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📆 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."

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📆 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.”

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📆 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.

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📆 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."

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📆 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."

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📆 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.

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📆 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.

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📆 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.)

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📆 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.

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📆 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.

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📆 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.

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📆 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.

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📆 Apr 2021 📰 How Novel Coronavirus Variants Could Complicate Our COVID-19 Vaccination Drive ✍️ Dr Vipin Vashishtha

Some of my peers working in the bigger COVID-19 hospitals in metropolitan cities have also observed that those who received vaccines and tested positive for COVID-19 within two weeks are both outnumbering those who haven’t been vaccinated and are running a more severe course of the disease. India’s health ministry hasn’t shared any such data thus far, however.

Could these apprehensions be true? Let’s find out.

Speculation that vaccines could paradoxically increase the risk of infections possibly originated following the 2009 influenza A (H1N1pdm09) pandemic, when 4 Canadian studies suggested that getting the seasonal influenza vaccine increased the risk of laboratory-confirmed infections. This led to 5 additional studies, each of which substantiated these initial findings.

One proposed mechanism for this phenomenon is called original antigenic sin. It was first used to describe how one’s first exposure to the influenza virus shapes the outcome of subsequent exposures to antigenically related strains. (The antigen is the part of the object that provokes the immune response – like the novel coronavirus’s spike protein.) This specific immune phenomenon explains the failure of the immune system to generate an immune response against related antigens.

When an individual is infected by an evolved strain with a new dominant antigen, slightly different from the original strain against which the person has been vaccinated, the immune system produces antibodies against the original strain. This happens through high-affinity memory B-cells that inhibit activation of naïve B-cells, resulting in a weak immune response against the newer strain. So the risk of infection paradoxically increased in vaccinated individuals compared to unvaccinated individuals.

This phenomenon could be at work when different variants of the SARS-CoV-2 virus are in play. As you may know, most existing COVID-19 vaccines are based on the wild strain that was circulating around the world last year. However, towards the end of 2020, many variants with mutations in the spike protein have emerged. These new variants have replaced their predecessors in most countries. In India as well, one or two key variants (B.1.1.7 and B.1.617) are feared to be circulating around the country.

So a vaccine may mount a strong immune response against the original epitopes contained in the ‘original’ strain due to preformed B-cells. (“The antibody recognises a particular part of the virus, called the epitope, and forms a bond with it using a part called the paratope” – source.) These preformed committed B-cells outnumber naïve B cells and prevent them from mounting a strong response that is specific to the epitopes contained in the new mutant.

As a result, the immune system becomes unable to mount a faster, stronger secondary response. The implication is that when the epitope varies slightly, then the immune system relies on the memories of the previous infection (with the wild variant) rather than mount another primary or secondary response to the new epitopes present in the new variant (B.1.617 or B.1.1.7).

As a result, the immunological response may be inadequate against the new variant – because the immune system depends on a memory instead of launching into a fresh response.

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📆 12 Oct 2023 📰 It’s good to feel bad after your COVID shot 🗞 National Geographic

Jeremy Warner has had six shots of the COVID vaccines. He’s an oncologist at Brown University in Providence, Rhode Island, where he treats immunocompromised patients with cancer who are especially vulnerable to COVID-19. To keep his patients safe, Warner rolls up his sleeves as soon as the U.S. Food and Drug Administration recommends a new vaccine, but he dreads the aftermath. "Each time I'm like, oh my God, I can't do this again!"

After each COVID shot Warner gets a fever, headaches, shaking chills, and painful, swollen joints along with the expected tenderness at the site of injection. "The worst was the second shot that lasted two or three days," recalls Warner. "This recent round, maybe one or two days."

The good news: new research shows that more side effects might be beneficial because they reflect greater production of virus-fighting antibodies after vaccination.

Fear of reactions make some people hesitant to get a COVID shot and a third of adults in one study blamed vaccine side effects for not taking the bivalent boosters last winter that targeted two strains—the original SARS-CoV-2 virus and an Omicron subvariant.

"[But] the side effects show the vaccine is working," says Drew Weissman, an immunologist at the University of Pennsylvania, whose research led the development of the mRNA vaccines, including Moderna's and Pfizer's. Weissman and Katalin Karikó were recently awarded the 2023 Nobel Prize in Physiology or Medicine for their work on modifying mRNA.

COVID-19 vaccines are overwhelmingly safe and effective. Fewer than 1% of the 10.1 million U.S. respondents who have completed health surveys through the Centers for Disease Control's V-safe program—launched in December 2020—have reported needing a medical care after vaccination.

But mRNA vaccines are among the most painful of vaccines, comparable to the shingles vaccine. Scientists don't yet know why. "There's still a lot that's being learned about the side effects of mRNA vaccines," says Deborah Fuller, a vaccinologist at University of Washington School of Medicine, Seattle.

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📆 15 Jul 2020 📰 SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls 🗞 Nature

Here we studied T cell responses against the structural (nucleocapsid (N) protein) and non-structural (NSP7 and NSP13 of ORF1) regions of SARS-CoV-2 in individuals convalescing from coronavirus disease 2019 (COVID-19) (n = 36). In all of these individuals, we found CD4 and CD8 T cells that recognized multiple regions of the N protein. Next, we showed that patients (n = 23) who recovered from SARS (the disease associated with SARS-CoV infection) possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 years after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2.

We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19 or contact with individuals who had SARS and/or COVID-19 (n = 37). SARS-CoV-2-specific T cells in uninfected donors exhibited a different pattern of immunodominance, and frequently targeted NSP7 and NSP13 as well as the N protein. Epitope characterization of NSP7-specific T cells showed the recognition of protein fragments that are conserved among animal betacoronaviruses but have low homology to ‘common cold’ human-associated coronaviruses.

Thus, infection with betacoronaviruses induces multi-specific and long-lasting T cell immunity against the structural N protein. Understanding how pre-existing N- and ORF1-specific T cells that are present in the general population affect the susceptibility to and pathogenesis of SARS-CoV-2 infection is important for the management of the current COVID-19 pandemic.

It is unclear why NSP7- and NSP13-specific T cells are detected and often dominant in unexposed donors, while representing a minor population in individuals who have recovered from SARS or COVID-19. It is, however, consistent with the findings of a previous study11, in which ORF1-specific T cells were preferentially detected in some donors who were not exposed to SARS-CoV-2 whereas T cells from individuals who had recovered from COVID-19 preferentially recognized structural proteins.

Induction of virus-specific T cells in individuals who were exposed but uninfected has been demonstrated in other viral infections24,25,26. Theoretically, individuals exposed to coronaviruses might just prime ORF1-specific T cells, as the ORF1-encoded proteins are produced first in coronavirus-infected cells and are necessary for the formation of the viral replicase–transcriptase complex that is essential for the subsequent transcription of the viral genome, which then leads to the expression of various RNA species18. Therefore, ORF1-specific T cells could hypothetically abort viral production by lysing SARS-CoV-2-infected cells before the formation of mature virions.

By contrast, in patients with COVID-19 and SARS, the N protein—which is abundantly produced in cells that secrete mature virions17—would be expected to preferentially boost N-specific T cells.

Notably, the ORF1 region contains domains that are highly conserved among many different coronaviruses9. The distribution of these viruses in different animal species might result in periodic human contact that induces ORF1-specific T cells with cross-reactive abilities against SARS-CoV-2. Understanding the distribution, frequency and protective capacity of pre-existing structural or non-structural protein-associated SARS-CoV-2 cross-reactive T cells could be important for the explanation of some of the differences in infection rates or pathology observed during this pandemic.

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📆 08 Oct 2023 📰 Decoding the twist: Coronavirus spike proteins reveal their intricate invasion dance 🗞 News Medical&Live Sciences

In a recent study published in the journal Nature, researchers use cryogenic electron microscopy (cryo-EM) in tandem with molecular dynamics simulation to reveal that the usually closed spike proteins of human coronavirus HKU1 drastically change on binding with a sarcoglycan-based primary receptor. These local and long-range conformational modifications result in the spike proteins transitioning to the open state and elucidate the mechanisms underlying coronavirus attachments.

These findings represent the first description of a human coronavirus exposing its S1B domains on demand, thereby suggesting that the mode of beta coronavirus attachment to host cells is even more complex and sophisticated than previously appreciated.

Since spike and other cell-surface virus proteins are used by the host immune system to identify and irradicate infections, the transition between open and closed S1B states allows the virus to safeguard itself against the host immune response when closed while retaining its infective potential in an open state. Barring rare exceptions, the pre-fusion spike proteins of all CoVs have been exclusively observed in the closed state.

Given that both open and closed states are known to science, research into the triggers/specific cues of transition between S1B states would shed light on the mechanisms by which CoV strains escape host immune detection and achieve the high virulence they are observed to.

These results suggest that the mode of CoV attachment to human cells may be far more sophisticated and complex than previously assumed. The study findings also imply the presence of dual receptor usage and S1A priming as a modality to escape host immune detection.

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📆 17 Jul 2020 📰 Your body fights viruses in different ways ✍️ Andy Larsen

Another study looked at eight people who were household contacts of COVID-19 cases, all of whom tested negative for antibodies later. Some had mild symptoms they thought might be COVID, others did not. But despite not having antibodies, six of the eight tested positive for having T cells specific to SARS-CoV-2.

In fact, another larger study estimated that the number of mildly-infected people who have these T cells to be about double the number of people who have detectable antibodies. If true, it looks like serological studies are undercounting how many people have some adaptive immune protection to the disease. More on this later.

Remember how we learned that some people who get COVID-19 have SARS-CoV-2 specific T cells but not antibodies? Well, here’s another twist: some people have SARS-CoV-2 specific T cells but no history with the disease at all. That’s right — they have no positive test, no symptoms, no reported contact with a COVID-19 case, no original SARS, no nothing; but they still have T cells that would likely protect them from the disease to some degree.

That’s the finding of a Nature study released Wednesday. In 19 of the 37 people studied with no known link to the virus and negative tests, they found SARS-CoV-2 specific T cells.

That’s more than half! It’s a big surprise.

What’s going on here?

Well, one hypothesis is that these people had been previously infected with the mild coronaviruses that cause the common cold, and the T cells were created as a result of that. But the authors of the study seem to find that unlikely, because the specific shape of the T cells they find don’t match the common-cold coronaviruses that we know about.

Instead, they wonder if there’s been a very mild coronavirus or coronaviruses floating around before that are more similar to SARS-CoV-2, perhaps also of animal origin. It’s very possible that we wouldn’t know about such a thing if it weren’t killing people like COVID-19 is, but people who got that low-key virus would have some form of T cell protection against the coronavirus we are battling now.

What’s left to find out? So, so much. For one, we don’t really know how representative that sample of 37 people is. That study is from Singapore. How many people in the U.S. have SARS-CoV-2-specific T cells? We need to find out.

We also don’t really know how protective T cells are against SARS-CoV-2, or even coronaviruses like it, in humans. Flu is a different kind of disease than COVID-19, and mice are pretty different than humans. We’ll be watching these people who have T cells to see if they can be infected, and if they are, what kind of disease severity they have. I think it’s reasonable to expect moderate but not total protection, but the answer could still be “no protection whatsoever.” We just don’t know yet.