📆 October 2020 📰 An autoimmune-like antibody response is linked with severe COVID-19 ✍️ Matthew Woodruff, Emory University
In the earliest days of the pandemic, many immunologists, including me, assumed that patients who produced high quantities of antibodies early in infection would be free from disease. We were wrong.
(...)
Several months into studying COVID-19, like other scientists, I’ve come to realize the picture is far more complicated. A recent research study published by my colleagues and me adds more evidence to the idea that in some patients, preventing dysregulated immune system responses may be as important as treating the virus itself.
I am an immunologist at Emory University working under the direction of Dr. Ignacio Sanz, Emory’s chief of rheumatology. Immune dysregulation is our specialty.
(...)
Antibodies are so powerful that cases of mistaken identity – when a B cell produces antibodies that attack a person’s own cells – can lead to widespread organ damage and establish a perpetual cycle of immune self-targeting. We refer to this state of self-destruction as an autoimmune disease.
To avoid autoimmune disaster, and to ensure effective response against the invading pathogen, B cells undergo a training process. Those that respond to the virus refine their antibodies and mature, ensuring potent antibodies capable of disabling the invader. B cells that target your own tissue are destroyed.
But that maturation process takes time. Two weeks of B cell “training” during a severe infection can mean the difference between life and death. Faster antibody responses are needed. To bridge that gap, the immune system has an alternative form of B cell activation – called extrafollicular activation – that generates fast-acting antibodies that seem to bypass many of the known safety checks that accompany a more precise response.
Extrafollicular responses develop quickly, are short-lived by design and die back when the more targeted responses emerge onto the scene...
Except when they don’t...
Patients suffering from severe COVID-19 may be experiencing a rogue antibody response similar to that seen in autoimmune diseases. The findi
📆 17 Nov 2024 📰 Scientists Uncover Hidden Long COVID Cases, Tripling Previous Estimates
Previous diagnostic studies estimated that 7 percent of the population suffers from long COVID. However, a new study using an AI tool developed by Mass General Brigham indicates a significantly higher rate of 22.8 percent.
The AI-based tool can sift through electronic health records to help clinicians identify cases of long COVID. The often-mysterious condition can encompass a litany of enduring symptoms, including fatigue, chronic cough, and brain fog after infection from SARS-CoV-2.
For the purposes of their study, Estiri and colleagues defined long COVID as a diagnosis of exclusion that is also infection-associated. That means the diagnosis could not be explained in the patient’s unique medical record but was associated with a COVID infection. In addition, the diagnosis needed to have persisted for two months or longer in a 12-month follow-up window.
Limitations of the study and AI tool include the fact that health record data the algorithm uses to account for long COVID symptoms may be less complete than the data physicians capture in post-visit clinical notes. Another limitation was the algorithm did not capture the possible worsening of a prior condition that may have been a long COVID symptom. For example, if a patient had COPD that worsened before they developed COVID-19, the algorithm might have removed the episodes even if they were long COVID indicators. Declines in COVID-19 testing in recent years also makes it difficult to identify when a patient may have first gotten COVID-19.
Researchers report that a new AI tool enhances the diagnostic process, potentially identifying more individuals who need care. Previous diag
📆 13 Nov 2024 📰 Researchers Discover COVID-19’s Secret to Evading Early Immune Response
An early and effective immune response is crucial for resolving viral infections and preventing post-infectious complications. The complement system, a pivotal element of antiviral immunity, is a cascade of proteins found in the bloodstream and at mucosal sites, such as the respiratory tract.
Activated through three different pathways, complement facilitates the clearance of virus particles by directly inducing their destruction (lysis). To prevent bystander damage to host cells, complement is rapidly inactivated by a set of host molecules referred to as complement regulatory proteins.
The new study led by Anna Ohradanova-Repic and colleagues from the Center for Pathophysiology, Infectiology, and Immunology at the Medical University of Vienna in collaboration with the team of Heribert Stoiber from the Institute of Virology at the Medical University of Innsbruck shows that SARS-CoV-2 hijacks three of these regulatory proteins, CD55, CD59, and Factor H, and thereby successfully shields itself from complement-mediated lysis.
By propagating SARS-CoV-2 in human cells, the researchers discovered that the virus particles acquire the cellular proteins CD55 and CD59. Further experiments showed that SARS-CoV-2 also binds to Factor H, another complement regulatory protein that is primarily found in the bloodstream.
Confronting the virus particles with active complement revealed that they are partially resistant to complement-mediated lysis. By removing CD55, CD59, and Factor H from the virus surface or inhibiting their biological functions, the researchers could successfully restore complement-mediated clearance of SARS-CoV-2.
The virus takes control of three key host proteins that suppress the activity of the complement system. Researchers at the Medical Universit
📆 22 Oct 2024 📰 New research uncovers how coronavirus evades immune defense 🗞️ News-Medical.Net
The Kobe University virologist Shoji Ikuo says, "The new coronavirus is so infectious that we wondered what clever mechanisms the virus employs to evade the innate immune system so effectively."
Shoji's team previously worked on the immune response to hepatitis viruses and investigated the role of a molecular tag called "ISG15" the innate immune system attaches to the virus's building blocks. Having learned that the novel coronavirus has an enzyme that is especially effective in removing this tag, he decided to use his team's expertise to elucidate the effect of the ISG15 tag on the coronavirus and the mechanism of the virus's countermeasures.
In a paper in the Journal of Virology, the Kobe University-led team is now the first to report that the ISG15 tag gets attached to a specific location on the virus's nucleocapsid protein, the scaffold that packages the pathogen's genetic material. For the virus to assemble, many copies of the nucleocapsid protein need to attach to each other, but the ISG15 tag prevents this, which is the mechanism behind the tag's antiviral action. "However, the novel coronavirus also has an enzyme that can remove the tags from its nucleocapsid, recovering its ability to assemble new viruses and thus overcoming the innate immune response," explains Shoji.
The novel coronavirus shares many traits with the SARS and MERS viruses, which all belong to the same family of viruses. And these viruses, too, have an enzyme that can remove the ISG15 tag. However, Shoji's team found that their versions are less efficient at it than the one in the novel coronavirus. And in fact, it has been reported recently that the previous viruses' enzymes have a different primary target. "These results suggest that the novel coronavirus is simply better at evading this aspect of the innate immune system's defense mechanism, which explains why it is so infectious," says Shoji.
The novel coronavirus SARS-CoV-2 has an enzyme that can counteract a cell's innate defense mechanism against viruses, explaining why it is m
📆 21 Oct 2024 📰 Indian population sees 30 per cent rise in antinuclear antibody positivity flollowing-COVID-19 infection 🗞️ India Economic Times
Antinuclear antibodies (ANA) are proteins produced by the immune system that mistakenly target the body’s own cells. While the immune system typically protects against infections, ANA positivity can lead to tissue damage and result in autoimmune diseases. Conditions such as rheumatoid arthritis, lupus, and thyroid disorders are often associated with ANA positivity and can cause symptoms like inflammation, joint pain, and fatigue. The presence of ANA serves as a key marker for healthcare professionals in diagnosing and monitoring autoimmune disorders.
The prevalence of ANA positivity substantially increased post-COVID. In 2019, the total ANA-positive cases stood at 39.3 per cent, while in 2022, it surged to 69.6 per cent. Females were found to have more positivity compared to males; however, this trend was similar to pre-COVID. The highest rate of ANA positivity was observed in individuals aged 31-45 years, followed by those aged 46-60 years. Individuals over 60 years consistently maintained high positivity rates in both the pre- and post-COVID periods. There was a notable 9 per cent increase in the nuclear homogeneous pattern, often linked to systemic lupus erythematosus (SLE) and rheumatoid arthritis, in 2022 compared to 2019.
Commenting on the study, Dr Alap Christy, Vice President & Scientific Business Head – Clinical Chemistry, Global Reference Laboratory, Metropolis Healthcare Limited, said, “The sharp rise in ANA positivity post-COVID is linked to the immune system’s intensified response to the virus. In some cases, this heightened immune activity causes the body to mistakenly attack its own tissues, triggering or worsening autoimmune diseases. Clinicians have increasingly observed a surge in autoimmune conditions following the pandemic, with research indicating that the body’s immune response to COVID-19 may be a key factor..."
The antinuclear antibody (ANA) test is recognised as one of the gold standard screening tools for diagnosing autoimmune diseases. However, ANA is just the starting point—once positive, it can be followed by a range of advanced tests such as ELISA and ImmunoBlot to confirm the diagnosis and understand the specific autoimmune condition.
📆 15 Feb 2024 📰 Researchers identify episodic MERS cases in Kenyan camels, evidence of infection in people 🗞️ CIDRAP
Year-long sampling of dromedary camels in northern Kenya reveals biphasic (two-phase) peaks of Middle East respiratory syndrome coronavirus (MERS-CoV) and identifies more than three case clusters over 3 weeks in camels from different areas, as well as a 15% infection rate in slaughterhouse workers.
For the study, published yesterday in Emerging Infectious Diseases, a University of Nairobi–led research team sampled 10 to 15 camels from 12 different regions 4 or 5 days a week from September 2022 to September 2023.
MERS is a respiratory disease caused by a relative of SARS-CoV-2, the coronavirus that causes COVID-19. MERS can cause severe lung infection, fever, cough, shortness of breath, and death. It was first discovered in humans in Saudi Arabia in 2012 and has since spread to many other countries. There is no vaccine against MERS, and treatment consists of supportive care.
Reverse transcription-polymerase chain reaction (RT-PCR) detected MERS-CoV RNA in 1.3% of camels. The incidence peaked in early October 2022, at 11.7%, and February 2023 (12.1%), corresponding to Kenya's dry seasons, when camel calves lose their maternal antibodies.
On enzyme-linked immunosorbent assay (ELISA), MERS-CoV IgG levels in 369 random samples showed an 80.8% seroprevalence of immunoglobulin G (IgG) antibodies. IgG levels were lowest in June and highest in March. IgG levels were negatively associated with RNA positivity.
IgG reactivity was identified in 7 of the 48 slaughterhouse workers (14.6%), with 1 of them showing evidence of MERS-CoV neutralizing antibodies. None were severely ill.
"Our sustained sampling of dromedary camels showed a biphasic MERS-CoV incidence in northern Kenya not observed in previous studies," the researchers said. "One explanation might be the short time of virus excretion in MERS-CoV–infected dromedaries, making viral RNA detection difficult without daily surveillance."
MERS-CoV antibody reactivity was identified in 7 of 48 camel-slaughterhouse workers (15%).
📆 19 Jan 2024 📰 What is ‘immunity theft’? How certain illnesses can leave you more vulnerable to other infections.
Having a COVID-19 infection can shore up your immunity to the virus, but can it also leave you more susceptible to getting sick with other illnesses? That's the theory laid out in a new scientific paper in JAMA Medical News and Perspectives, which looks at a possible tie between COVID and the recent surge in respiratory illnesses. The term “immunity theft” is being used to describe this phenomenon, although it hasn't been well-studied at this point.
It's important to point out that “immunity theft” is not a medical term. However, it's used to describe the theory that SARS-CoV-2, the virus that causes COVID-19, “steals” immunity, leaving some people who have had the virus more vulnerable to other infections.
Dr. William Schaffner, an infectious disease specialist and professor at the Vanderbilt University School of Medicine, tells Yahoo Life that the idea of immunity theft is a “fascinating hypothesis,” but notes that there isn't a lot of science to back it up at this point.
Still, he says there is some data to suggest this could be real. “There is preliminary data from the field that would suggest that, if you've had a serious communicable disease, you may be more vulnerable to another infection for a period of time,” Schaffner says.
Can immunity theft happen with other health conditions?
Yes, say experts. People who get measles, for example, “lose immune protection against other infections” for a period of time afterward, Dr. Patrick Jackson, an infectious disease physician at UVA Health, tells Yahoo Life. “The measles virus infects immune cells that give us long-lasting immune memory and wipes them out," he explains. Schaffner agrees. “Measles infection clearly seems to have some impact on the immune system,” he says, noting that people can have more vulnerability to other infectious diseases for months after having measles.
The phenomenon can also happen with the flu, Russo says. “Post-influenza, you have a period of time where people may get better and then develop a bacterial superinfection,” he says. “That's because the influenza infection suppresses the immune response, making individuals more susceptible.”
But Russo says it's “less well sorted out” whether this is also the case with COVID-19. “Immunity theft is a real thing that can happen,” says Jackson. “But I haven't seen convincing evidence this is a significant issue with SARS-CoV-2.”
"Immunity theft" isn't a medical term, but some are using it to describe how certain infections impact the immune system, leaving people mor
📆 11 Jan 2024 📰 In patients with long COVID, immune cells don 🗞️ EurekAlert!
While the overall number of T cells and the quantity of T cells that react specifically with the SARS-CoV-2 virus were similar between people with long COVID and those that recovered without lingering symptoms, the researchers pinpointed several significant differences. Notably, a subset of T cells known as CD4 T cells, which are responsible for the overall coordination of immune responses, were in a more inflammatory state in people with long COVID.
“Not every person with long COVID had these pro-inflammatory cells, but we only saw them in the long COVID group,” says Kailin Yin, PhD, postdoctoral fellow in the Roan lab and co-first author of the study. “It underscores the idea that there isn’t just one uniform thing that characterizes all individuals with long COVID.”
In a different subset of T cells known as CD8 T cells, which normally kill cells that are infected by viruses or bacteria, the researchers observed signs of exhaustion preferentially in people with long COVID. These signs, interestingly, were observed only in T cells that recognize the SARS-CoV-2 virus, not in the broader population of CD8 T cells.
“Such exhaustion is typically seen in chronic viral infections such as HIV, and means the T cell branch of the immune system stops responding to a virus and no longer kills infected cells,” says Peluso, assistant professor in the UCSF Department of Medicine and co-first author. “This finding fits with some hypotheses that long COVID, or at least some cases of it, are caused by persistent infections by the SARS-CoV-2 virus.”
The team also found an unusually high numbers of “tissue-homing” T cells, which are T cells that are prone to migrating to tissues throughout the body. This was observed not only by CyTOF, but also two other technologies, including one that monitors individual cells for thousands of different proteins they’re capable of producing.
“This was really interesting because in other studies we’re carrying out in mice, we also see high levels of tissue-homing receptors being associated with behavioral changes after recovery from SARS-CoV-2 infection,” Roan says. “In this current study, we don’t look at specific tissues, but our results indirectly suggest that in long COVID, something is happening within tissues, recruiting T cells to migrate there.”
Finally, the researchers showed that in people with long COVID, levels of antibodies against SARS-CoV-2 are unusually high, and they don’t synchronize as they usually do with levels of T cells that fight the virus.
<p>People with long COVID have dysfunctional immune cells that show signs of chronic inflammation and faulty movement into organs, among oth
📆 10 Jan 2024 📰 We Are in a Big Covid Wave. But Just How Big? 🗞️ The New York Times
What experts really want to know, said Marisa Eisenberg, a professor at the University of Michigan who runs a wastewater monitoring lab for five sites, is how much virus there is relative to the number of people around - the wastewater equivalent of the per-capita case count.
Some labs "normalize" the data — that is, they adjust the denominator - by looking at the number of gallons flowing through the plant, Professor Eisenberg said. But many sites use something called "pepper mild mottle virus," a virus that infects pepper plants.
"People have studied this in human sewage and found we shed pretty consistent levels of this pepper virus," she said. "So that's a measurement of how many people went to the bathroom in the sewer shed today."
Wastewater data has become perhaps the best metric to track the spread of the virus in the U.S., but it’s an imperfect tool.
📆 07 Oct 2023 📰 SARS-CoV-2 virus found to migrate within neurons and infect the brain 🗞 Medical Express
"In this study, we demonstrated that infection of the olfactory bulb is common to all variants and not linked to any particular one, nor to any particular clinical manifestation such as anosmia," explains Guilherme Dias de Melo, first author of the study and researcher in the Institut Pasteur's Lyssavirus, Epidemiology and Neuropathology Unit.
Moreover, the researchers identified a genetic sequence linked to anosmia in the ancestral (Wuhan) virus. When this genetic sequence, which encodes the ORF7ab protein, is deleted or truncated—which is the case in certain variants less likely to produce anosmia—the incidence of olfactory loss in infected animals is lower even though the degree of neuronal infection via the olfactory bulbs remains unchanged.
"This suggests that anosmia and neuronal infection are two unrelated phenomena," says Guilherme Dias de Melo. "If we follow this line of reasoning, it is quite possible that even an asymptomatic—and therefore clinically benign—infection is characterized by the spread of the virus in the nervous system."
... "The next step will be to understand, from the animal model, whether the virus is able to persist in the brain beyond the acute phase of infection, and whether the presence of the virus can induce persistent inflammation and the symptoms described in cases of long COVID, such as anxiety, depression and brain fog."
The emergence of different variants of SARS-CoV-2 has produced a wide range of clinical profiles and symptoms in patients. For the first tim
📆 19 Dec 2023 📰 Wanted: A Covid Booster That Actually Works ✍️ F.D. Flam 🗞 Bloomberg
Pfizer is struggling because not enough people are getting annual Covid shots. The problem is that the boosters aren’t very effective.
... There’s another problem facing Covid booster campaigns: the fast evolution of the virus and the stubborn tendency of our immune systems to insist on fighting the original variant, since that’s what we were first vaccinated against.
This stubborn tendency is called imprinting, and may explain why so many fully vaccinated, multiple-boosted people have gotten omicron not just once but sometimes two or three times. It also explains data showing that the bivalent booster offered in 2022, with components of the initial strain and omicron, didn’t produce any more omicron-neutralizing antibodies than the original booster.
The 2023 boosters don’t have the original strain — they are monovalent and aimed at the omicron sub-variant XBB.1.5, which was dominant earlier in the year. Many scientists say this is a big improvement. A study published last month in Nature showed that repeat exposures to omicron through infection or omicron-only booster shots can start to override the immune imprinting that has our immune systems stuck on the extinct original version of this virus.
Peking University researcher Yunlong (Richard) Cao, who headed the study, said exposure to omicron generates what are called naïve B cells, and over time these become tuned to fight omicron. After two exposures, the body is better able to fight off future exposures to omicron.
As a caveat, he said, this study involved subjects in China who were very rarely exposed to the virus before omicron, and who got a different kind of vaccine called an inactivated virus. Similar studies that followed people who got mRNA shots saw no overriding of the imprinting.
Cao said the mRNA vaccines are more immunogenic than the ones used in China, which can make them more powerful but might render the imprinting effect stronger too. It might take people in the US and elsewhere more exposures to omicron-only boosters or infections to retune their immune systems toward the new version of the virus — though the virus will continue to evolve as well.
📆 11 Dec 2023 📰 Study reveals SARS-CoV-2 virus found in lungs for up to 18 months after infection 🗞 The Week
In a study conducted by the Institut Pasteur and the Alternative Energies and Atomic Energy Commission (CEA), researchers have discovered that the SARS-CoV-2 virus, responsible for causing COVID-19, can persist in the lungs for up to 18 months after infection. Published in the esteemed journal Nature Immunology, the study highlights the link between the virus's long-term presence and a potential failure of the body's innate immune response...
"We observed persistent inflammation in primates infected with SARS-CoV-2 over extended periods, leading us to suspect the presence of the virus in the body," explained Michaela Muller-Trutwin, Head of the Institut Pasteur's HIV, Inflammation, and Persistence Unit.
... Nicolas Huot, the first author of the study and a researcher in the Institut Pasteur's HIV, Inflammation, and Persistence Unit, expressed astonishment at the discovery of viruses in immune cells known as alveolar macrophages long after regular PCR tests indicated no presence of the virus. Furthermore, these viruses were found capable of replication.
To better understand the role of innate immunity in controlling viral reservoirs, the scientists focused on natural killer (NK) cells. Muller-Trutwin emphasised the importance of studying the cellular response of innate immunity, stating, "Yet it has long been known that NK cells play an important role in controlling viral infections."
The study revealed that in some cases, macrophages infected with SARS-CoV-2 became resistant to destruction by NK cells. However, in other instances, NK cells adapted to the infection, becoming adaptive NK cells and effectively destroying the resistant macrophages.
... Individuals with lower levels of long-term virus exhibited adaptive NK cell production, while those with higher levels not only lacked adaptive NK cells but also experienced reduced NK cell activity.
Omicron strain shows lower levels of persistent virus in lungs, study suggests
📆 13 May 2021 📰 The 60-Year-Old Scientific Screwup That Helped Covid Kill ✍️ Megan Molteni 🗞 Wired
She tried another tack. Everyone agreed that tuberculosis was airborne. So she plugged “5 microns” and “tuberculosis” into a search of the CDC’s archives. She scrolled and scrolled until she reached the earliest document on tuberculosis prevention that mentioned aerosol size. It cited an out-of-print book written by a Harvard engineer named William Firth Wells. Published in 1955, it was called Airborne Contagion and Air Hygiene...
In the words of Wells’ manuscript, she found a man at the end of his career, rushing to contextualize more than 23 years of research. She started reading his early work, including one of the studies Jimenez had mentioned. In 1934, Wells and his wife, Mildred Weeks Wells, a physician, analyzed air samples and plotted a curve showing how the opposing forces of gravity and evaporation acted on respiratory particles. The couple’s calculations made it possible to predict the time it would take a particle of a given size to travel from someone’s mouth to the ground. According to them, particles bigger than 100 microns sank within seconds. Smaller particles stayed in the air. Randall paused at the curve they’d drawn. To her, it seemed to foreshadow the idea of a droplet-aerosol dichotomy, but one that should have pivoted around 100 microns, not 5.
One night she read about experiments Wells did in the 1940s in which he installed air-disinfecting ultraviolet lights inside schools. In the classrooms with UV lamps installed, fewer kids came down with the measles. He concluded that the measles virus must have been in the air. Randall was struck by this. She knew that measles didn’t get recognized as an airborne disease until decades later. What had happened?
Part of medical rhetoric is understanding why certain ideas take hold and others don’t. So as spring turned to summer, Randall started to investigate how Wells’ contemporaries perceived him. That’s how she found the writings of Alexander Langmuir, the influential chief epidemiologist of the newly established CDC. Like his peers, Langmuir had been brought up in the Gospel of Personal Cleanliness, an obsession that made handwashing the bedrock of US public health policy. He seemed to view Wells’ ideas about airborne transmission as retrograde, seeing in them a slide back toward an ancient, irrational terror of bad air—the “miasma theory” that had prevailed for centuries. Langmuir dismissed them as little more than “interesting theoretical points.”
But at the same time, Langmuir was growing increasingly preoccupied by the threat of biological warfare. He worried about enemies carpeting US cities in airborne pathogens. In March 1951, just months after the start of the Korean War, Langmuir published a report in which he simultaneously disparaged Wells’ belief in airborne infection and credited his work as being foundational to understanding the physics of airborne infection.
How curious, Randall thought. She kept reading.
... Wells [decided] to investigate what role particle size played in the likelihood of natural respiratory infections. He designed a study using tuberculosis-causing bacteria. The bug was hardy and could be aerosolized, and if it landed in the lungs, it grew into a small lesion. He exposed rabbits to similar doses of the bacteria, pumped into their chambers either as a fine (smaller than 5 microns) or coarse (bigger than 5 microns) mist. The animals that got the fine treatment fell ill, and upon autopsy it was clear their lungs bulged with lesions. The bunnies that received the coarse blast appeared no worse for the wear.
For days, Randall worked like this—going back and forth between Wells and Langmuir, moving forward and backward in time. As she got into Langmuir’s later writings, she observed a shift in his tone. In articles he wrote up until the 1980s, toward the end of his career, he admitted he had been wrong about airborne infection. It was possible.
A big part of what changed Langmuir’s mind was one of Wells’ final studies. Working at a VA hospital in Baltimore, Wells and his collaborators had pumped exhaust air from a tuberculosis ward into the cages of about 150 guinea pigs on the building’s top floor. Month after month, a few guinea pigs came down with tuberculosis. Still, public health authorities were skeptical. They complained that the experiment lacked controls. So Wells’ team added another 150 animals, but this time they included UV lights to kill any germs in the air. Those guinea pigs stayed healthy. That was it, the first incontrovertible evidence that a human disease—tuberculosis—could be airborne, and not even the public health big hats could ignore it.
The groundbreaking results were published in 1962. Wells died in September of the following year. A month later, Langmuir mentioned the late engineer in a speech to public health workers. It was Wells, he said, that they had to thank for illuminating their inadequate response to a growing epidemic of tuberculosis. He emphasized that the problematic particles—the ones they had to worry about—were smaller than 5 microns.
Inside Randall’s head, something snapped into place. She shot forward in time, to that first tuberculosis guidance document where she had started her investigation. She had learned from it that tuberculosis is a curious critter; it can only invade a subset of human cells in the deepest reaches of the lungs. Most bugs are more promiscuous. They can embed in particles of any size and infect cells all along the respiratory tract.
What must have happened, she thought, was that after Wells died, scientists inside the CDC conflated his observations. They plucked the size of the particle that transmits tuberculosis out of context, making 5 microns stand in for a general definition of airborne spread. Wells’ 100-micron threshold got left behind. “You can see that the idea of what is respirable, what stays airborne, and what is infectious are all being flattened into this 5-micron phenomenon,” Randall says. Over time, through blind repetition, the error sank deeper into the medical canon. The CDC did not respond to multiple requests for comment.
ON FRIDAY, APRIL 30, the WHO quietly updated a page on its website. In a section on how the coronavirus gets transmitted, the text now states that the virus can spread via aerosols as well as larger droplets. As Zeynep Tufekci noted in The New York Times, perhaps the biggest news of the pandemic passed with no news conference, no big declaration. If you weren’t paying attention, it was easy to miss.
In early May, the CDC made similar changes to its Covid-19 guidance, now placing the inhalation of aerosols at the top of its list of how the disease spreads. Again though, no news conference, no press release.
In July, the two women sent slides to Anthony Fauci, director of the National Institutes of Allergy and Infectious Diseases. One of them showed the trajectory of a 5-micron particle released from the height of the average person’s mouth. It went farther than 6 feet—hundreds of feet farther. A few weeks later, speaking to an audience at Harvard Medical School, Fauci admitted that the 5-micron distinction was wrong—and had been for years. “Bottom line is, there is much more aerosol than we thought,” he said. (Fauci declined to be interviewed for this story.)
All pandemic long, scientists brawled over how the virus spreads. Droplets! No, aerosols! At the heart of the fight was a teensy error with
📆 10 Nov 2021 📰 Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2
Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1,2,3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4,5,6,7,8,9,10,11), would expand in vivo to support rapid viral control, aborting infection.
We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication–transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort).
SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.
There is wide variability in the outcome of exposure to SARS-CoV-2, ranging from severe illness to asymptomatic infection, to those individuals who remain negative according to standard diagnostic tests. Recent studies have identified SARS-CoV-2 T cell reactivity in prepandemic samples5,6,7,8,9,10,11,15,16,17,18 and isolated cases of exposed individuals who have not seroconverted with single-time-point screening4,16,19,20,21,22. We studied an intensively monitored cohort of HCWs with potential exposure during the first UK pandemic wave (23 March 2020), comparing those with or without PCR and/or antibody evidence of SARS-CoV-2 infection.
We postulated that, in HCWs for whom PCR and the most sensitive binding and neutralizing antibody tests remained repeatedly negative (SN-HCWs), T cell assays might distinguish a subset of SN-HCWs with a subclinical, rapidly terminated (abortive) infection. We hypothesized that these individuals would exhibit pre-existing memory T cells with cross-reactive potential, obviating the time required for de novo T cell priming and clonal expansion.
In SN-HCWs, and in an additionally recruited cohort of medical students and laboratory staff with stored prepandemic samples that remained seronegative after close contact with cases, we had the opportunity to compare SARS-CoV-2-specific memory T cells with those that were already present in the same individual before, or at the time of, potential exposure.
We included an analysis of the understudied T cells directed against the core RTC within open reading frame 1ab (ORF1ab) (RNA polymerase co-factor non-structural protein 7 (NSP7), RNA polymerase NSP12 and helicase NSP13, hereafter the RTC); these are putative targets for pre-existing responses with pan-Coronaviridae reactivity, because they are likely to be highly conserved due to their key early roles in the viral life cycle.
Consistent with this, in cases in which immunity against other viruses (including hepatitis B virus (HBV), hepatitis C virus (HCV), HIV and Japaneses encephalitis virus (JEV)) has been described in exposed seronegative individuals, T cells were more likely to target non-structural proteins, such as polymerase, compared with in individuals with a seropositive infection23,24,25,26,27.
Seronegative healthcare workers with an innate signature of infection preferentially expand pre-existing T cells targeting the conserved rep
📆 27 Dec 2022 📰 Three years on, the pandemic — and our response — have been jolting. Here’s what even the experts didn’t see coming ✍️ Helen Branswell 🗞 STAT
The biggest surprise, hands down: How the virus has evolved
In the early days of the pandemic, before the new virus had a name, people who had studied coronaviruses offered reassuring predictions about the stability of the virus, which has implications for how often people might be reinfected and how frequently vaccines would need to be updated.
Coronaviruses don’t change very quickly, they aren’t as mutable as, say, influenza viruses, those experts said. In fact, the spike protein on the virus’ exterior, the one that attaches to human cells and triggers infection, cannot change too much without losing its ability to infect, they assured the rest of us.
Many of the people STAT interviewed cited SARS-CoV-2’s evolution as their biggest surprise of the pandemic. “It’s been wild, in my view,” said Marion Koopmans, head of virology at Erasmus Medical Center in Rotterdam, the Netherlands.
Anthony Fauci, retiring head of the National Institute of Allergy and Infectious Diseases, also listed it as his number 1 surprise. “What has surprised me most about Covid is the continual evolution of new variants leading to an unprecedented persistence of the pandemic phase over three years,” he said.
... Most viruses evolve in a stepwise fashion known as “drift,” adding change after change to an existing strain. But some of the Covid variants look more like old versions of the virus were hyper mutated, possibly in a persistently infected person. When those viruses started to spread, they replaced the viruses that had been circulating. The Alpha, Beta, Gamma and Omicron variants of concern are examples of this type of evolution, called saltation, Thomas Peacock and colleagues wrote in a preprint article posted in late November.
In the hope that lessons for the next pandemic can be found in the things we didn’t anticipate this time, STAT asked 23 experts what had sur
📆 19 Oct 2023 📰 COVID Viral Load Peaks Later Now Than Early in Pandemic
A paper published in Clinical Infectious Diseasesopens in a new tab or window has been generating discussion among experts, who say high levels of population immunity are responsible for the shift.
That paper, by Nira Pollock, MD, PhD, of Boston Children's Hospital, and colleagues, found that viral loads in the Omicron era peak about 4 days after the onset of symptoms, compared with a peak at symptom onset early in the pandemic.
They found that on PCR testing, median cycle threshold (Ct) values hit their lowest point -- which is consistent with peak viral load -- on the fourth day of symptoms.
Using Ct values to predict rapid antigen results, the researchers estimated a sensitivity of 30% to 60% on the first day of symptoms, rising to 80% to 93% on the fourth day of symptoms.
Early in the pandemic, they wrote, a single negative antigen test had "reasonable negative predictive value," with studies reporting 90% to 95% sensitivity in the first week of symptoms. Now, overall predicted sensitivity in the first week is about 60% to 80%, they said.
"Our data in combination with others' suggest that symptomatic individuals testing positive for SARS-CoV-2 by PCR currently may not reliably test positive on a rapid antigen test until the 3rd, 4th, or even 5th day of symptoms," they wrote.
Peak on day 4 of symptoms, rather than day 1, has implications for rapid tests, experts say
📆 Jan 2023 📰 Exposed seronegative: Cellular immune responses to SARS-CoV-2 in the absence of seroconversion 🗞 Frontiers
Determining which antigens are targeted in SARS-CoV-2 ESNs provides insight into mechanisms of response. T-cells targeting the replication-transcription complex (RTC) of SARS-CoV-2 were described by Swadling et al. (2022) in ESNs (7). The RTC is comprised of the RNA polymerase NSP12, a co-factor NSP7, and the helicase NSP13 (37). Its expression early in the SARS-CoV-2 replication cycle makes the RTC a target for rapidly-induced T-cell responses (7). The authors identified fivefold-higher RTC-specific T-cell responses in ESNs compared to unexposed controls. Furthermore, cellular immunity in ESNs preferentially targeted the RTC over structural proteins compared to seropositive individuals. However, the authors did not assay cellular responses to other NSPs.
In a study of six ESN sexual partners of HSV-2-infected individuals by Posavad et al. (2010), T cell responses in ESNs were skewed towards peptides expressed early in the virus replication cycle, whereas HSV-2 seropositive individuals more frequently generated responses to structural proteins present in virions. The authors speculated that this skew in ESNs reflected early T-cell engagement with infected cells before the production of infectious virions. Together, these data support a model whereby rapid T-cell responses targeting early translated NSPs may prevent infection from gaining a foothold.
To prevent infection before seroconversion, a rapid cellular response appears critical. Chandran et al. (2021) assayed weekly nasopharyngeal swabs and blood samples from HCWs, and demonstrated that SARS-CoV-2 specific T-cell proliferation can occur before PCR positivity (42). These rapid responses may originate from pre-existing, cross-reactive T-cells specific for human coronaviruses (HCoVs). Cross-recognition of SARS-CoV-2 by HCoV-specific T-cells has been widely described (43–50), and T-cells from COVID-19 convalescents preferentially target conserved epitopes over SARS-CoV-2-specific epitopes (49). HCWs display higher levels of HCoV-specific T-cells than community controls (28), which may contribute to the abundance of ESNs amongst HCWs. The activation of cross-reactive T-cells by related viruses has been termed ‘heterologous immunity’ (51). This is distinct from autologous viral infection in that neutralising antibody responses to the heterologous virus may be suboptimal, allowing cellular memory to dominate.
The RTC is highly conserved between SARS-CoV-2 and HCoVs (7). Tetramer staining of T-cells with an HCoV-HKU1 homologue of the RTC component NSP7 showed strong responses in SARS-CoV-2 ESNs. Swadling et al. (2022) suggested that prior exposure to HCoV-HKU1 generates cross-reactive T-cells specific for NSP7, enabling rapid abortion of SARS-CoV-2 infection (7). A study of camel workers in Saudi Arabia identified both CD4+ and CD8+ responses to Middle-East Respiratory Syndrome coronavirus in four highly-exposed seronegative individuals, suggesting that the ESN phenomenon may be common to other human-infective coronaviruses.
Cellular immunity is able to clear SARS-CoV-2 infection in isolation; patients with X-linked agammaglobulinemia who cannot produce antibodies eventually clear SARS-CoV-2 infection, and mount higher magnitude CD8+ T-cell responses to SARS-CoV-2 compared to immunocompetent individuals (54). However, in Wang et al. (2021) the magnitude of the SARS-CoV-2-specific CD4+ T-cell response was twice as high in infected individuals compared to ESNs. This casts doubt on their role in protection against infection.
The factors determining whether infection will occur following exposure to SARS-CoV-2 remain elusive. Certain SARS-CoV-2-exposed individuals
