Amazing Science

The COVID-19 pandemic has affected hundreds of millions of individuals and caused more than six million deaths. The prolonged pandemic duration and the continual inter-individual transmissibility have contributed to the emergence of a wide variety of SARS-CoV-2 variants. Genomic surveillance and phylogenetic studies have shown that substantial mutations in crucial supersites of spike glycoprotein modulate the binding affinity of the evolved SARS-COV-2 lineages to ACE2 receptors and modify the binding of spike protein with neutralizing antibodies.

The immunological spike mutations have been associated with differential transmissibility, infectivity, and therapeutic efficacy of the vaccines and the immunological therapies among the new variants. This review highlights the diverse genetic mutations assimilated in various SARS-CoV-2 variants. The implications of the acquired mutations related to viral transmission, infectivity, and COVID-19 severity are discussed. This review also addresses the effectiveness of human neutralizing antibodies induced by SARS-CoV-2 infection or immunization and the therapeutic antibodies against the ascended variants.

Published March 30, 2024:

https://doi.org/10.1007/s15010-024-02223-y 

Katalin Karikó and Drew Weissman laid the groundwork for immunizations that were rolled out during the pandemic at record-breaking speed. This year’s Nobel Prize in Physiology or Medicine has been awarded to biochemist Katalin Karikó and immunologist Drew Weissman for discoveries that enabled the development of mRNA vaccines against COVID-19. The vaccines have been administered more than 13 billion times, saved millions of lives and prevented millions of cases of severe COVID-19, said the Nobel committee. Karikó, who is at Szeged University in Hungary, and Weissman, at the University of Pennsylvania in Philadelphia (UPenn), paved the way for the vaccines’ development by finding a way to deliver genetic material called messenger RNA into cells without triggering an unwanted immune response. They will each receive an equal share of the prize, which totals 11 million Swedish krona (US$1 million). Karikó is the 13th female scientist to win a Nobel Prize in medicine or physiology. She was born in Hungary, and moved to the United States in the 1980s. “Hopefully, this prize will inspire women and immigrants and all of the young ones to persevere and be resilient. That’s what I hope,” she tells Nature.

A new chapter

The COVID-19 vaccines developed by Moderna and the Pfizer–BioNTech collaboration deliver mRNA that instructs cells to create copies of a protein that is found on SARS-CoV-2 virus particles, called the spike protein. This stimulates the body to make antibodies that target the protein, as well as triggering other immune responses. For decades, mRNA vaccines were considered unfeasible because the injection of mRNA into the body triggered an immune reaction that immediately broke down the mRNA. In the mid-2000s, working at UPenn, Karikó and Weissman demonstrated that swapping one type of molecule in mRNA, called uridine, with a similar one called pseudouridine bypasses the cells’ innate immune defences[1].

“I’m delighted to see them recognized,” says Robin Shattock, a vaccine scientist at Imperial College London, who has worked on mRNA vaccines. “Their contribution was really fundamental in the success of the COVID-19 vaccines, and I think will underlie RNA technology for some time to come.” “They demonstrated that changing the type of the RNA nucleotides within the vaccine altered the way in which cells see it,” said John Tregoning, a vaccine immunologist at Imperial College London, in a press statement for the UK Science Media Centre. “This increased the amount of vaccine protein made following the injection of the RNA, effectively increasing the efficiency of the vaccination: more response for less RNA. This discovery has opened a new chapter for medicine,” said Nobel committee member Qiang Pan Hammarström, an immunologist at the Karolinska Institute in Stockholm, at a press conference after the prize announcement. “Investment in long-term basic research is very important.”

https://doi.org/10.1038/d41586-023-03046-x

Moderna's newest vaccine and new shots from Pfizer and Novavax are slated to roll out within weeks, pending potential approvals from the Food and Drug Administration.

Moderna’s newest Covid vaccine generated a robust immune response against the now-dominant Eris variant and another rapidly spreading strain of the virus in an early clinical trial, the biotech company recently stated. The updated shot is designed to target omicron subvariant XBB.1.5, but the results suggest that the injection may still be effective against newer variants of the virus that are gaining ground nationwide. That includes Eris and another variant nicknamed Fornax, both of which are also descendants of the omicron virus variant.

Moderna’s vaccine and new shots from Pfizer and Novavax are slated to roll out within weeks, pending potential approvals from the U.S. Food and Drug Administration. Meanwhile, Covid-related hospitalizations fueled by Eris and other variants continue to accelerate but remain below the summer peak that strained hospitals this time last year. Eris, also known as EG.5, accounted for 17.3% of all cases as of earlier this month, according to the Centers for Disease Control and Prevention. The World Health Organization designated Eris a “variant of interest,” meaning it will be monitored for mutations that could make it more severe. Fornax, or FL 1.5.1, is also beginning to surge in parts of t he U.S. It accounted for 8.6% of all cases nationwide as of earlier this month, the CDC said. A Pfizer spokesperson on Thursday said the company’s own updated Covid shot effectively neutralized XBB.1.5 and Eris, among other variants, in a recent trial on mice.

A new analysis published in The Lancet Microbe shows how the SARS-CoV-2 virus spreads from the nose to the air and surfaces in the immediate surroundings. The findings are the second batch of results to come from the COVID-19 Human Challenge Program, led by Imperial College London and partners, and provide granular insights into how people infected with SARS-CoV-2 spread the virus to their immediate surroundings. In February 2021, 36 healthy, young participants with no previous immunity to the virus were infected with SARS-CoV-2 under controlled clinical conditions in a residential facility at the Royal Free Hospital in London, where they could be carefully monitored. They remained at the facility until they were no longer infectious. The facility enabled researchers to track the course of infection in great detail, with the clinical team taking daily swabs from participants' noses and mouths, as well as environmental samples of the air and swabs of surfaces in their rooms.

Viral emissions

Out of 36 initial participants, a total of 18 became infected. Analysis showed that two individuals emitted substantially more virus into the air than the other infected participants, but displayed no significantly worse symptoms. The researchers suggest this may represent the small proportion of individuals who have potential to be highly infectious, sometimes described as "superspreading." Analysis found large amounts of viral RNA in air samples, in exhaled breath, as well as swabs of participants hands and on surrounding surfaces, including frequently touched surfaces such as door handles and TV remote controls, showing how an infected person contaminates their surrounding environment and can spread the virus. Viral emissions correlated strongly with the level of virus detected in people's noses, more than in their throat, highlighting the nose as a significant route for infected people shedding virus into the air and environment. According to the researchers, the latest analysis further highlights the routes by which the virus is transmitted from person to person—directly into the air, depositing onto nearby surfaces, and transferred from contaminated hands to frequently touched surfaces, such as door handles and remote controls.

Reliable indicators

They also show that positive lateral flow tests and visible symptoms were reliable indicators of when people were infectious and emitting virus into the air and environment. The vast majority of virus was emitted after people noticed their first symptoms, with very little virus released into the environment before that (pre-symptomatically). They found no significant link between the severity of participants' symptoms and the amount of virus they shed into the environment. According to the researchers, the findings highlight the need to reinforce public health messaging around proper face mask use, hand washing and surface cleaning, as well as how human challenge studies continue to add to our knowledge of COVID-19 infection and transmission. Dr. Anika Singanayagam, NIHR Academic Clinical Lecturer in the Department of Infectious Disease at Imperial College London, and joint first author of the study, said, "Our latest findings add to the existing body of knowledge on COVID-19 transmission. By studying infection in a controlled environment, we can collect unique, detailed measurements of virus emitted that allow us to understand how and when people with COVID-19 are contagious to others. These types of measurements are challenging to collect in real-world studies. "Our data indicate that much of the virus people shed comes from the nose, further highlighting the importance of face masks covering the nose as well as the mouth when they're used. But it also shows how virus can be transferred from hands to contaminate surfaces, like door handles or remote controls, which become a source of infection."

Dr. Jay, Jie Zhou, research associate in the Department of Infectious Disease at Imperial College London, and joint first author of the study, said, "Understanding when infected people are contagious and how to detect when they are contagious is important—it can help us to use interventions like face masks or social distancing more effectively. The data in our study highlights that being aware of, and acting on, the first minor symptoms that signal an infection, coupled with frequent self-testing with lateral flow tests, can effectively reduce onward spread." Professor Wendy Barclay, head of the Department of Infectious Disease at Imperial College London, said, "One of the most important things we need to know for controlling the spread of respiratory viruses, such as SARS-CoV-2, is when are people who are actively infected with the virus most likely to infect others? That information can help to tell us how the virus will spread, and how best to use interventions to stop the outbreak. "Human challenge studies enable us to gain granular insights into the infection which we might not otherwise be able to. They play an important role in our understanding of infectious diseases, and should be considered a part of future pandemic preparedness."

Previous findings

The latest findings add to several key clinical insights already gained from the COVID-19 Human Challenge Program, published in February 2022. These include that symptoms start to develop on average two days after contact with the virus, that infection first appears in the throat, infectious virus peaks about five days into infection and, at that stage, is significantly more abundant in the nose than the throat. The first analysis also found that lateral flow tests (LFTs) are a reassuringly reliable indicator of whether infectious virus is present in the nose and throat (i.e., whether they are a likely to be infectious to other people).

Original research published (June 9, 2023) at The Lancet Microbe:

https://doi.org/10.1016/S2666-5247(23)00101-5 

Researchers reviewed data on the incidence of autoimmune diseases in the post-acute coronavirus disease 2019 period.

Background

COVID-19 has caused unprecedented morbidity and mortality across the globe. The immune protection conferred by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and prior COVID-19 history, coupled with developing effective therapeutic agents, has reduced COVID-19-associated mortality. However, post-COVID-19 conditions continue to increase, particularly new-onset autoimmune diseases in COVID-19 convalescents. Autoimmune diseases have been reported following COVID-19 among adults; however, the prevalence and magnitude of the diseases, and the incidence risks among individuals infected with SARS-CoV-2, compared to uninfected individuals, are not well-characterized. Improving understanding of the impact of COVID-19 on the risk of developing post-acute COVID-19 complications, such as autoimmune disease, could aid in implementing preventive measures and initiating prompt treatment to prevent COVID-19-associated morbidities. The findings would also be highly relevant for future pandemics and to analyze the long-term protective effects of COVID-19 vaccines.

About the review

In the review, researchers presented findings of two large-scale cohort studies, evaluating the incidence of autoimmune diseases following acute SARS-CoV-2 infections using participants' electronic medical records.

Evidence on post-COVID autoimmune disease obtained before the studies

Studies comprising pediatric COVID-19 patients suffering from multisystem inflammatory syndrome among children (MIS-C) have indicated that COVID-19 results in dysregulated immunological responses. The clinical manifestations of MIS-C overlap with hyperinflammatory syndromes, including macrophage activation syndrome, Kawasaki disease, and toxic shock syndrome. The pathophysiology of COVID-19-associated immunological dysfunction includes molecular mimicry by SARS-CoV-2 proteins, multiorgan involvement due to the presence of angiotensin-converting enzyme 2 (ACE2) receptors, essential for SARS-CoV-2 entry into host cells, bystander immune cell activation, autoantigen release following SARS-CoV-2-induced tissue damage, superantigen-regulated lymphocyte activation, and epitope spread. Additionally, factors such as genetic susceptibility, age, and comorbidities may contribute to COVID-19 pathogenesis. A previous study comparing the immune responses in SARS-CoV-2 infection and autoimmune disease reported that tissue damage in both conditions is mainly immune-regulated, demonstrated by the presence of anti-nuclear antibodies, anti-Ro/SSA antibodies, and lupus anticoagulant cold agglutinins in both conditions. A retrospective analysis was performed from January 31, 2020, to June 30, 2021, using the Clinical Practice Research Datalink Aurum database, comprising data from 458,147 and 1,818,929 SARS-CoV-2-infected and uninfected adults, respectively, residing in England. A study preprint reported that the incidence of inflammatory bowel disease, psoriasis, and type 1 diabetes was significantly related to COVID-19.

Findings of the two cohort studies assessed post-COVID autoimmune disease

Chang et al. utilized the TriNetX health research network, comprising six million adults across 48 health organizations globally. The propensity score-matched SARS-CoV-2-infected and uninfected groups comprised 887,455 COVID-19 vaccinees each. Post-COVID-19 autoimmune disease incidence was evaluated between January 1, 2020, and December 31, 2021. At six months of follow-up, autoimmune disease incidence was significantly greater in SARS-CoV-2-infected individuals, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, type 1 diabetes, and inflammatory bowel disease, with adjusted hazards ratios (aHR) of 2.99,2.98, 1.96, 2.68, and 1.78, respectively. Post-COVID autoimmune disease risk was consistent across ages. Tesch et al. conducted a study, yet to be peer-reviewed, to evaluate autoimmune disease risks among 640,701 unvaccinated individuals having polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infections in 2020. The findings showed that COVID-19 patients were 43.0% more likely to acquire autoimmune conditions, within three to 15.0 months of infection, compared to over one million age- and sex-matched uninfected individuals. Among autoimmune diseases, the incidence rate ratio (IRR) values were the highest for vasculitis. Further, among those with prior history of autoimmune diseases, COVID-19 resulted in a 23.0% higher risk of another autoimmune disease. Generally, most autoimmune diseases were not COVID-19-specific; however, an essential aspect of SARS-CoV-2 infection was a considerable rise in the incidence and spectrum of autoimmune diseases following acute COVID-19.

Conclusions

Based on the review findings, COVID-19 elevates autoimmune disease risks. Due to the retrospective study designs, the two cohort studies could not provide a causal association between COVID-19 and autoimmune disease development. However, the temporal relationship with COVID-19 history provides reliable and compelling evidence that COVID-19 is associated with elevated autoimmune disease development risks. Health governments and authorities must conduct future studies on the topic to obtain national data and increase the generalizability of the findings. The definitive mechanisms, including genetic and epigenetic predilection, underlying the association and related pathophysiology are not completely understood. However, further research must be performed using particular gene-deficient experimental animals, bioinformatic analysis, and biological approaches, e.g., analyzing transcriptomic pandemic data to obtain genomic signatures, and host responses to viral triggers must be evaluated.

Research cited published (April 12, 2023) In Nature Reviews Rheumatology:

https://www.nature.com/articles/s41584-023-00964-y 

A decade after a landmark report on Americans' shorter lives, the problem has only gotten worse. Unlike other wealthy nations, U.S. life expectancy has not bounced back from the pandemic. Just before Christmas, federal health officials confirmed life expectancy in America had dropped for a nearly unprecedented second year in a row – down to 76 years. While countries all over the world saw life expectancy rebound during the second year of the pandemic after the arrival of vaccines, the U.S. did not. Then, last week, more bad news: Maternal mortality in the U.S. reached a high in 2021. Also, a paper in the Journal of the American Medical Association found rising mortality rates among U.S. children and adolescents. "This is the first time in my career that I've ever seen [an increase in pediatric mortality] – it's always been declining in the United States for as long as I can remember," says the JAMA paper's lead author Steven Woolf, director emeritus of the Center on Society and Health at Virginia Commonwealth University. "Now, it's increasing at a magnitude that has not occurred at least for half a century." Across the lifespan, and across every demographic group, Americans die at younger ages than their counterparts in other wealthy nations. How could this happen? In a country that prides itself on scientific excellence and innovation, and spends an incredible amount of money on health care, the population keeps dying at younger and younger ages.

An unheard alarm

One group of people are not surprised at all: Woolf and the other researchers involved in a landmark, 400-page study ten years ago with a name that says it all: "Shorter Lives, Poorer Health." The research by a panel convened by the National Academy of Sciences and funded by the National Institutes of Health compared U.S. health and death with other developed countries. The results showed – convincingly – that the U.S. was stalling on health advances in the population while other countries raced ahead. The authors tried to sound an alarm, but found few in the public or government or private sectors were willing to listen. In the years since, the trends have worsened. American life expectancy is lower than that of Cuba, Lebanon, and Czechia.

Ten years later, here's a look back at what that eye-popping study found, and why the researchers involved believe it's not too late to turn the trends around.

Beyond bad habits

Americans are used to hearing about how their poor diets and sedentary lifestyles make their health bad. It can seem easy to brush that off as another scold about eating more vegetables and getting more exercise. But the picture painted in the "Shorter Lives" report could shock even those who feel like they know the story. "American children are less likely to live to age 5 than children in other high-income countries," the authors write on the second page. It goes on: "Even Americans with healthy behaviors, for example, those who are not obese or do not smoke, appear to have higher disease rates than their peers in other countries." The researchers catalog what they call the "U.S. health disadvantage" – the fact that living in America is worse for your health and makes you more likely to die younger than if you lived in another rich country like the U.K., Switzerland or Japan. "We went into this with an open mind as to why it is that the U.S. had a shorter life expectancy than people in other countries," says Woolf, who chaired the committee that produced the report. After looking across different age and racial and economic and geographic groups, he says, "what we found was that this problem existed in almost every category we looked at." That's why, says Eileen Crimmins, professor of gerontology at the University of Southern California who was also on the panel that produced the report, they made a deliberate choice to focus on the health of the U.S. population as a whole. "That was a decision – not to emphasize the differences in our population, because there is data that actually shows that even the top proportion of the U.S. population does worse than the top proportion of other populations," she explains. "We were trying to just say – look, this is an American problem."

Digging into the 'why'

The researchers were charged with documenting how Americans have more diseases and die younger and to explore the reasons why. "We were very systematic and thorough about how we thought about this," says Woolf. The panel looked at American life and death in terms of the public health and medical care system, individual behaviors like diet and tobacco use, social factors like poverty and inequality, the physical environment, and public policies and values. "In every one of those five buckets, we found problems that distinguish the United States from other countries." Yes, Americans eat more calories and lack universal access to health care. But there's also higher child poverty, racial segregation, social isolation, and more. Even the way cities are designed makes access to good food more difficult. "Everybody has a pet thing they worry about and say, 'it's oral health' or 'it's suicides' – everyone has something that they're legitimately interested in and want to see more attention to," says John Haaga, who was the director of the Division of Behavioral and Social Research at the National Institute on Aging at NIH, before he retired. "The great value of an exercise like this one was to step back and say, 'OK, all of these things are going on, but which of them best account for these long-term population level trends that we're seeing?' " The answer is varied. A big part of the difference between life and death in the U.S. and its peer countries is people dying or being killed before age 50. The "Shorter Lives" report specifically points to factors like teen pregnancy, drug overdoses, HIV, fatal car crashes, injuries, and violence.

"Two years difference in life expectancy probably comes from the fact that firearms are so available in the United States," Crimmins says. "There's the opioid epidemic, which is clearly ours – that was our drug companies and other countries didn't have that because those drugs were more controlled. Some of the difference comes from the fact that we are more likely to drive more miles. We have more cars," and ultimately, more fatal crashes. "When we were doing it, we were joking we should call it 'Live free and die,' based on the New Hampshire slogan, ['Live free or die']," Crimmins says. "The National Academy of Sciences said, 'That's outrageous, that's too provocative.' " There are some things Americans get right, according to the "Shorter Lives" report: "The United States has higher survival after age 75 than do peer countries, and it has higher rates of cancer screening and survival, better control of blood pressure and cholesterol levels, lower stroke mortality, lower rates of current smoking, and higher average household income." But those achievements, it's clear, aren't enough to offset the other problems that befall many Americans at younger ages. All of this costs the country tremendously. Not only do families lose loved ones too soon, but having a sicker population costs the country as much as $100 billion every year in extra health care costs. "Behind the statistics detailed in this report are the faces of young people – infants, children, and adolescents – who are unwell and dying early because conditions in this country are not as favorable as those in other countries," the paper's authors wrote....

A new discovery in the fight against COVID-19 could lead to a long-lasting vaccine that works on all currently known variants of the ever-mutating virus. With new COVID variants and subvariants evolving faster and faster, each chipping away at the effectiveness of the leading vaccines, the hunt is on for a new kind of vaccine — one that works equally well on current and future forms of a novel coronavirus.

Recently, researchers at the National Institutes of Health (NIH) in Maryland think they have found a new approach to vaccine design that could lead them to a long-lasting jab. As an added bonus, it also might also work on other coronaviruses, not just the SARS-CoV-2 virus that causes COVID-19.

The NIH team reported its findings in a peer-reviewed study that appeared in the journal Cell Host & Microbe earlier this month. The key to the NIH’s potential vaccine design is a part of the virus called the “spine helix.” It’s a coil-shaped structure inside the spike protein, the part of the virus that helps it grab onto and infect host cells. Lots of current vaccines target the spike protein. But none of them specifically target the spine helix. And yet, there are good reasons to focus on that part of the pathogen.

Whereas many regions of the spike protein tend to change a lot as the virus mutates, the spine helix doesn’t. That gives scientists “hope that an antibody targeting this region will be more durable and broadly effective,” Joshua Tan, the lead scientist on the NIH team, told The Daily Beast. Vaccines that target and “bind,” say, the receptor-binding domain region of the spike protein might lose effectiveness if the virus evolves within that region. The great thing about the spine helix, from an immunological standpoint, is that it doesn’t mutate. At least, it hasn’t mutated yet, three years into the COVID pandemic. So a vaccine that binds the spine helix in SARS-CoV-2 should hold up for a long time. And it should also work on all the other coronaviruses that also include the spine helix—and there are dozens of them, including several such as SARS-CoV-1 and MERS that have already made the leap from animal populations and caused outbreaks in people.

To test their hypothesis, the NIH researchers extracted antibodies from 19 recovering COVID patients and tested them on samples of five different coronaviruses, including SARS-CoV-2, SARS-CoV-1 and MERS. Of the 55 different antibodies, most zeroed in on parts of the virus that tend to mutate a lot. Just 11 targeted the spine helix. But those 11 that went after the spine helix worked better, on average, on four of the coronaviruses. A fifth virus, HCoV-NL63, shrugged off all the antibodies.

The NIH team isolated the best spine-helix antibody, COV89-22, and also tested it on hamsters infected with the latest subvariants of the Omicron variant of COVID. “Hamsters treated with COV89-22 showed a reduced pathology score,” the team found. The results are promising. “These findings identify a class of antibodies that broadly neutralize coronaviruses by targeting the stem helix,” the researchers wrote. Don’t break out the champagne quite yet.

“Although these data are useful for vaccine design, we have not performed vaccination experiments in this study and thus cannot draw any definitive conclusions with regard to the efficacy of stem helix-based vaccines,” the NIH team warned. It’s one thing to test a few antibodies on hamsters. It’s another to develop, run trials with and get approval for a whole new class of vaccine. “It is really hard and most things that start out as good ideas fail for one reason or another,” James Lawler, an infectious disease expert at the University of Nebraska Medical Center, told The Daily Beast. And while the spine-helix antibodies appear to be broadly effective, it’s unclear how they stack up against antibodies that are more specific. In other words, a spine-helix jab might work against a bunch of different but related viruses, but work less well against any one virus than a jab that’s tailored specifically for that virus. “Further experiments need to be done to evaluate if they will be sufficiently protective in humans,” Tan said of the spine-helix antibodies.

There’s a lot of work to do before a spine-helix vaccine might be available at the corner pharmacy. And there are a lot of things that could derail that work. Additional studies could contradict the NIH team’s results. The new vaccine design might not work as well on people as it does on hamsters. The new jab could also turn out to be unsafe, impractical to produce or too expensive for widespread distribution. Barton Haynes, a Duke University immunologist, told The Daily Beast he looked at spine-helix vaccine designs last year and concluded they’d be too costly to warrant major investment. The main problem, he said, is that the spine-helix antibodies are less potent and “tough to induce” from their parent B-cells. The harder the pharmaceutical industry has to work to produce a vaccine, and the more vaccine it has to pack into a single dose in order to compensate for lower potency, the less cost-effective a vaccine becomes for mass-production. Maybe a spine-helix jab is in our future. Or maybe not.

Either way, it’s encouraging that scientists are making incremental progress toward a more universal coronavirus vaccine. One that could work for many years on a wide array of related viruses. COVID for one isn’t going anywhere. And with each mutation, it risks becoming unrecognizable to the current vaccines. What we need is a vaccine that’s mutation-proof.

Publication cited published in Cell Host and Microbe (Nov. 7, 2022):

https://doi.org/10.1016/j.chom.2022.10.010 

The virus that causes COVID-19 is a prolific sack of genes that targets not just humans but nonhuman animals as well. And just as humans and animals can infect one another, animals can also infect other animals, says Amélie Desvars-Larrive, an epidemiologist at the University of Veterinary Medicine in Vienna. Scientists have learned a lot about how COVID spreads in humans but less about how it spreads between animals. To make it easier to study the connections among humans, animals and the virus, Desvars-Larrive and a team of researchers gathered scattered reports of COVID-infected mammals from all over the world to create a public database. Understanding how the virus spreads between nonhuman mammals, and then between those mammals and humans, can help us better manage the current pandemic—and prepare for the next one.

“We can’t continue to focus on humans, to have an anthropocentric point of view on this pandemic,” Desvars-Larrive says.  COVID has proved highly contagious among many mammal species: Infections have run rampant among captive mink, and fur farmers have had to kill their entire stocks to stop it. Deer appear particularly susceptible to the virus. Many cat species, both big and small, seem to get it as well. Barbara Han, a disease ecologist at the Cary Institute of Ecosystem Studies in Millbrook, N.Y., who was not involved in the database project, says having this kind of information in one place—rather than split among multiple sources managed by different organizations and government agencies—will likely make it faster and easier for her team to predict how the virus behaves. The database is growing as more animals are tested and reports shared, and scientists hope it will help them to track animal-to-animal COVID infections as well as transmission between animals and humans. Han says that beyond just tallying individual infected species, the database will make it easier for scientists to study how the COVID-causing SARS-CoV-2 virus affects mammal communities and entire ecosystems. “People are fascinated that this pathogen is now in [so many] animals and what it might mean for us,” Han says. “If we don’t have good information about which animals have it now, we can’t get those answers.”

Database at https://vis.csh.ac.at/sars-ani/ 

For an antiviral agent to act as an effective biological barrier on nasal mucosal surface, the formulation preferably has to be maintained on the site of action for several hours, and the nasal spray dispenser can be utilized for administering the solution to the upper respiratory tract. A "first-in-man" clinical study of the nasal spray containing anti-SARS-CoV-2 antibodies derived from bovine colostrum was conducted.

The study on healthy volunteers was undertaken to evaluate how long the bovine antibodies would be maintained on the nasopharyngeal surface after administration of nasal spray. In addition, the study enabled to determine which of the two concentrations of antibodies should be used in the final nasal-spray formulation. The volunteers were followed up for 4h after administration of antibody spray and sampling was done at different time-points during this period. The concentration of antibodies from patient samples was measured using ELISA analysis. In addition, as this was a "first-in-man" study any adverse events following the administration of spray were also monitored.

More details

A new Penn Medicine study finds components of the SARS-CoV-2 virus remain in the gut of some long COVID patients, causing persistent inflammation, vagus nerve dysfunction, and neurological symptoms. Patients with long COVID—the long-term symptoms like brain fog, fatigue, or memory loss in the months or years following COVID-19—can exhibit a reduction in circulating levels of the neurotransmitter serotonin, according to new research published in Cell. The study, led by researchers from the Perelman School of Medicine, sheds new light on the mechanisms of how persistent inflammation after contracting the SARS-CoV-2 virus can cause long-term neurological symptoms. “Many aspects of the basic biology underlying long COVID have remained unclear. As a result, we are lacking effective tools for the diagnosis and treatment of the disease,” says senior author Maayan Levy, an assistant professor of microbiology at Penn Medicine. “Our findings may not only help to untangle some of the mechanisms that contribute to long COVID, but also provide us with biomarkers that can help clinicians diagnose patients and objectively measure their response to individual treatments.”

In a collaboration between Penn’s departments of Microbiology, Pathology and Laboratory Medicine, and Physical Medicine and Rehabilitations’ Post COVID Assessment and Recovery Clinic, researchers evaluated the effects of long COVID in blood and stool samples from various clinical studies and in small animal models. The researchers found that when tryptophan absorption is reduced by persistent viral inflammation, serotonin is depleted, leading to disrupted vagus nerve signaling, which in turn can cause several of the symptoms associated with long COVID, such as memory loss. “Clinicians treating patients with long COVID have been relying on personal reports from those patients to determine if their symptoms are improving. Now, our research shows that there are biomarkers we may be able to use to match patients to treatments or clinical trials that address the specific causes of their long COVID symptoms, and more effectively assess their progress,” says co-senior author, Sara Cherry, a professor of pathology and laboratory medicine. The authors took this insight one step further, to identify if replenishing tryptophan or serotonin in patients who exhibit deficiencies could treat long COVID symptoms. They demonstrated that serotonin levels could be restored, and memory impairment reversed, through treatment with serotonin precursors or selective serotonin reuptake inhibitors.

Read more at Penn Medicine News.

Study published in Cell (Oct. 16, 2023):

https://doi.org/10.1016/j.cell.2023.09.013 

A new U.K. study showed that symptoms of a cold can linger well beyond the main period of illness, suggesting that rather like “long Covid,” “long colds” can also exist. 

• he study, published Friday in scientific journal The Lancet, showed that non-Covid infections can be associated with a range of illnesses more than four weeks after the initial infection.
• After studying 10,171 participants, scientists at the Queen Mary University of London concluded that there may be long-lasting health impacts from other respiratory infections.
• They were unable to say whether the symptoms of “long colds” would last as long as those of “long Covid.”

The study, published Friday in scientific journal The Lancet, showed that non-Covid infections can be associated with a range of illnesses more than four weeks after the initial infection. After studying 10,171 participants, scientists at the Queen Mary University of London concluded that there may be long-lasting health impacts from other respiratory infections, such as the common cold, that are unrecognized. They were unable to say whether the symptoms of “long colds” would last as long as those of “long Covid.” “Post-acute infection syndromes are not a new phenomenon; indeed, many cases of chronic fatigue syndrome are reported to follow an infection-like episode. Nonetheless, these syndromes often go undiagnosed owing to the wide range of symptoms and lack of diagnostic tests,” an introduction to the research on The Lancet website said.

There were similarities between the symptoms of those with “long Covid” and “long colds,” but typical post-Covid issues such as taste and smell deficiencies and dizziness were less common in people suffering from long colds. “Long Covid” typically refers to a range of mid- and long-term effects that can emerge following a Covid infection — including fatigue, breathlessness and cognitive dysfunction. The term “long Covid” was coined in spring 2020 when people who had had Covid-19 did not fully recover for several weeks or months after they were first infected. The World Health Organization defines it as “the continuation or development of new symptoms three months after the initial infection ... with these symptoms lasting for at least two months with no other explanation.”

Research published in eClinical Medicine (Oct. 6, 2023):

https://doi.org/10.1016/j.eclinm.2023.102251

At-home testing is becoming a thing not just for COVID-19, but for seasonal flu and other infections. Here's what you need to know. B efore COVID-19, figuring out whether a sore throat, fever, and runny nose were caused by a cold, flu, or strep wasn’t a top priority. You either powered through, knowing you’d be miserable for a few days but would probably feel better soon or you visited the doctor’s office, urgent care, or emergency room where you might get a test to figure out which virus or bacteria was behind your misery, and maybe a prescription to treat it. But even doctors often don’t order tests, preferring instead to make diagnoses based on symptoms. During the pandemic, however, it became more critical to know who was infected with SARS-CoV-2 so those people could isolate and not spread the virus. At-home test kits became household products, and most people are by now adept at squeezing out a few drops of solution onto a card, sticking a swab up their nose, swirling the swab in the testing liquid, and waiting for a result.

Tests for COVID-19

A number of companies, offer at-home test kits for COVID-19 that people can buy without a prescription. Most of these are rapid antigen tests, which pick up antigens, or substances that the SARS-CoV-2 virus makes. While they are relatively accurate, because it takes some time for levels of these antigens to build up after an infection, these tests are less reliable in the day or so immediately after exposure to the virus. That’s why doctors recommend repeating the test a couple of days apart. Then there are PCR, or molecular, tests, that are closer to the gold standard used in laboratories, and rely on finding the smallest genetic signatures of the virus and amplifying them. Cue Health sells a palm-sized COVID-19 PCR device that people can purchase for $300 that allows for 10 at-home tests and doesn’t require a prescription. The device reads a saliva sample and provides results to a smartphone app in 20 minutes. Other testing companies, such as Labcorp and Everlywell, also sell PCR-based tests for COVID-19, but they are technically collection kits, which means that you have to send a saliva sample into a lab to get results, which can mean critical days will pass before you get results.

Tests for seasonal flu

There is only one at-home test authorized by the FDA for influenza: Lucira, now owned by Pfizer, makes a combined flu and COVID-19 molecular test. The kit uses a PCR-related method of amplifying and reading any viral genes in a sample, providing a result in about 30 minutes. In coming months, eMed, a digital health company that sells test kits and telehealth services, plans to offer that kit, as well another that is currently being reviewed by the U.S. Food and Drug Administration. (The combined kit currently available on eMed’s website only tests for COVID-19 and provides a survey to help telemedicine professionals determine if a user likely has the flu.)

Tests for RSV

There currently aren’t at-home tests for RSV, because typically only infants and the elderly are at risk for severe illness. Doctors’ offices, hospitals, and urgent care centers can perform RSV tests that provide results in about 30 minutes.

The advantages of at-home testing

The currently cumbersome journey from symptoms to treatment rests on people making appointments with their doctors or at an urgent care center and could be contributing to the spread of viruses. Self-testing could reduce some of that risk since people are most infectious while they are waiting to get tested and receive treatment. Ideally, if someone tests themselves at home and finds they are positive for influenza or COVID-19, for example, they don’t necessarily have to physically visit their doctor or go into an urgent care or emergency room, where they could spread the virus to others. Instead, they could video conference with a doctor who could assess their symptoms and at-home test results, then write a prescription for, say, oseltamivir if it’s the flu, or Paxlovid if it’s COVID-19. “If you’re trying to minimize morbidity and mortality, and cut down on transmission, then [at-home] testing is an incredible tool to have,” says Thomas Denny, chief operating officer of the Duke University Human Vaccine Institute.

One of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as “long COVID”) which has emerged as a consequence of the SARS-CoV-2 epidemic. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. In this study, our goal was to assess the plasma metabolome in a total of 100 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC–MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin were measured in long COVID patients by immunoenzymatic assay.

The comparison of paired COVID-19/long COVID-19 samples revealed 53 metabolites that were statistically different. Compared to controls, 27 metabolites remained dysregulated even after two years. Post-COVID-19 patients displayed a heterogeneous metabolic profile. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients. Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.

Scientific Reports (August 1, 2023):

https://doi.org/10.1038/s41598-023-39049-x 

Scientists are still working to unpack the mystery of why some people keep catching the virus while others seem to be resistant. In the meantime, people like Marion have been left with more questions than answers. 

The first time Marion Carrett tested positive for COVID, she didn't think much of it. It was at the height of Australia's Omicron wave, and the virus was striking all around her. The second time, she figured she was just unlucky.  Then came a third positive test.

And a fourth. It wasn't until she caught it a fifth time however, that she began to suspect she was dealing with something more than bad luck. After traveling from her Gold Coast home to Melbourne, Marion was forced to turn right around when the by-then familiar symptoms started. "That's when I went, 'Okay, well, this is out of control. I can't go on holidays, I can't go anywhere'," she says. Over the following 5 months, she would test positive for COVID another five times — returning a negative result between each one. 

After what she believes were 10 separate infections, including nine in the past 10 months, Marion's life is now a shadow of what it once was. Interstate and overseas trips have been canceled because the risk of falling ill is too great. Theatre tickets have been given away time and time again. Weeks have been spent in bed, isolated away from her mother and niece, who she shares a house with. Recently Marion has resorted to giving up going into the office, resolving to spend three months working from home in a desperate attempt to out-maneuver the virus at least long enough to get a fifth vaccine dose. Right now, she says, a six-month break between illnesses is little more than a pipe dream. "I'm really fortunate that I have a job that can be done at home," the 51-year-old Gold Coast resident says. "But I don't really want to be locked in there forever."

Almost as soon as SARS-CoV-2 — the virus that causes COVID — made the jump to humans, frantic work began to understand the biological lottery that dictates who gets it and how serious the infection is. More than three years later, scientists have some answers, but the exact biological conditions that create a NOVID (people who have never caught the virus), someone extremely susceptible like Marion, or most people in between, remain a mystery.

The possible suspects

While we don't yet have the full picture, scientists do have some theories about what makes someone more susceptible to COVID reinfection. The first, and most obvious, possibility to rule out is environmental causes. The more COVID you're exposed to, the more likely you are to catch it. For example, if you spend a lot of time mingling with large groups in enclosed spaces, you probably have a higher risk of getting COVID repeatedly than someone who rarely leaves their home and wears a mask when they do. The next thing to look at is someone's acquired immune response, which Dr Steain says can be "highly variable" and influenced by things like age, diet, lifestyle or gender. "We know that we have people who are quite high responders, who generate robust, quite long-lasting immune responses and other people who for some reason just don't seem to respond as well to vaccination," Dr Steain says. 

Most people are still not eligible for a second booster, but the FDA will revisit the topic after an expert panel meets in June. The Food and Drug Administration on Tuesday approved a second omicron booster from Moderna and Pfizer for people over the age of 65 and immunocompromised individuals.

Why it matters: An additional dose of the bivalent vaccine can help high-risk individuals with waning immunity to COVID, the FDA said.

• Most people who have received a single shot of the bivalent vaccine aren't eligible for a second dose, but the FDA could revise criteria after an expert panel meets to discuss the topic in June.

Details: Tuesday's decision means those over 65 can get a second booster no sooner than four months after the first.

• Immunocompromised people may receive the second shot at least two months after receiving the first dose "and additional doses may be administered at the discretion of, and at intervals determined by, their health care provider," the FDA said.
• The agency made additional changes, saying that unvaccinated people may receive a single dose of the bivalent vaccine as their first shot, rather than multiple doses of the original monovalent vaccine.
• Children between six months and five years old who have received up to three doses of the monovalent vaccine may receive a bivalent vaccine shot, but the number of doses they receive "will depend on the vaccine and their vaccination history," per the FDA.
• The monovalent shots from Moderna and Pfizer are no longer authorized for use in the U.S.

What they're saying: "At this stage of the pandemic, data support simplifying the use of the authorized mRNA bivalent COVID-19 vaccines and the agency believes that this approach will help encourage future vaccination," said Peter Marks, director of FDA's Center for Biologics and Research.

• "Evidence is now available that most of the U.S. population 5 years of age and older has antibodies to SARS-CoV-2 ... either from vaccination or infection that can serve as a foundation for the protection provided by the bivalent vaccines," Marks added.

Catch up fast: An FDA advisory committee in January unanimously recommended that the U.S. replace initial doses of the original COVID monovalent shots with bivalent ones to target omicron subvariants, directing Pfizer, Moderna and Novavax to focus on bivalent vaccines.

Researchers have developed a molecule that, when administered nasally, effectively prevents the disease caused by all known variants COVID. University of Helsinki researchers have developed a molecule that, when administered nasally, effectively prevents the disease caused by all known variants of the SARS-CoV-2 virus. The molecule, called TriSb92, can be a crucial tool in preventing the transmission and spread of the virus, particularly in anticipation of future pandemics. In laboratory animal studies, TriSb92 was confirmed to offer effective protection against coronavirus infection by identifying a region in the spike protein of the coronavirus that is common to all current variants of the virus and inhibiting its functioning. The molecule is effective in preventing infection when administered nasally, even after a few hours of exposure, unlike face masks. Postdoctoral Researcher Anna R. Mäkelä from Professor Kalle Saksela’s research group explains that experiments carried out in cell cultures indicate that TriSb92 also encompasses the very latest variants, including XBB, BF7, and BQ.1.1.  Moreover, the molecule remains fully functional at room temperature for at least 18 months, making it well-suited for use as a nasal spray. The results have been published in the Nature Communications journal.

While the worst stage of the coronavirus pandemic is, at least for the time being, behind us, nasally administered protection can be a crucial help in preventing the spread of the virus in the future.  The latest variants of the virus effectively avoid the immune protection provided by both vaccines and the COVID-19 disease, and current vaccines are not effective in preventing transmission, Mäkelä says. The nasal spray can also protect individuals who do not gain sufficient immunity from vaccines, such as immunocompromised individuals and the elderly. According to the researchers, the molecule could also work against future animal-borne close relatives of SARS-CoV-2, which are expected to be the cause of entirely new coronavirus pandemics.  The region in the coronavirus’s spike protein affected by the TriSb92 molecule has remained almost unchanged in all viral variants so far emerged, making it effective against future SARS-CoV-2 variants, Mäkelä confirms. The molecule is easily and inexpensively produced and could be a very important first line of defence in curbing such a new pandemic, pending the development, production, and distribution of vaccines, she adds. The sherpabody-technology used by the researchers is also applicable to the prevention of many other viral diseases, particularly influenza and other respiratory viruses.  “The whole approach stems from a technical solution based on a binder protein platform developed in Finland, which was not originally intended for the development of an antiviral drug. It provides an opportunity for many other new initiatives based on the accurate identification of diseased cells or pathogens in patients,” Mäkelä says. In the next stage, the molecule must be tested in clinical trials, after which it could be made commercially available. “Successful commercialisation of the nasal spray could lead to the creation of a thriving Finnish business,” Mäkelä points out.

Research cited published (March 24, 2023) in Nature Communications:

https://doi.org/10.1038/s41467-023-37290-6

Scientists have recently discovered a protein expressed in the lung that blocks SARS-CoV-2 infection and serves as a natural protective barrier in the human body. This protein, the leucine-rich repeat-containing protein 15 (LRRC15), is an inbuilt receptor that binds the SARS-CoV-2 virus without passing on the infection.

This finding offers a promising pathway to develop new drugs to prevent viral infection from coronaviruses like COVID-19 or deal with fibrosis in the lungs. The study has been published in the journal PLOS Biology. It was led by Professor Greg Neely with his team members Dr Lipin Loo, a postdoctoral researcher, and PhD student Matthew Waller at the Charles Perkins Centre and the School of Life and Environmental Sciences.

The study is one of three independent papers that reveal this specific protein’s interaction with COVID-19. “Alongside two other groups, one at Oxford, the other at Brown and Yale in the USA, we found a new receptor in the LRRC15 protein that can stop SARS-CoV-2. We found that this new receptor acts by binding to the virus and sequestering it which reduces infection,” Professor Neely explains. “For me, as an immunologist, the fact that there's this natural immune receptor that we didn't know about, that's lining our lungs and blocks and controls virus, that's crazy interesting. We can now use this new receptor to design broad acting drugs that can block viral infection or even suppress lung fibrosis.”

What is LRRC15?

The COVID-19 virus infects humans by using a spike protein to attach to a specific receptor in our cells. It primarily uses a protein called the angiotensin-converting enzyme 2 (ACE2) receptor to enter human cells. Lung cells have high levels of ACE2 receptors, which is why the COVID-19 virus often causes severe problems in this organ of infected people. Like ACE2, LRRC15 is a receptor for coronavirus, meaning the virus can bind to it. But unlike ACE2, LRRC15 does not support an active infection. It can, however, stick to the virus and immobilize it. In the process, it prevents other vulnerable cells from becoming infected.

“We think it acts a bit like Velcro, molecular Velcro, in that it sticks to the spike of the virus and then pulls it away from the target cell types,” Dr Loosaid. LRRC15 is present in many locations such as lungs, skin, tongue, fibroblasts, placenta and lymph nodes. But the researchers found human lungs light up with LRRC15 after infection. “When we stain the lungs of healthy tissue, we don't see much of LRRC15, but then in COVID-19 lungs, we see much more of the protein,” Dr Loosaid. “We think this newly identified protein could be part of our body’s natural response to combating the infection creating a barrier that physically separates the virus from our lung cells most sensitive to COVID-19.”

Implications of the research

“When we studied how this new receptor works, we found that this receptor also controls antiviral responses, as well as fibrosis, and could link COVID-19 infection with lung fibrosis that occurs during long COVID,” Mr Waller said. “Since this receptor can block COVID-19 infection, and at the same time activate our body’s anti-virus response, and suppress our body’s fibrosis response, this is a really important new gene,” Professor Neely said. “This finding can help us develop new antiviral and anti-fibrotic medicines to help treat pathogenic coronaviruses, and possibly other viruses or other situations where lung fibrosis occurs. For fibrosis, there are no good drugs: for example, idiopathic pulmonary fibrosis is currently untreatable.”

Fibrosis is a condition in which lung tissue becomes scarred and thickened, causing breathing difficulties. COVID-19 can cause inflammation and damage to the lungs, leading to fibrosis. The authors said they are developing two strategies against COVID-19 using LRRC15 that could work across multiple variants – one which targets the nose as a preventative treatment, and another aimed at the lungs for serious cases. The researchers also said that the presence or lack of LRRC15, which is involved in lung repair, is an important indication of how severe a COVID-19 infection might become. “A group at Imperial College London independently found that absence of LRRC15 in the blood is associated with more severe COVID, which supports what we think is happening.” Dr Loo said. “If you have less of this protein, you likely have serious COVID. If you have more of it, your COVID is less severe. “We are now trying to understand exactly why this is the case.” The research involved screening human cell cultures for genes and investigating the lungs of human COVID-19 patients.

bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution.

This phylogenetic tree represents the clade distribution of global SARS-CoV-2 viral genomes since the beginning of the pandemic. In the center is the reference Wuhan-1 strain, with outside samples now separated by nucleotide divergence. The last few months have led to an explosion of new variants with further mutations in the viral spike resulting in further antibody evasion, and also carrying changes in many other viral proteins. Some recently sequenced viral genomes from samples collected in Southeast Asia (not shown in this figure) display over a hundred nucleotides changes when compared to Wuhan-1. The graph was generated with nextstrain.org