, Electron, Electron Microscopy, Enzyme, Glycan, Glycans, Immune Response, Lungs, Microscopy, Monoclonal Antibody, Mutation, Pandemic, Protein, Receptor, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Virus

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Lakshmi Supriya

Lakshmi Supriya got her BSc in Industrial Chemistry from IIT Kharagpur (India) and a Ph.D. in Polymer Science and Engineering from Virginia Tech (USA).

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Increasing compliance with existing restrictions can stop the spread of COVID-19 virus, says expert

Responses from 9 500 inhabitants in 11 countries in a study financed by the EU have given the researchers an insight into how governments should act to stop the spread of the virus.

"Implementing a combination of many restrictions has the opposite effect. Increase compliance with existing restrictions instead," says Sofia Wikman, researcher at University of Gävle.

In an online questionnaire, researchers asked citizens about 44 different restrictive public health measures aimed to limit the spread of the virus to see how efficient citizens found them. What restrictions are seen as infringements of individual liberties? What views and demographic factors impact compliance? What is the best way for governments to improve citizens' compliance?

There were 9543 responses to the survey and respondents came from 11 countries: United Kingdom, Belgium, the Netherlands, Bulgaria, Czechia, Finland, India, Latvia, Poland, Rumania and Sweden

Best measures according to citizens

The new study provides researchers with unique responses concerning what measures the citizens find to be the most effective, and which ones they see as undermining their human rights.

Responses reveal that politicians should start with the least restrictive and most effective public health measures first in case of pandemic emergencies.

Measures require balancing between the negative financial, psychological, and social effects and protection of human rights."

Sofia Wikman, Researcher, University of Gävle

Countries with public lack of confidence in the government should invest in efforts that persuade men

The results reveal that there are significant differences between countries concerning perceived effectiveness, restrictiveness and compliance.

  • In countries where there is a public lack of confidence in the government, governments should increase their efforts to persuade their citizens, especially the men, that the measures are effective.
  • Financial compensation should be provided to citizens who have lost their job or income due to the measures implemented to improve measure compliance.
  • Use solely evidence-based information in public campaigns.
  • Refrain from implementing measures perceived as more restrictive for citizens' human rights than effective and that lack objective evidence on their effectiveness in preventing the spread of the virus.
Source:

University of Gävle

Journal reference:

Georgieva, I., et al. (2021) Perceived Effectiveness, Restrictiveness, and Compliance with Containment Measures against the Covid-19 Pandemic: An International Comparative Study in 11 Countries. International Journal of Environmental Research and Public Health. doi.org/10.3390/ijerph18073806.

Posted in: Disease/Infection News | Healthcare News

Tags: Pandemic, Public Health, Virus

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