Category: COVID

Scientists Pry Open Secrets of a Potent Antibody against COVID

Even as the structure of SARS-CoV-2 changes with different variants of the virus (grey), the J08 antibody (blue) can still bind it, Scripps researchers showed. Credit: Scripps Research

Scientists have revealed the secrets of a potent antibody against SARS-CoV-2 that was discovered in COVID survivors. The antibody has a broadly neutralising effect, and is able to retain its efficacy against a wide range of variants – though not Omicron.

In 2021, Scripps Research and Toscana Life Sciences scientists screened the blood of 14 COVID-19 survivors to find the most potent antibodies against the SARS-CoV-2 virus. One of the most promising finds, now in stage II/III trials, was an antibody dubbed J08, which seemed to be capable of both preventing and treating COVID. 

Now, the same group has visualised exactly how J08 binds to different SARS-CoV-2 variants in different conformations, explaining what makes the monoclonal antibody so potent. The research, published in Proceedings of the National Academy of Sciences, suggests that the J08 antibody’s flexibility will likely keep it effective against future COVID variants.

“Even though we can’t predict what variants of COVID will emerge next, understanding the details of J08 reveals what works against the virus, and perhaps how we can engineer antibodies to be even more potent,” explained senior author Andrew Ward, PhD at Scripps Research.

On exposure to a virus like SARS-CoV-2, the body creates a variety of antibodies that bind to different sections of the virus to clear it from the body. There is considerable interest in why certain naturally produced antibodies such as J08 more effective than others. In the months after Ward and his collaborators first identified J08, it became clear that the antibody, unlike many others, was potent against a variety of COVID variants.

The researcher mapped the three-dimensional structure of J08 as it bound to the spike protein of SARS-CoV-2. J08 was confirmed to successfully attach to the Alpha, Beta, Gamma and Delta variants, preventing replication. However, J08 attached to the Omicron variant about 7 times more slowly, and then quickly detached. About 4000 times more J08 was needed to fully neutralise Omicron SARS-CoV-2 compared to the other variants.

“With variants other than Omicron, this antibody binds quickly and doesn’t come off for hours and hours,” says co-first author Gabriel Ozorowski, a senior staff scientist in the Ward lab at Scripps Research. “With Omicron, we were initially happy to find that it still binds, but it falls off very quickly. We identified the two structural changes that cause this.”

The team showed that, for all the variants, J08 binds to a very small section of the virus – a section that generally stays the same even as the virus mutates. Moreover, J08 could attach in two completely different orientations, like a key that manages to unlock a door whether it is right side up or upside down. 

“This small, flexible footprint is part of why J08 is able to withstand so many mutations – they don’t impact the antibody binding unless they happen to be in this one very small part of the virus,” said co-first author Jonathan Torres, lab manager of the Ward lab at Scripps Research.

The Omicron variant of SARS-CoV-2, however, had two mutations (known as E484A and Q493H) that changed the small area of the virus that directly interfaces with J08, anchoring it in place. Ward and his collaborators found that if just one of these mutations is present, J08 can still bind and neutralise the virus strongly, but mutations in both are what make it less effective against the Omicron variant.

The researchers said the new results support the continued clinical trials of the monoclonal antibody based on J08.

“I think we’re pretty confident that future variants won’t necessarily have both of these two critical mutations at the same time like Omicron,” remarked Ozorowski, “so that makes us hopeful that J08 will continue being very effective.”

Source: Scripps Research

Steroids after Severe COVID Reduces One-year Mortality by 51%

Photo by Stephen Andrews on Unsplash

Researchers have shown that severe inflammation during hospitalisation for COVID increases post-recovery mortality risk by 61% – but this risk is reduced again by 51% if anti-inflammatory steroids are prescribed upon discharge. We need to think of COVID as a potentially chronic disease that requires long-term management, argue the authors, whose results are published in Frontiers in Medicine.

Evidence continues to gather that ‘long COVID’, that is, continued negative health impacts months after apparent recovery from severe COVID, is an important risk for some patients. For example, researchers showed last December that hospitalised patients who seemingly recovered from severe COVID run more than double the risk of dying within the next year, compared to those with only mild COVID or who never had COVID.

Now, the same research team shows that among patients hospitalised for COVID who seemingly recovered, severe systemic inflammation during their hospitalisation is a risk factor for death within one year.

“Here we show that the stronger the inflammation during the initial hospitalisation, the greater the probability that the patient will die within 12 months after seemingly ‘recovering’ from COVID.”

Professor Arch G Mainous III

“COVID is known to create inflammation, particularly during the first, acute episode. Our study is the first to examine the relationship between inflammation during hospitalisation for COVID and mortality after the patient has ‘recovered’,” said first author Professor Arch G Mainous III at the University of Florida Gainesville.

“Here we show that the stronger the inflammation during the initial hospitalisation, the greater the probability that the patient will die within 12 months after seemingly ‘recovering’ from COVID.”

Prof Mainous and colleagues analysed electronic health records of 1207 adults hospitalised with COVID in 2020 or 2021 within the University of Florida health system, with at least a one year follow-up after discharge. As a proxy for the severity of systemic inflammation during hospitalisation, they used a common and validated measure: C-reactive protein (CRP), secreted by the liver in response to a signal by active immune cells.

Widespread inflammation in the body

As expected, the blood concentration of CRP during hospitalisation was strongly correlated with the severity of COVID: 59.4mg/L for patients not needing supplemental oxygen, 126.9 mg/L for those who needed extra oxygen without mechanical ventilation, and 201.2 mg/L for the most severe cases, who required ventilation through a ventilator or through ECMO.

After correcting for risk factors, patients with the highest CRP concentration measured their during their hospital stay had a 61% greater risk of all-cause mortality within one year of discharge than patients with the lowest CRP concentration.

Prof Mainous said: “Many infectious diseases are accompanied by an increase in inflammation. Most times the inflammation is focused or specific to where the infection is. COVID is different because it creates inflammation in many places besides the airways, for example in the heart, brain, and kidneys. High degrees of inflammation can lead to tissue damage.”

Importantly, the authors showed that the increased all-cause mortality risk associated with severe inflammation was reduced again by 51% if the patient was prescribed anti-inflammatory steroids after their hospitalisation.

These results mean that the severity of inflammation during hospitalisation for COVID can predict the risk of subsequent serious health problems, including death, from ‘long COVID’. They also imply that current recommendations for best practice may need to be changed, to include more widespread prescription of orally taken steroids to COVID patients upon their discharge.

COVID as a chronic disease?

The authors propose that COVID should be seen as a potentially chronic disease.

“When someone has a cold or even pneumonia, we usually think of the illness being over once the patient recovers. This is different from a chronic disease, like congestive heart failure or diabetes, which continue to affect patients after an acute episode. We may similarly need to start thinking of COVID as having ongoing effects in many parts of the body after patients have recovered from the initial episode,” said Prof Mainous.

“Once we recognise the importance of ‘long Covid’ after seeming ‘recovery’, we need to focus on treatments to prevent later problems, such as strokes, brain dysfunction, and especially premature death.”

Source: Frontiers

Diabetes Almost Doubles COVID Mortality Risk

Diabetes - person measures blood glucose
Photo by Photomix Company from Pexels

Compared to those without diabetes, the COVID mortality risk for people with diabetes is almost double, with almost three times the risk of being critically or severely ill, according to a review of research by researchers from the University of Aberdeen.

Fortunately, the review study, which is published in Endocrinology, Diabetes and Metabolism, also found that good management of the condition can mitigate against the risks.

Specifically, it was found that while diabetes presents a significant risk of severe illness and death with COVID, good glycaemic control in these patients can mitigate this risk.

The researchers reviewed findings from 158 studies, encompassing more than 270 000 participants from around the world to determine COVID’s impact on people with diabetes.

The pooled results showed that people with diabetes were 1.87 times more likely to die with COVID, 1.59 times more likely to be admitted to ICU, 1.44 times more likely to require ventilation, and 2.88 times more likely to be classed as severe or critical, when compared to patients without diabetes.

This is the first time a study has looked at the risks of COVID in patients with diabetes while factoring in the patients’ location and thereby highlighting potential healthcare resources available as well as possible ethnic differences and other societal factors.

Patients in China, Korea and the Middle East were found to be at higher risk of death than those from EU countries or the US. This, they suggested, may be the result of differences in healthcare systems and affordability of healthcare which may explain the finding that maintaining optimal glycaemic control, significantly reduces adverse outcomes in patients with diabetes and COVID.

Stavroula Kastora, who worked on the study explained: “We found that following a COVID infection, the risk of death for patients with diabetes was significantly increased in comparison to patients without diabetes.

“Equally, collective data from studies around the globe suggested that patients with diabetes had a significantly higher risk of requiring an intensive care admission and supplementary oxygen or being admitted in a critical condition in comparison to patients without diabetes.

“However, we found that the studies that reported patient data from the EU or US displayed less extreme differences between the patient groups. Ultimately, we have identified a disparity in COVID outcomes between the eastern and western world. We also show that good glycaemic control may be a protective factor in view of COVID-related deaths.

“In light of the ongoing pandemic, strengthening outpatient diabetes clinics, ensuring consistent follow up of patients with diabetes and optimising their glycaemic control could significantly increase the chances of survival following a COVID infection.”

Source: University of Aberdeen

Excess Deaths from COVID Nearly 15 Million – WHO

Source: Pixabay CC0

The World Health Organization (WHO) estimates that the full death toll associated directly or indirectly with the COVID pandemic (described as “excess mortality”) was approximately 14.9 million, with a range of 13.3 million to 16.6 million.  

“These sobering data not only point to the impact of the pandemic but also to the need for all countries to invest in more resilient health systems that can sustain essential health services during crises, including stronger health information systems,” said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. “WHO is committed to working with all countries to strengthen their health information systems to generate better data for better decisions and better outcomes.”

Excess mortality is calculated as the difference between the number of deaths that have occurred and the number that would be expected in the absence of the pandemic based on data from earlier years. 

Excess mortality includes deaths directly associated with COVID (due to the disease) or indirectly (due to the pandemic’s impact on health systems and society). Deaths linked indirectly to COVID are attributable to other health conditions for which people were unable to access prevention and treatment because health systems were overburdened by the pandemic. Excess death numbers can be influenced also by deaths averted during the pandemic due to lower risks of certain events, such as car accidents or occupational injuries. 

The estimate for a 24-month period (2020 and 2021) finds that the excess deaths (84%) are largely concentrated in South-East Asia, Europe, and the Americas. Some 68% of excess deaths are concentrated in just 10 countries globally. Middle-income countries account for 81% of the 14.9 million excess deaths (53% in lower-middle-income countries and 28% in upper-middle-income countries) over the 24-month period, with high-income and low-income countries each accounting for 15% and 4%, respectively. 

The estimates confirm that the global death toll was higher for men than for women (57% male, 43% female) and higher among older adults. A better picture of COVID mortality data comes from excess deaths per 100 000 instead of mortality counts, which can seem skewed due to population size.

“Measurement of excess mortality is an essential component to understand the impact of the pandemic. Shifts in mortality trends provide decision-makers information to guide policies to reduce mortality and effectively prevent future crises. Because of limited investments in data systems in many countries, the true extent of excess mortality often remains hidden,” said Dr Samira Asma, Assistant Director-General for Data, Analytics and Delivery at WHO. “These new estimates use the best available data and have been produced using a robust methodology and a completely transparent approach.”

The production of these estimates is a result of a global collaboration supported by the work of the Technical Advisory Group for COVID-19 Mortality Assessment and country consultations. 

Source: World Health Organization

Closure Threat for SA’s COVID Vaccine Plant as Orders Dry up

Female scientist in laboratory
Photo by Gustavo Fring on Pexels

South Africa’s COVID vaccine production plant, the first of its kind in Africa is at risk of closure after failing to secure a single according to a report from Reuters. President Cyril Ramaphosa is reported to be in talks with three other African nations in effort to save the venture.

The World Health Organization had called the licensing deal between Johnson & Johnson and Aspen Pharmacare to manufacture the Aspenovax COVID vaccine, a “transformative moment” in the pursuit of equitable access to vaccines. The vaccine is the J&J adenovirus vector vaccine sold under the Aspen brand.

However, after initial vaccine delivery shortfalls, the African continent is now well stocked with vaccines, while the poor infrastructure hampers vaccine distribution.

“There’ve been no orders received for Aspenovax,” Reuters reported, citing a phone conversation with Aspen senior director Stavros Nicolaou.

“If we don’t get orders, we would have to repurpose these lines back into other things that we were previously doing,” he told CapeTalk.

There are several other such vaccine plants in various stages, as the African Union aims at 60% of locally produced vaccines for continent locally by 2040, up from the current 1%.

“If Aspen doesn’t get production, what chance is there for any of the other initiatives?” Nicolaou remarked.

Regarding possible options, he said: “We are exploring various options. It is our medium-to-long-term objective to look at providing a sterile [processing] platform and solutions for the continent but the short-term needs to be sorted out.”

Moderna announced an agreement with Kenya to set up its first mRNA manufacturing facility in Africa with the aim of producing up to 500 million doses a year.

Source: Seeking Alpha

Two Doses of Pfizer or J&J Vaccine are Effective vs Severe Omicron

Image of a syring for vaccination
Photo by Mika Baumeister on Unsplash

A South African-led study published in the New England Journal of Medicine has shown that two doses of the Pfizer or the Johnson and Johnson (J&J) vaccine are equally effective against severe COVID caused by the omicron variant.

The omicron variant has been shown to escape antibody neutralisation by both the Pfizer/BioNTech mRNA and the Johnson & Johnson adenovirus viral vector vaccine, the only two COVID vaccines available in South Africa. As of May 1, 44.8% of adults in South Africa had been fully vaccinated. Assessing vaccine effectiveness is critical for national vaccine programs.

Starting in October 2021, health care workers who were participating in phase 3b of the Sisonke study of the early vaccine access program were eligible to receive a second dose of the J&J vaccine. Discovery Health data was accessed for Pfizer vaccine effectiveness. Severe COVID was defined as hospitalisation or admission to an intensive care unit (ICU) or to high care.

Vaccine effectiveness was compared between the two vaccine groups according to the number of days since the second vaccine dose had been administered. However longer follow-ups were not available for the J&J group as booster had been initiated later for them.

PCR results were analysed from participants who had received two doses of the Pfizer vaccine given at least 42 days apart or two doses of the J&J vaccine given 4 to 6 months apart. Among these participants, the test positivity rate was 34%; of those with a positive PCR test, 1.6% had been admitted to a hospital and 0.5% to an ICU or to high care.

Effectiveness against hospitalisation in the J&J group, was found to be 55% within 13 days after the second dose, 74% at 14 to 27 days, and 72% at 1 to 2 months. For the Pfizer group, the vaccine’s effectiveness was 81% within 13 days after the second dose, 88% at 14 to 27 days, 70% at 1 to 2 months, 71% at 3 to 4 months, and 67% at > 5 months. Among J&J vaccine recipients, the vaccine effectiveness against ICU admission or high care was 69% at 14 to 27 days and 82% at 1 to 2 months after the second dose; among the Pfizer recipients, effectiveness against ICU admission or high care was 70% at 1 to 2 months, 73% at 3 to 4 months, and 71% at > 5 months.

Gray et al concluded, “After two doses, both vaccines were equally effective against severe disease caused by the omicron variant. These estimates of vaccine effectiveness were calculated in a South African population with a high background prevalence of SARS-CoV-2 exposure during the Covid-19 pandemic. These data provide reassurance about the continued value of the national Covid-19 vaccine program during a surge in the omicron variant.”

Natural Facial Asymmetry Affects Mask Fit

Image by Quicknews

In research published in Physics of Fluids, researchers used computer modelling investigate mask fit and found that face shape, especially natural facial asymmetry, influences the most ideal fit. The findings suggested that double masking with improperly fitted masks may not greatly improve mask efficiency and produces a false sense of security.

Using more layers results in a less porous face covering, leading to more flow forced out the sides, top, and bottom of masks with a less secure fit. Double layers increase filtering efficiency only with good mask fit, however they could also lead to difficulties in breathing.

The researchers modelled a moderate cough jet from a mouth of an adult male wearing a cloth mask over the nose and mouth with elastic bands wrapped around the ears. They calculated the maximum volume flow rates through the front of mask and peripheral gaps at different material porosity levels.

To create a more realistic 3D face shape and size, the researchers used head scan data for 100 adult male and 100 adult female heads.

Their model showed how the slight asymmetry typical in all facial structures can affect proper mask fitting. For example, a mask can have a tighter fit on the left side of the face than on the right side.

“Facial asymmetry is almost imperceivable to the eye but is made obvious by the cough flow through the mask,” explained co-author Tomas Solano, from Florida State University. “For this particular case, the only unfiltered leakage observed is through the top. However, for different face shapes, leakage through the bottom and sides of the mask is also possible.”

Producing individually customised ‘designer masks’ is not practical at large scales. Still, better masks can be designed for different populations by revealing general differences between male and female or child versus elderly facial structures and the associated air flow through masks.

Source: American Institute of Physics

Omicron Sub-lineages are Evolving Increased Immune Escape Potential

SARS-CoV-2 lineages. Credit: Professor Ryan Gregory, University of Guelph

A paper published May 1 on the medRxiv preprint server on two new sub-lineages of Omicron, BA.4 and BA.5, reported evidence that they may escape immunity conferred by previous BA.1 infection. The study’s authors suggest that this immune escape potential may drive another wave of infections.

In recent weeks, the BA.4 and BA.5 variants have been detected circulating in South Africa, and are close descendants of the Omicron BA.2 lineage.

Researchers isolated live BA.4 and BA.5 viruses and tested their ability to evade infection to 24 participants who had been infected with BA.1 but unvaccinated and 15 vaccinated participants with breakthrough BA.1 infection.

In unvaccinated individuals, FRNT50, the inverse of the dilution for 50% neutralisation, declined from 275 for BA.1 to 36 for BA.4 and 37 for BA.5, a 7.6 and 7.5-fold drop, respectively. In vaccinated BA.1 breakthroughs, FRNT50 declined from 507 for BA.1 to 158 for BA.4 (3.2-fold) and 198 for BA.5 (2.6-fold). Absolute BA.4 and BA.5 neutralisation levels were about 5-fold higher in this group versus unvaccinated BA.1 infected participants.

The observed escape of BA.4 and BA.5 from immunity elicited by BA.1 was more moderate than of BA.1 against previous immunity, the researchers found. The researchers warned that the low absolute neutralisation levels for BA.4 and BA.5, particularly in the unvaccinated group, are unlikely to protect well against symptomatic infection. They suggest that, based on neutralisation escape, BA.4 and BA.5 have potential to result in a new infection wave.

Experts warn however that even these sub-lineages are unlikely to be the last, with plenty of potential remaining for new mutations.

Professor of evolutionary biology T. Ryan Gregory at the University of Guelph, Canada, laid out in a series of tweets that these new sub-lineages are not the final “Pokemon” evolution of SARS-CoV-2. He warned that with all of the replication that is still going on, the virus is still mutating rapidly, especially around the Spike protein, and thus is capable of producing new variants.

Alpha and Delta, which drove two major waves around the world with high levels of mortality, did not give rise to Omicron, but now the variants of concern are increasingly emerging from within the Omicron clade. Prof Gregory noted that a growing number of variants are being seen with transmission or immune escape advantages.

“Sorry to say it, but this pandemic isn’t over,” he concluded.

Montelukast Can Block Harmful SARS-CoV-2 Protein and Protect Immune Cells

Targeting Nsp1 with montelukast helps prevent shutdown of host protein synthesis Credit: Mohammad Afsar

Montelukast can bind to and block a crucial protein produced by SARS-CoV-2, reducing viral replication in human immune cells, according to a new study by researchers at the Indian Institute of Science (IISc).

Montelukast has been around for more than 20 years and is usually prescribed to reduce inflammation caused by conditions like asthma, hay fever and hives.

In the study, published in eLife, the researchers showed that the drug binds strongly to the C-terminal, which is one end of a SARS-CoV-2 protein called Nsp1, which is one of the first viral proteins unleashed inside human cells. NSp1 can bind to ribosomes inside immune cells, shutting down production of vital proteins that the immune system needs, thereby weakening it. Nsp1 could therefore be a target to reduce the virus’s damage.

“The mutation rate in this protein, especially the C-terminal region, is very low compared to the rest of the viral proteins,” explained IISc’s Assistant Professor Tanweer Hussain, senior author of the study. Since Nsp1 is unlikely to change in future variants, targeting it with drugs is a viable strategy, he added.

The researchers screened more than 1600 FDA-approved drugs with computational modelling to find the ones that bound strongly to Nsp1, coming up with a shortlist of drugs including montelukast and saquinavir, an anti-HIV drug. “The molecular dynamic simulations generate a lot of data, in the range of terabytes, and help to figure out the stability of the drug-bound protein molecule. To analyse these and identify which drugs may work inside the cell was a challenge,” said Mohammad Afsar, first author of the study.

The researchers then cultured human cells which produced Nsp1, treated them with montelukast and saquinavir separately, and found that only montelukast was able to rescue the inhibition of protein synthesis by Nsp1.

“There are two aspects [to consider]: one is affinity and the other is stability,” explained Afsar. This means that the drug needs to not only bind to the viral protein strongly, but also stay bound for a sufficiently long time to prevent the protein from affecting the host cell, he adds. “The anti-HIV drug (saquinavir) showed good affinity, but not good stability.” Montelukast, on the other hand, was found to bind strongly and stably to Nsp1, allowing the host cells to resume normal protein synthesis.

The researchers then tested the effect of the drug on live viruses and found that the drug was able to reduce viral numbers in infected cells in the culture.

“Clinicians have tried using the drug … and there are reports that said that montelukast reduced hospitalisation in COVID patients,” said A/Prof Hussain, adding that the exact mechanisms behind it still need to be fully understood. His team plans to work with chemists to see if they can modify the structure of the drug to increase its potency, and also plan to continue the hunt for more drugs.

Source: Indian Institute of Science

South Africa on Cusp of Fifth Wave as Public Apathy Mounts

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South Africa is now on the cusp of a fifth wave, experts warn, as indicators rise and new variants begin to circulate. Social media monitoring indicates a level of public apathy.

After a period of reduced cases, cases rose for three consecutive days, prompting concern. Health Department deputy director-general, Nicholas Crisp, noted possible explanations.

“It may be associated with one of the sub-variants of Omicron, certainly that is what’s dominant at the moment but it also might be just because we are all a bit lax at the moment, we don’t wear our masks so diligently,” he said.

Crisp said that they would be watching the data closely, before pronouncing on whether this was indeed the start of the fifth wave.

“We are not sure if this is the variant that’s going to do whatever is going to happen in the fifth wave, what we are seeing at the moment is what we call a flare-up,” Crisp said.

Wastewater monitoring has seen an uptick in coronavirus levels, according to the NICD’s weekly brief [PDF]. The BA.4 and BA.5 Omicron variants have been observed but it is not clear what impact they will have on the fifth wave. The Delta variant has been sequenced in wastewater, but the significance of this is still unclear.

Gauteng has reported the highest weekly incidence at 27.4 per 100 000 people, followed by Western Cape (23.4 per 100 000), and KwaZulu-Natal (13.4 per 100 000). However, testing rates are down in a number of provinces. The highest incidence is among young teenagers.

As of 25 April, 1954 new cases with a 19.3% positivity rate were recorded by the NICD.

The Health Department’s Vaccine Social Listening progamme has seen a significant drop in engagement across social media, down by 50% on Twitter, 60% on Facebook. Engagements with digital news articles are down 70%. Fears over a fifth wave have been dismissed on social media as “fear mongering” and there is a belief that “covid-19 is over”.

Business Leadership South Africa chief executive Busi Mavuso said the fifth wave will test the government’s new COVID regulations.

Writing in her weekly open letter, Mavuso noted South Africa is currently in the 30 day transition period from the end of the state of disaster on 5 April and the new National Health Act regulations.

She noted some risk, with mistakes from earlier regulations being built upon. However, increased background immunity levels was credited with the reduced impact of the Omicron wave in hospitalisation and deaths. Based on the assumption that the new wave will be less impactful, economically damaging measures can be avoided.

Mavuso added that the previous waves have proven that the country can find the best balance in managing the pandemic and the economy if there is full consultation so that the consequences of regulations can be understood and planned for. “I look forward to engaging our public sector counterparts to find that balance.”

Wits University’s Professor Shabir Madhi said that with a clear increase in cases, the country was on the cusp of a resurgence. The country will however be much better positioned with higher immunity levels and a demonstrated decoupling of infections and disease severity.

Further lockdowns would likely be unnecessary, given how past lockdowns have repeatedly failed.