- Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters Nature.com
- Pre-existing immunity shapes mucosal SARS-CoV-2-specific antibody responses News-Medical.Net
- Do COVID-19 Monoclonal Antibody Treatments Really Work? What Two Years of Patient Data Reveal SciTechDaily
- Fc-γR-dependent antibody effector functions are required for vaccine-mediated protection against antigen-shifted variants of SARS-CoV-2 Nature.com
- Study identifies ultra-broad SARS-CoV-2 neutralizing antibodies that target various spike epitopes News-Medical.Net
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Tag Archives: Variants
Statement on the update of WHO’s working definitions and tracking system for SARS-CoV-2 variants of concern and variants of interest – who.int
- Statement on the update of WHO’s working definitions and tracking system for SARS-CoV-2 variants of concern and variants of interest who.int
- Potential recombination between SARS-CoV-2 and MERS-CoV: calls for the development of Pan-CoV vaccines | Signal Transduction and Targeted Therapy Nature.com
- Spike-induced humoral immunity and its association with antibody-dependent cellular cytotoxicity potency News-Medical.Net
- Study Identifies Human Genes Enabling SARS-CoV-2 Infection Weill Cornell Medicine Newsroom
- Tracking SARS-CoV-2 variants and resources Nature.com
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Emergence and spread of two SARS-CoV-2 variants of interest in Nigeria – Nature.com
- Emergence and spread of two SARS-CoV-2 variants of interest in Nigeria Nature.com
- Changes in SARS-CoV-2 antibody titers after COVID-19 vaccination News-Medical.Net
- Breakthrough SARS-CoV-2 infections among patients with cancer following two and three doses of COVID-19 mRNA vaccines: a retrospective observational study from the COVID-19 and Cancer Consortium The Lancet
- Influenza A virus suppresses SARS-CoV-2 replication during co-infection News-Medical.Net
- SARS-CoV-2 rebound with and without antivirals The Lancet
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New COVID Variants Are Escaping the Immune System. Here’s What That Means.
BA.5, BQ.1.1, and XBB? It’s no wonder people are struggling to keep all the circulating variants of COVID-19 straight right now. Whether you want to call them “alphabet soup,” “Scrabble,” or “Kraken,” we’ve been reminded time and again that it’s not the name of the subvariant that matters, but rather the way it interacts with our immune systems. And as we enter into our fourth year with COVID-19, scientists are most concerned with how well prior infections, vaccinations, and boosters can protect us against emerging variants of the virus.
The answers are starting to roll in—and they’re not looking great for us. In a letter published on Jan. 18 in The New England Journal of Medicine, researchers from Beth Israel Deaconess Medical Center and Los Alamos National Laboratory detail the nasty abilities of variants BQ.1.1 and XBB.1 to escape incapacitation from COVID-specific antibodies. This is cause for concern because as the authors wrote, these variants “may reduce the efficacy of current mRNA vaccines.”
Before Aug. 31 in the U.S., available COVID-19 boosters were monovalent, meaning they contained viral genetic material from one strain of the virus. The updated boosters are bivalent and were created with genetic material from the original COVID-19 strain as well as Omicron variant strains with the hope of offering better protection against new and emerging variants.
Unfortunately, these early data seem to show that two of the newest variants can dodge even the bivalent boosters. In their study, the researchers took serum samples from 16 people who received a monovalent booster in 2021, 15 who received a monovalent booster in 2022, and 18 people who received a bivalent booster in September 2022. In all three cohorts, the concentration of neutralizing antibodies—which immobilize copies of the virus and prevent them from infecting cells—fighting the original Wuhan strain shot up after participants received boosters, from the hundreds or thousands to the tens of thousands.
But their immune response against some of the newest viral variants was severely diminished, even compared to ones that came directly before. The authors found that neutralizing antibody concentrations to variants BQ.1.1 and XBB.1 were between 53 and 232 times lower than those to the original strain of COVID-19, depending on the booster received. These variants were even better than a recent Omicron variant at evading the immune system and escaping neutralizing antibodies.
On Jan. 11, the World Health Organization released a risk assessment about XBB.1.5, writing that BQ and XBB variants are “the most antibody-resistant variants to date” but cautioning that “[t]here is currently no data on real world vaccine effectiveness against severe disease or death” for these variants.
It’s clear that these variants aren’t good news, but future research is needed to suss out just how bad they will turn out to be. This study is one early indication that as sick as we might be of the COVID-19 pandemic, we aren’t out of the woods just yet.
Off-Patent Liver Disease Drug Could Stop COVID-19 and Protect Against Future Variants
Researchers at Cambridge University have found that a previously existing, off-patent medication may be effective in preventing COVID-19 and potentially guarding against future variants of the virus. The discovery was made through a combination of experiments using mini-organs, donor organs, animal studies, and patient data.
Unique experiments involved ‘mini-organs’, animal research, donated human organs, volunteers, and patients.
- Cambridge scientists have shown that a widely-used drug to treat liver disease can prevent
Cambridge scientists have identified an off-patent drug that can be repurposed to prevent COVID-19 – and may be capable of protecting against future variants of the virus – in research involving a unique mix of ‘mini-organs’, donor organs, animal studies, and patients.
The research, published recently in the journal Nature, showed that an existing drug used to treat a type of liver disease is able to ‘lock’ the doorway by which SARS-CoV-2 enters our cells, a receptor on the cell surface known as ACE2. Because this drug targets the host cells and not the virus, it should protect against future new variants of the virus as well as other coronaviruses that might emerge.
If confirmed in larger clinical trials, this could provide a vital drug for protecting those individuals for whom vaccines are ineffective or inaccessible as well as individuals at increased risk of infection.
Dr. Fotios Sampaziotis, from the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge and Addenbrooke’s Hospital, led the research in collaboration with Professor Ludovic Vallier from the Berlin Institute of Health at Charité.
Bile duct/liver organoid infected with SARS-CoV-2 – red indicates the virus. Credit: Teresa Brevini
Dr. Sampaziotis said: “Vaccines protect us by boosting our immune system so that it can recognize the virus and clear it, or at least weaken it. But vaccines don’t work for everyone – for example patients with a weak immune system – and not everyone has access to them. Also, the virus can mutate into new vaccine-resistant variants.
“We’re interested in finding alternative ways to protect us from SARS-CoV-2 infection that are not dependent on the immune system and could complement vaccination. We’ve discovered a way to close the door to the virus, preventing it from getting into our cells in the first place and protecting us from infection.”
From mini-organs and animals…
Dr. Sampaziotis had previously been working with organoids – ‘mini-bile ducts’ – to study diseases of the bile ducts. Organoids are clusters of cells that can grow and proliferate in culture, taking on a 3D structure that has the same functions as the part of the organ being studied.
Using these, the researchers found – rather serendipitously – that a molecule known as FXR, which is present in large amounts in these bile duct organoids, directly regulates the viral ‘doorway’ ACE2, effectively opening and closing it. They went on to show that ursodeoxycholic
Perfused lung. Credit: Teresa Brevini
In this new study, his team showed that they could use the same approach to close the ACE2 doorway in ‘mini-lungs’ and ‘mini-guts’ – representing the two main targets of SARS-CoV-2 – and prevent viral infection.
The next step was to show that the drug could prevent infection not only in lab-grown cells but also in living organisms. For this, they teamed up with Professor Andrew Owen from the University of Liverpool to show that the drug prevented infection in hamsters exposed to the virus, which are used as the ‘gold-standard’ model for pre-clinical testing of drugs against SARS-CoV-2. Importantly, the hamsters treated with UDCA were protected from the delta variant of the virus, which was new at the time and was partially resistant to existing vaccines.
Professor Owen said: “Although we will need properly-controlled randomized trials to confirm these findings, the data provide compelling evidence that UDCA could work as a drug to protect against COVID-19 and complement vaccination programs, particularly in vulnerable population groups. As it targets the ACE2 receptor directly, we hope it may be more resilient to changes resulting from the evolution of the SARS-CoV-2 spike, which result in the rapid emergence of new variants.”
… to human organs…
Next, the researchers worked with Professor Andrew Fisher from Newcastle University and Professor Chris Watson from Addenbrooke’s hospital to see if their findings in hamsters held true in human lungs exposed to the virus.
The team took a pair of donated lungs not suitable for transplantation, keeping them breathing outside the body with a ventilator and using a pump to circulate blood-like fluid through them to keep the organs functioning while they could be studied. One lung was given the drug, but both were exposed to SARS-CoV-2. Sure enough, the lung that received the drug did not become infected, while the other lung did.
Professor Fisher said: “This is one of the first studies to test the effect of a drug in a whole human organ while it’s being perfused. This could prove important for organ transplantation – given the risks of passing on COVID-19 through transplanted organs, it could open up the possibility of treating organs with drugs to clear the virus before transplantation.”
… to people
Moving next to human volunteers, the Cambridge team collaborated with Professor Ansgar Lohse from the University Medical Centre Hamburg-Eppendorf in Germany.
Professor Lohse explained: “We recruited eight healthy volunteers to receive the drug. When we swabbed the noses of these volunteers, we found lower levels of ACE2, suggesting that the virus would have fewer opportunities to break into and infect their nasal cells – the main gateway for the virus.”
While it wasn’t possible to run a full-scale clinical trial, the researchers did the next best thing: looking at data on COVID-19 outcomes from two independent cohorts of patients, comparing those individuals who were already taking UDCA for their liver conditions against patients not receiving the drug. They found that patients receiving UDCA were less likely to develop severe COVID-19 and be hospitalized.
A safe, affordable variant-proof drug
First author and PhD candidate Teresa Brevini from the University of Cambridge said: “This unique study gave us the opportunity to do really translational science, using a laboratory finding to directly address a clinical need.
“Using almost every approach at our fingertips we showed that an existing drug shuts the door on the virus and can protect us from COVID-19. Importantly, because this drug works on our cells, it is not affected by mutations in the virus and should be effective even as new variants emerge.”
Dr. Sampaziotis said the drug could be an affordable and effective way of protecting those for whom the COVID-19 vaccine is ineffective or inaccessible. “We have used UDCA in clinic for many years, so we know it’s safe and very well tolerated, which makes administering it to individuals with high COVID-19 risk straightforward.
“This tablet costs little, can be produced in large quantities fast and easily stored or shipped, which makes it easy to rapidly deploy during outbreaks – especially against vaccine-resistant variants, when it might be the only line of protection while waiting for new vaccines to be developed. We are optimistic that this drug could become an important weapon in our fight against COVID-19.”
Reference: “FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2” by Teresa Brevini, Mailis Maes, Gwilym J. Webb, Binu V. John, Claudia D. Fuchs, Gustav Buescher, Lu Wang, Chelsea Griffiths, Marnie L. Brown, William E. Scott III, Pehuén Pereyra-Gerber, William T. H. Gelson, Stephanie Brown, Scott Dillon, Daniele Muraro, Jo Sharp, Megan Neary, Helen Box, Lee Tatham, James Stewart, Paul Curley, Henry Pertinez, Sally Forrest, Petra Mlcochova, Sagar S. Varankar, Mahnaz Darvish-Damavandi, Victoria L. Mulcahy, Rhoda E. Kuc, Thomas L. Williams, James A. Heslop, Davide Rossetti, Olivia C. Tysoe, Vasileios Galanakis, Marta Vila-Gonzalez, Thomas W. M. Crozier, Johannes Bargehr, Sanjay Sinha, Sara S. Upponi, Corrina Fear, Lisa Swift, Kourosh Saeb-Parsy, Susan E. Davies, Axel Wester, Hannes Hagström, Espen Melum, Darran Clements, Peter Humphreys, Jo Herriott, Edyta Kijak, Helen Cox, Chloe Bramwell, Anthony Valentijn, Christopher J. R. Illingworth, UK-PBC research consortium, Bassam Dahman, Dustin R. Bastaich, Raphaella D. Ferreira, Thomas Marjot, Eleanor Barnes, Andrew M. Moon, Alfred S. Barritt IV, Ravindra K. Gupta, Stephen Baker, Anthony P. Davenport, Gareth Corbett, Vassilis G. Gorgoulis, Simon J. A. Buczacki, Joo-Hyeon Lee, Nicholas J. Matheson, Michael Trauner, Andrew J. Fisher, Paul Gibbs, Andrew J. Butler, Christopher J. E. Watson, George F. Mells, Gordon Dougan, Andrew Owen, Ansgar W. Lohse, Ludovic Vallier and Fotios Sampaziotis, 5 December 2022, Nature.
DOI: 10.1038/s41586-022-05594-0
The research was largely funded by UK Research & Innovation, the European Association for the Study of the Liver, the NIHR Cambridge Biomedical Research Centre and the Evelyn Trust.
Head Trauma and PTSD May Increase Genetic Variant’s Impact on Alzheimer’s Risk
Summary: The risk of developing Alzheimer’s disease and dementia-related symptoms is higher in those with TBI and PTSD who carry the APOE E4 gene.
Source: Veterans Affairs Research Communications
In a study of Veterans led by Dr. Mark Logue, a statistician in the National Center for PTSD at the VA Boston Healthcare System, researchers concluded that PTSD, TBI, and the ε4 variant of the APOE gene show strong associations with Alzheimer’s disease and related dementias (ADRD).
The medical community has never researched the simultaneous impact of post-traumatic stress disorder (PTSD), traumatic brain injury (TBI) and genetic risk factors in a large cohort until now. They first found a greater percentage of ADRD in Veterans with PTSD and in those with TBI, relative to those without, as well as higher rates of ADRD in Veterans who had inherited the ε4 variant. Logue and his team then looked for interactions between the ε4 variant, PTSD, and TBI using a mathematical model.
The study found an increase in risk due to PTSD and TBI in Veterans of European ancestry who inherited the ε4 variant. In Veterans of African ancestry, the impact of PTSD didn’t vary as a function of ε4, but the TBI effect and interaction with ε4 was even stronger. Other studies have suggested that ε4 may magnify the effects of a head injury and/or combat-related stress.
“These additive interactions indicate that ADRD prevalence associated with PTSD and TBI increased with the number of inherited APOE ε4 alleles,” Logue and his colleagues wrote. “PTSD and TBI history will be an important part of interpreting the results of ADRD genetic testing and doing accurate ADRD risk assessment.”
Capitalizing on VA’s Million Veteran Program
The researchers carried out the study by accessing data from VA’s Million Veteran Program (MVP), one of the world’s largest databases of health and genetic information. MVP is aimed at learning how genes, lifestyle, and military exposures affect health and illness, with more than 900,000 Veterans enrolled in its climb to 1 million and beyond.
With more than 40% of the Veteran population above the age of 75, the number of former Service Members at risk for Alzheimer’s and other forms of dementia is rising. While large cohort studies have shown that PTSD and TBI increase the risk of dementia in Veterans, Logue and his colleagues investigated further by studying these risk factors along with the APOE ε4 variant. Most people don’t inherit that variant, but those who do inherit it from one parent (one copy) or both of their parents (two copies).
“Research has shown that if you inherit one copy of ε4, you’re at increased risk of Alzheimer’s disease,” he said, “and if you inherit two copies, you are at much higher risk.”
The number of ε4 variants a person inherits is fixed at birth, but their impact differs with age, according to Logue, who is also an Army Veteran and an associate professor at Boston University.
“The risk of Alzheimer’s disease increases with age for all of the APOE genotypes,” he said. “But when compared to people with two copies of the common variant, the difference in risk for those with a copy of ε4 appears to peak somewhere between age 65 and 70 and then decrease after that. Again, that doesn’t mean that your chances of Alzheimer’s decrease after that, just that the difference between the risk for those with and without ε4 diminishes.”
The study showed that the risk associated with PTSD and head injury was larger for ε4 carriers. Their model led the researchers to expect that for 80-year-old Veterans of European ancestry who didn’t inherit the ε4 variant, the percentage of ADRD would be 6% greater for those with PTSD compared to those without. But for 80-year-old Veterans of European ancestry who inherited two copies of ε4, the percentage of ADRD would be 11% higher for those with PTSD than those without.
Clear link between PTSD, TBI on dementia risk a surprise
Logue was most surprised to see such clear evidence of a link between PTSD and head trauma on dementia risk.
“I’ve worked in Alzheimer’s disease genetics for over a decade now, and I was used to seeing a clear impact of APOE ε4 on Alzheimer’s risk,” he says. “However, in this cohort, the effects of PTSD and head injury were just as clear and looked similar to the effect of inheriting ε4 from one of your parents.”
Next, Logue and his colleagues would like to use MVP data to research other risk factors that are relevant to Veterans, with the goal of learning how they may interact with Alzheimer’s risk variants. They are also looking to do genome-wide association scans to try to find new Alzheimer’s and dementia risk variants. The most recent large-scale genome-wide association study of Alzheimer’s identified some 80 variants linked to the risk of Alzheimer’s, Logue said, noting that those variants were rare or had a much smaller impact than ε4.
MVP data can be used to boost power for this type of study, he added, but PTSD and TBI history will be an important part of interpreting the results of ADRD genetic testing and conducting accurate ADRD risk assessments.
“We know that genes play a large role in Alzheimer’s risk, but they don’t tell the whole story,” Logue explained.
“Right now, no genetic test can tell you if you’re certain to develop Alzheimer’s disease. Tests can only give an estimate of your likelihood of developing Alzheimer’s that may be higher or lower than average. Our study shows that these estimates will be more accurate if they incorporate more than just age and genetics.
See also
“In Veterans, a history of head injuries and PTSD can also make a large difference in dementia risk, so using that information will allow for more accurate measurement of the chances of developing dementia.”
About this neurology research news
Author: Mike Richman
Source: Veterans Affairs Research Communications
Contact: Mike Richman – Veterans Affairs Research Communications
Image: The image is in the public domain
Original Research: Open access.
“Alzheimer’s disease and related dementias among aging veterans: Examining gene‐by‐environment interactions with post‐traumatic stress disorder and traumatic brain injury” by Mark W. Logue et al et al. Alzheimer’s & Dementia
Abstract
Alzheimer’s disease and related dementias among aging veterans: Examining gene‐by‐environment interactions with post‐traumatic stress disorder and traumatic brain injury
Introduction
Post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) confer risk for Alzheimer’s disease and related dementias (ADRD).
Methods
This study from the Million Veteran Program (MVP) evaluated the impact of apolipoprotein E (APOE) ε4, PTSD, and TBI on ADRD prevalence in veteran cohorts of European ancestry (EA; n = 11,112 ADRD cases, 170,361 controls) and African ancestry (AA; n = 1443 ADRD cases, 16,191 controls). Additive-scale interactions were estimated using the relative excess risk due to interaction (RERI) statistic.
Results
PTSD, TBI, and APOE ε4 showed strong main-effect associations with ADRD. RERI analysis revealed significant additive APOE ε4 interactions with PTSD and TBI in the EA cohort and TBI in the AA cohort. These additive interactions indicate that ADRD prevalence associated with PTSD and TBI increased with the number of inherited APOE ε4 alleles.
Discussion
PTSD and TBI history will be an important part of interpreting the results of ADRD genetic testing and doing accurate ADRD risk assessment.
An ACE2 decoy irreversibly inactivates SARS-CoV-2, even antibody-resistant variants
I have to admit it: I am very tired of COVID-19, stories about it, and everything related to it. Enough already! I thoroughly do not relish this topic. We all want to move on, even if COVID apparently doesn’t.
But I do like to see an innovative approach that sticks it to a disease, and that’s what we’ve got here. Researchers from the Dana Farber Cancer Institute, Harvard University, Boston University, Colorado State University, and Massachusetts General Hospital have devised a therapeutic protein that mimics SARS-CoV-2’s point of attack — the ACE2 receptor — not only distracting the virus from binding real ACE2 receptors, but irreversibly inactivating it. Check it out in the open-access December 7 article in Science Advances.
Vaccines are the first line of defense, of course, so stay up to date! I’ll always remember my first one against COVID, at Gillette Stadium (even though I’m not exactly a Patriots fan). The fact that a huge urban community could come together and direct its resources and facilities for the common good like that was really inspirational to me.
But I’ve thought all along that the best second line of defense against this thing is not so much using antibodies, but tricking it into attaching to something it thinks is the ACE2 receptor, a protein that normally can be found sticking up out of the surface of human cells in the lungs, heart, kidneys, and intestine. This study shows the soundness of that approach but then also takes it a step further.
It turns out that when the SARS-CoV-2 virus fully engages with a real ACE2 receptor, its spike protein — which you see sticking out of the virus in all those endless images of it — undergoes an irreversible change that commits it to invading the cell but eliminates its further ability to attach to an ACE2 receptor. The spike protein actually breaks apart into two pieces, and the one that can attach to ACE2 is forever lost:
If we could design an ACE2 decoy the right way, then, maybe the virus would attach to it and be fooled into thinking it has attacked a cell, and the spike protein would undergo the same irreversible breakup and wouldn’t be able to go after cells anymore. The more spike proteins we could hit on a viral particle, the lamer it would become:
Going into this research, this was an aspect that wasn’t clear. Would an ACE2 decoy be able to not only attach to the virus, but also to trick it into inactivating itself in practice?
If so, we’d have a couple of key advantages over antibodies.
Therapeutic antibodies against SARS-CoV-2 are directed at the spike protein, too, and that totally makes sense because that’s what you want to interfere with, so the virus can’t attack your cells. But antibodies attach to the spike protein in whatever random way they end up doing it, not by mimicking ACE2. So while a garden-variety antibody will stick to the virus just fine, it won’t cause this irreversible and disabling change because the virus doesn’t think it’s found an ACE2; it just thinks it has a big piece of gum stuck to its face.
The other thing is, the spike protein evolves quickly, so an antibody that works great on one variant might do poorly with a new variant. We have definitely seen that in practice. Omicron, for example, is pretty resistant to a number of antibodies that worked on older variants like Delta, because Omicron’s spike protein has evolved a lot; it’s got more than 30 mutations in it! So those old antibodies don’t recognize it anymore. Even Paxlovid, a small-molecule antiviral, is losing its grip on newer variants as well.
But no matter how much a virus changes, its spike protein had better keep its ability to stick to human ACE2. If it doesn’t, that virus goes straight into the evolutionary dustbin. So, if we can design a decoy that looks just like ACE2 to the virus and also has good stability and safety in the body, then we’ll have a weapon that works against all variants of SARS-CoV-2, new and old, no matter how much they evolve, and in fact even against other nasty coronaviruses that might arise in the future.
OK then, so what does a good ACE2 decoy need to have? It’s got to…
- Look a lot like ACE2 so that all viral variants recognize it and want to go after it
- Be free to float around, not be attached to cells like real ACE2
- Have a reasonably long life in the body
- Be able to penetrate into tissues where the virus may be hiding
- Avoid having the blood-altering functions of real ACE2, so we don’t overdo that
- Not cause an immune-response apocalypse in the patient
Part 1 is pretty straightforward. We know what ACE2 looks like when it’s in place and working on the surface of a cell (see the main diary picture). So we’ve got to keep the part that sticks to the spike protein intact. The main question is, how much of it should we keep? The authors tried a few different things there, and truthfully that’s a bit of trial and error. But in the end they found that it worked better when they kept more of the ACE2 protein, even the parts that the spike protein doesn’t attach to.
We can actually hit parts 2, 3, and 4 all at once by combining our ACE2 decoy with the bottom half of an antibody (its “Fc” region). That sets up our decoy to behave like a conventional antibody, except with its business end designed by us. Here’s how a natural antibody compares to this “Fc fusion” we’ll make:
Like any other antibody, this Fc-fusion decoy will be soluble, it’ll hang around for a while, and it will be able to penetrate most tissues, even the placenta.
Part 5 isn’t too hard. ACE2’s important job, when it’s not being commandeered by viruses, is to modify hormones that regulate blood pressure. So unless there were some benefit to changing that, which has never been demonstrated, we’d rather not play around with it by adding a ton of active ACE2 all over the place. Luckily, all we have to do is change two amino acids in our ACE2 decoy to make it inactive but still keep its ACE2-like structure.
And Part 6, the immune apocalypse! When an antibody sticks to something, its Fc region can attract a rogues’ gallery of cells from the immune system to attack said thing:
But again, in the spirit of not messing around too much, the authors tweaked Fc (once again with two specific amino acid changes) so it doesn’t have that ability. Not to say that’s necessarily the best choice; others have left Fc alone and let it be active in their Fc-fusion designs. The question is, do we want to encourage an inflammatory response in a patient that’s already got lots of inflammation due to COVID-19? So I’d say I agree with the authors here that we should put active Fc on the backburner. Let’s just hobble the virus particles and leave it at that for the time being.
So, how did the ACE2 decoy perform? First of all, in human cells, it neutralized “original” SARS-CoV-2 (WA01/2020) very well, as did a panel of common anti-COVID therapeutic antibodies (sotrovimab, cilgavimab, tixagevimab, casirivimab, and imdevimab). But against Omicron, all those others lost a lot of their potency, as the FDA has also observed and warned about, but the ACE2 decoy actually gained potency. The decoy was shown to attach effectively to Alpha, Beta, Gamma, Delta, Epsilon, and Omicron variants.
It also had a respectable half-life in the blood serum of hamsters of 52 hours. That’s not as good as a real antibody, but it’s not bad either.
And the answer to the other big question — Can the ACE2 decoy cause the spike protein to change irreversibly like real ACE2 can? — was yes. The decoy was shown to cause the S1 and S2 components of the spike protein to break apart from each other, more so at higher doses, and not at all when no decoy was added.
So clinical trials are up next, and we do have reason for optimism there. As of 2020, there were 13 FDA-approved drugs of the Fc-fusion type, so it’s not like we’re in uncharted waters. We know this approach can be safe and effective, and hopefully this one follows the same trajectory.
As always, I don’t mean to imply that this is the only group studying this or that it’s going to singlehandedly solve all the world’s problems, but I just want to give a flavor of what is going on in this field, what the thinking is, and where it seems to be going.
But if it’s successful, we’ll have an approach that’s no longer subject to the whims of a mutating virus but instead sets a booby trap at the only door the virus can use to get in. And it’ll give us a blueprint to help us be better prepared against future viral pandemics. Silver lining!
Scientists Fear BQ.1 COVID Variants Are Deadly Like the 2020 Wave
The new COVID-19 subvariants that are becoming dominant all over the world aren’t just more contagious than previous variants and subvariants—they might cause more severe disease, too.
That’s an ominous sign if, as experts predict, there’s a new global wave of COVID in the coming months. It’s one thing to weather a surge in infections that mostly results in mild disease. Cases go up but hospitalizations and deaths don’t. But a surge in serious disease could lead to a surge in hospitalizations and deaths, too.
It could be like 2020 or 2021, all over again. The big difference is that we now have easy access to safe and effective vaccines. And the vaccines still work, even against the new subvariants.
A new study from The Ohio State University is the first red flag. A team led by Shan-Lu Liu, co-director of HSU’s Viruses and Emerging Pathogens Program, modeled new SARS-CoV-2 subvariants including BQ.1 and its close cousin, BQ.1.1.
The team confirmed what we already knew: BQ.1 and other new subvariants, most of them the offspring of the BA.4 and BA.5 forms of the Omicron variant, are highly contagious. And the same mutations that make them so transmissible also make them unrecognizable to the antibodies produced by monoclonal therapies, rendering those therapies useless.
That should be reason enough to pay close attention as BQ.1 and its cousins outcompete BA.4 and BA.5 and become dominant in more countries and states. But then Liu and his teammates also checked the subvariants’ “fusogenicity.” That is, how well they fuse to our own cells. “Fusion between viral and cellular membrane is an important step of viral entry,” Liu told The Daily Beast.
In general, the greater the fusogenicity, the more severe the disease. Liu and his colleagues “observed increased cell-cell fusion in several new Omicron subvariants compared to their respective parental subvariants,” they wrote in their study, which appeared online on Oct. 20 and is still under peer review at New England Journal of Medicine.
If these new subvariants are indeed more transmissible and more severe, they could reverse an important trend as the COVID pandemic grinds toward its fourth year. The trend, so far, has for each successive major variant or subvariant to be more contagious but cause less severe disease.
That trend, combined with widespread vaccination and new therapies, led to what scientists call a “decoupling” of infections and deaths. COVID cases occasionally spike as some new, highly-contagious new variant or subvariant becomes dominant. But because these new forms of SARS-CoV-2 cause less severe disease, deaths don’t increase nearly as much.
That decoupling, along with the availability of vaccines and therapies, has allowed most people all over the world to get back to some kind of normal in the past year or so. If BQ.1 or another highly fusogenic subvariant re-couples infections and deaths, that new normal could become a new nightmare. “More hospitalizations and deaths,” is how Ali Mokdad, a professor of health metrics sciences at the University of Washington Institute for Health who was not involved in the OSU study, summed it up.
It’s possible we’ve already seen the first recoupling. Since the new subvariants began seriously competing for dominance in recent months, epidemiologists watched COVID statistics carefully in order to spot any real-world impacts.
Singapore was a false flag. The tiny Asian city-state had a quick, up-and-down surge in cases this month that some experts initially worried might involve a dangerous new subvariant. But the country’s health ministry sequenced a lot of viral samples, fast, and determined that BA.5 was the culprit. Singapore’s high rate of vaccination and boosting—92 percent of residents have their prime jabs and 80 percent are boosted—tamped down the BA.5 surge without a major spike in deaths.
But then there’s Germany, where cases also surged this month. German authorities haven’t yet determined which variant or subvariant is to blame, but it’s worth noting that BQ.1 is spreading fast all over Europe.
And there are signs of recoupling in Germany. In October, the country registered as many as 175,000 new cases a day—matching the peak of the previous wave back in July. But 160 Germans died every day on average in the worst week of the current surge, whereas just 125 died per day in the worst week of the summer surge. “We could see the same patterns in other European countries… and in the U.S.,” Mokdad said.
There’s still a lot we don’t know about the latest COVID subvariants. And their real-world impact won’t come into focus until we get good data out of Germany. “Close monitoring of new variants and studying their properties are critical,” Liu said.
But one thing is clear. For all their transmissibility and fusogenicity, the new subvariants haven’t significantly escaped the immune effects of the leading vaccines. And the latest “bivalent” boosters, formulated specifically for BA.4 and BA.5, should maintain the vaccines’ effectiveness as long as the dominant subvariants are closely related to Omicron.
Get vaccinated and stay current on your boosters. It’s impossible to stress this too much. Yes, BQ.1 and its cousins exhibit some alarming qualities that could bend the arc of the pandemic back toward widespread death and disruption.
But only if you’re unvaccinated or way behind on your boosters.
These COVID symptoms are now the most common as variants evolve
Don’t shrug off that sneeze or scratch at the back of your throat. As
coronavirus
variants continue to evolve and become more difficult to detect, so do COVID symptoms, allowing more people to spread the virus without realizing it.
Signs of infection are increasingly hard to tell apart from symptoms of a common cold or flu, according to the latest update from the ongoing
Zoe Health Study, a joint project by
researchers
at Harvard, Stanford, and King’s College in London.
A mild runny nose, headache or sore throat could now precede a positive test result with one of the many offshoots of omicron.
Other indicators commonly reported during earlier phases of the pandemic, such as loss of taste and smell, have dropped down the list.
In addition to finding generally milder symptoms caused by omicron than earlier variants, the study showed that symptoms also varied by vaccination status.
For example, nasal congestion is the third-most-frequently-cited symptom in people who have completed their initial two-dose vaccination series, while those who have only received one jab reported sneezing, and for the unvaccinated, it’s fever.
“What changed is people’s overall immunity,” said Peter Chin-Hong, an infectious disease expert at UCSF who was not involved with the study. “On a continuous scale, as their bodies become more experienced with COVID, the symptoms are milder overall.”
In other words, the threat of the virus remains unchanged. But thanks to widespread immunity derived from the vaccines and prior infection, most people are now better equipped to fight off the most severe manifestations of the disease.
“Through painful steps — many deaths and millions of infections — as a population our immune system has become stronger and smarter,” said Jorge Salinas, an epidemiologist at Stanford, who was also not involved in the study. “Humans are not the same as in 2020. We now can recognize the virus and modulate the response to infection.”
Breaking down the data into three categories — fully vaccinated, partially vaccinated, and unvaccinated — the Zoe Health researchers found the four most commonly reported symptoms of COVID-19 among all the groups now are sore throat, runny nose, a persistent cough and headache.
“Generally, we saw similar symptoms of COVID-19 being reported overall in the app by people who had and hadn’t been vaccinated,” the researchers wrote. “However, fewer symptoms were reported over a shorter period of time by those who had already had a jab, suggesting that they were falling less seriously ill and getting better more quickly.”
So how did the lists differ? Here are the top symptoms by each group, based on daily data gathered by the U.K.-based Zoe app.
Fully vaccinated
1. Sore throat
2. Runny nose
3. Blocked nose
4. Persistent cough
5. Headache
One vaccine dose
1. Headache
2. Runny nose
3. Sore throat
4. Sneezing
5. Persistent cough
Unvaccinated
1. Headache
2. Sore throat
3. Runny nose
4. Fever
5. Persistent cough
Despite the evolving nature of the virus, the
Centers for Disease Control and Prevention website
still highlights loss of smell, shortness of breath and fever on its list of tell-tale signs of infection, even though they ranked at Nos. 6, 29, and 8, respectively, on the Zoe list for vaccinated individuals.
“A persistent cough now ranks at number 5 if you’ve had two vaccine doses, so is no longer the top indicator of having COVID,” the researchers said.
A
yearlong study
earlier this year of more than 60,000 people tested for the coronavirus in San Francisco found similar shifts in
COVID-19 symptoms
over time — including fewer reports of loss of smell, once considered a trademark of the illness.
More people reported symptoms of upper respiratory infection during the omicron surge than in earlier waves, according to the researchers at UCSF and the Chan Zuckerberg Biohub in coordination with
the San Francisco Latino Task Force. Patients also experienced fewer instances of systemic issues such as fever and body aches.
“Our report and others showed a transition happened with most common clinical symptoms with omicron to higher proportion of persons with congestion, more common to have sore throat, and less common to have loss of smell or taste compared to delta and prior variant,” said Dr. Diane Havlir, a UCSF infectious disease expert and senior author of the San Francisco study.
Salinas said these changes are to be expected: “It’s beginning to behave like other respiratory viruses.”
But as COVID-19 symptoms become milder and easier to ignore, the urgency to test becomes greater. Public health officials anticipate another swell in cases this winter with people spending more time indoors and traveling for the holidays.
Detecting positive cases early is vital to slowing the spread of the virus and preventing more immune-evasive strains of the virus from emerging.
There’s no guarantee that future variants will continue to cause milder disease, even among the vaccinated.
Chin-Hong said testing is also a good safeguard for high-risk individuals, especially if they run into potential delays in procuring treatments such as the in-demand antiviral medication Paxlovid.
“A lot of people are not getting diagnosed now because they don’t think it’s a big deal,” he said. “But getting a diagnosis will open the door to getting therapy.”
A previous version of this story misstated the most common symptoms for unvaccinated people and those with one dose.
Aidin Vaziri (he/him) is a San Francisco Chronicle staff writer. Email: avaziri@sfchronicle.com
Omicron BA.5 is declining as emerging variants gain ground: CDC data
The U.S. faces at least seven different versions of Covid-19 omicron as the nation heads into winter when health officials are expecting another wave of viral infections.
Although the omicron BA.5 variant remains dominant in the country, it is starting to lose some ground to other versions of the virus, according to data from the Centers for Disease Control and Prevention published on Friday.
Omicron BA.5 has splintered into several new but related variants that include BQ.1, BQ.1.1 and BF.7. The U.K. Health Security Agency, in a report earlier this month, said these three variants are demonstrating a growth advantage over BA.5, which was the most contagious version to date.
In the U.S., omicron BA.5 makes up about 68% of all new infections, down from about 80% at the beginning of October. BQ.1, BQ.1.1 and BF.7 are now causing about 17% of new infections combined, according to the CDC data.
About 3% of new infections are attributable to BA.2.75. and BA.2.75.2, which are related to the omicron BA.2 variant that caused a bump in cases during the spring but was pushed out.
Scientists at Peking University in China found that omicron BA.2.75.2 and BQ.1.1 were the most adept at evading immunity from prior BA.5 infection and several antibody drugs. The study, published earlier in October, has not been peer reviewed.
Dr. Ashish Jha, the White House Covid response coordinator, said earlier this week that U.S. health officials are closely monitoring these variants because they are good at evading prior immunity.
“The reason we’re tracking them is because they either have a lot more immune invasiveness or they render many of our treatments ineffective,” Jha said. “Those are the two major things that get our attention.”
But Jha said the new omicron boosters that the U.S. started rolling out last month should provide better protection than the first-generation vaccines against these emerging variants. The boosters target BA.5 and the emerging variants are all omicron and most descend from BA.5.
Jha called on all eligible Americans to get the new boosters by Halloween so they will have full protection for Thanksgiving when family holiday gatherings kick into full swing.
But the scientists at Peking University said the immune evasiveness of variants like BA.2.75.2 and BQ.1.1 could mean that the BA.5 booster shots will not provide sufficiently broad protection.
It’s unclear how much more effective the boosters will prove in the real world. The Food and Drug Administration authorized the shots without direct human data, relying instead on clinical trials from a similar shot that was developed against the original version of omicron, BA.1.
Pfizer and BioNTech on Thursday published the first human data from their BA.5 shots. They triggered a significant boost to the immune system against omicron BA.5 in a lab study that looked at blood samples from adults ages 18 and older, the companies said.