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Juan Lama
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The Orthocoronavirinae subfamily is large comprising four highly divergent genera. Four seasonal coronaviruses were circulating in humans prior to the coronavirus disease 2019 pandemic. Infection with these viruses induced antibody responses that are relatively narrow with little cross-reactivity to spike proteins of other coronaviruses. Here, we report that infection with and vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces broadly cross-reactive binding antibodies to spikes from a wide range of coronaviruses including members of the sarbecovirus subgenus, other betacoronaviruses including Middle Eastern respiratory syndrome coronavirus, and extending to alpha-, gamma-, and delta-coronavirus spikes. These data show that the coronavirus spike antibody landscape in humans has profoundly been changed and broadened as a result of the SARS-CoV-2 pandemic. While we do not understand the functionality of these cross-reactive antibodies and their impact, there is the possibility that they may lead to enhanced resistance of the population to infection with newly emerging coronaviruses with pandemic potential. IMPORTANCE As demonstrated by severe acute respiratory syndrome coronavirus 2, coronaviruses pose a significant pandemic threat. Here, we show that coronavirus disease 2019 mRNA vaccination can induce significant levels of cross-reactive antibodies against diverse coronavirus spike proteins. While these antibodies are binding antibodies that likely have little neutralization capacity and while their contribution to cross-protection is unclear, it is possible that they may play a role in protection from progression to severe disease with novel coronaviruses. Published in mBio (Dec. 19, 2023):
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Juan Lama
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Outcomes in COVID-19 patients may be better in those recently infected with endemic coronaviruses. There are four common cold coronaviruses that we all catch at some stage. We generate antibodies to them, but our immune memory of them fades over time, and we get re-infected. Their names are all too easily forgotten—OC43, HKU1, 229E, and NL63—but our immune systems may nevertheless remember them for a time. There have been hints that exposure to these common coronaviruses might offer some protection from COVID-19, mostly by looking at signs of immune memory in blood samples taken from before the pandemic. A study in the Journal of Clinical Investigation reports the first clinical evidence linking recent endemic coronavirus infections to less severe COVID-19 and even a reduced death rate in patients. The authors at Boston University School of Medicine found evidence for this by poring over the medical records of thousands of patients who had visited Boston Medical Center as inpatients or outpatients, most probably for respiratory illnesses, between 2015 and 2020. Each person had been assessed for infection using a PCR test that screens for bacteria and viruses, including the four endemic coronaviruses. In total, 15,928 patients had at least one such PCR test. Of them, 875 tested positive for an endemic coronavirus (this group was called eCoV+), while the remaining 15,053 people never had a documented coronavirus infection (termed eCoV-). Of the entire cohort, a total of 1,812 (11.4 percent) later returned for a SARS-CoV-2 test during the initial COVID-19 surge in Boston between March 12 and June 12. “Our study is the first to examine people with known endemic coronavirus infections, and compare them to people who, as far as we know, don’t have any recent documented coronavirus infections,” says Manish Sagar, the lead author of the study and a virologist at Boston Medical Center. The infection rate for SARS-CoV-2 was no different between those who had a recently recorded endemic coronavirus infection (eCoV+) and those who did not have a positive test (eCoV-). This led the authors to conclude that a recent infection with endemic coronaviruses did not keep SARS-CoV-2 at bay—both groups were just as likely to become infected with the pandemic virus. When the researchers peered closer at the data, they observed an important difference between the two groups. “The COVID-19 disease is actually much less severe in those patients who had documented endemic coronavirus infections,” says Sagar. The odds of intensive care unit (ICU) admission were significantly lower in eCoV+ than in eCoV- patients, and there was “a trend towards lower odds of mechanical ventilation,” the authors write in their report. The data also show that among hospitalized patients who had previous positive test results for endemic coronavirus, 4.8 percent of them died compared with 17.7 percent among those in the group without such a test result. Local immune memory may help explain these results. Such “heterotypic immunity,” says immunologist Joseph Mizgerd, director of the pulmonary center at Boston University School of Medicine, occurs when immune memory is etched into the lungs and/or nose. It’s common after other types of respiratory infections and might offer protection against SARS-CoV-2 if elicited by endemic coronaviruses. Although the Boston group did not measure this type of immunity in patients, they now hypothesize that local immunity gained from endemic coronaviruses helps limit lung injury during COVID-19. “We are testing that in ongoing experiments,” Mizgerd says by email. He adds that such cross-reactive immunity is often mediated by memory T cells, which can localize in the lung, and he notes that lung-localized heterotypic T cells can prevent severe lung infection during pneumonias caused by other types of respiratory pathogens. If indeed prior infection does ramp up protection against SARS-CoV-2, the study could not answer how long it takes for any such benefit to taper off. Nor did the work shed light on which of the four endemic coronaviruses in particular might be offering protection against the pandemic virus. The scientists are seeking funding to expand their research and include data from other institutions.... Study cited available in J. Clinical Investigation: https://doi.org/10.1172/JCI143380
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Juan Lama
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Research on archived blood does not bear out hopes that antibodies against ‘seasonal’ coronaviruses can protect against severe COVID-19. Paul Bieniasz and Theodora Hatziioannou at the Rockefeller University in New York City and their colleagues analysed 37 blood-serum samples collected before 2020 from people in the United Kingdom (D. Poston et al. Preprint at medRxiv https://doi.org/fc4g; 2020). All of the study participants had tested positive for one of the seasonal human coronaviruses, which can cause the common cold. The team found that each serum sample contained antibodies that could disable at least one common-cold coronavirus, blocking the virus’s ability to infect human cells in a lab dish. But the serum could not disable a hybrid virus that had been engineered to carry SARS-CoV-2’s spike protein, a crucial player in the virus’s invasion of host cell The results suggest that antibodies to common-cold coronaviruses do not have a major role in determining why some people with COVID-19 fare worse than others, the authors say. The findings have not yet been peer reviewed. Preprint available at medRxiv (Oct. 11, 2020): https://doi.org/10.1101/2020.10.08.20209650
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Juan Lama
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T cell reactivity against SARS-CoV-2 was observed in unexposed people; however, the source and clinical relevance of the reactivity remains unknown. It is speculated that this reflects T cell memory to circulating ‘common cold’ coronaviruses. It will be important to define specificities of these T cells and assess their association with COVID-19 disease severity and vaccine responses. Recent studies have shown T cell reactivity to SARS-CoV-2 in 20–50% of unexposed individuals; it is speculated that this is due to T cell memory to common cold coronaviruses. Here, Crotty and Sette discuss the potential implications of these findings for disease severity, herd immunity and vaccine development.... Original review Published in Nature (July 7, 2020): https://doi.org/10.1038/s41577-020-0389-z
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Juan Lama
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On January 9 of this year, Chinese state media reported that a team of researchers led by Xu Jianguo had identified the pathogen behind a mysterious outbreak of pneumonia in Wuhan as a novel coronavirus. Although the virus was soon after named 2019-nCoV, and then renamed SARS-CoV-2, it remains commonly known simply as the coronavirus. While that moniker has been catapulted into the stratosphere of public attention, it’s somewhat misleading: Not only is it one of many coronaviruses out there, but you’ve almost certainly been infected with members of the family long before SARS-CoV-2’s emergence in late 2019. Coronaviruses take their name from the distinctive spikes with rounded tips that decorate their surface, which reminded virologists of the appearance of the sun’s atmosphere, known as its corona. Various coronaviruses infect numerous species, but the first human coronaviruses weren’t discovered until the mid-1960s. “That was sort of the golden days, if you will, of virology, because at that time the technology became available to grow viruses in the laboratory, and to study viruses in the laboratory,” says University of Texas Southwestern Medical Center pediatrician Jeffrey Kahn, who studies respiratory viruses. But the two coronaviruses that were identified at the time, OC43 and 229E, didn’t elicit much research interest, says Kahn, who wrote a review on coronaviruses a few years after the SARS outbreak of 2003. “I don't believe there was a big effort to make vaccines against these because these were thought to be more of a nuisance than anything else.” The viruses cause typical cold symptoms such as a sore throat, cough, and stuffy nose, and they seemed to be very common; one early study estimated that 3 percent of respiratory illnesses in a children’s home in Georgia over seven years in the 1960s had been caused by OC43, and a 1986 study of children and adults in northern Italy found that it was rare to come across a subject who did not have antibodies to that virus (an indicator of past infection)......
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Juan Lama
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Four seasonal coronaviruses—2 of which are betacoronaviruses, like SARS-CoV-2—cause about 30% of common colds. Instead of helping to fight off COVID-19, antibodies to these pathogens may interfere with the SARS-CoV-2 immune response, a recent study of health care workers suggests. Although these preexisting antibodies are ubiquitous, individuals’ varying levels of them might factor into the broad spectrum of responses to the novel coronavirus, which range from immunity against infection all the way to severe respiratory distress and death. Almost since the COVID-19 pandemic began, scientists have investigated how immunity to the seasonal coronaviruses might influence infections with SARS-CoV-2, a new but related virus. A number of reports now show that preexisting common cold coronavirus antibodies are active in SARS-CoV-2 infections, according to Patrick Wilson, PhD, a professor of pediatrics and a scientist in the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine, who was not involved with the new study. Last year, Wilson and colleagues at the University of Chicago, where he was based at the time, found that people with severe acute SARS-CoV-2 infections had substantial numbers of antibody–secreting B cells that reacted to common cold coronaviruses. The cells had highly mutated and variable genes, likely indicating that they predated the patients’ novel coronavirus infections. As for an influence on COVID-19, one early 2021 University of Pennsylvania study concluded that preexisting antibodies to common cold coronaviruses did not correlate with SARS-CoV-2 protection. But the overall findings have been inconsistent. Taken together, it’s hard to say which way they lean because the studies’ scope, participants, and methods have varied, according to Maureen McGargill, PhD, the senior author of the recent health care workers study and an associate faculty member in immunology at St Jude Children’s Research Hospital, where the research took place. “Keeping these caveats in mind, there were seven reports that concluded high levels of common coronavirus immunity was beneficial, while four reported that it was detrimental, and three reported that it did not have an impact,” McGargill wrote in an email to JAMA. In her study, published in Cell Host & Microbe this January, she and St Jude colleagues investigated whether different levels of preexisting immunity to common cold coronaviruses influenced the likelihood of becoming infected with SARS-CoV-2 or accounted for diverse outcomes following infection. “This is important to study as we still do not understand why some individuals are more susceptible than others to SARS-CoV-2 infection,” she explained.... Published in JAMA (Jan. 26, 2022): https://doi.org/10.1001/jama.2022.0326
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Juan Lama
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A provocative study suggests that certain colds may leave antibodies against the new coronavirus, perhaps explaining why children are more protected than adults. It’s been a big puzzle of the pandemic: Why are children so much less likely than adults to become infected with the new coronavirus and, if infected, less likely to become ill? A possible reason may be that many children already have antibodies to other coronaviruses, according to researchers at the Francis Crick Institute in London. About one in five of the colds that plague children are caused by viruses in this family. Antibodies to those viruses may also block SARS-CoV-2, the new coronavirus causing the pandemic. In a study published Friday in Science, the group, led by George Kassiotis, who heads the Retroviral Immunology Laboratory at the institute, reports that on average only 5 percent of adults had these antibodies, but 43 percent of children did. Researchers who did not participate in the study were intrigued by the finding. H. Benjamin Larman, an immunologist at Johns Hopkins School of Medicine, called it a “well-done study that puts forward a compelling theory which is supported by their data.” Stephen J. Elledge, a genetics professor at Harvard Medical School and Brigham and Women’s Hospital, had a similar response. He and others have found many people have antibodies to common colds caused by other coronaviruses; in laboratory studies, these antibodies also block the new coronavirus. In March, as the pandemic was just beginning, Dr. Kassiotis and his colleagues decided to develop a highly sensitive antibody test. To assess it, they examined blood samples taken before the pandemic from over 300 adults and 48 children and adolescents, comparing them with samples from more than 170 people who had been infected with the new coronavirus. The scientists expected samples taken before the pandemic to have no antibodies that attacked the new coronavirus. Those were to be the controls for the test the scientists were developing. Instead, they found that many children, and some adults, carried one antibody in particular that can prevent coronaviruses, including the new one, from entering cells. This antibody attaches itself to a spike that pokes out of coronaviruses. While the tip of the spike is unique to the new coronavirus, the base is found in all coronaviruses, Dr. Kassiotis said. In lab tests, antibodies to the base of the spike prevented the new coronavirus from entering cells in order to reproduce. Now the researchers are planning to expand their study to monitor thousands of children and adults. Some have antibodies that can block the new coronavirus in lab tests. Others do not. “If they have the pandemic strain, are they protected?” Dr. Kassiotis asked. Will they get sick, he wondered, or will the infection be all but undetectable? Dr. Elledge and his colleagues at Harvard developed their own highly specific, sensitive and exhaustive antibody test, VirScan. It is able to detect a diverse collection of antibodies with that are directed at any of more than 800 places on the new coronavirus, including the antibody that Dr. Kassiotis and his colleagues studied. After examining blood taken from 190 people before the pandemic emerged, Dr. Elledge and his colleagues concluded that many already had antibodies, including the one targeting the base of the spike — presumably from infections with related coronaviruses that cause colds... Cited study published in Science (Nov. 6, 2020): https://doi.org/10.1126/science.abe1107
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Juan Lama
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The COVID-19 pandemic has claimed the lives of more than one million people worldwide. The causative agent, SARS-CoV-2, is a member of the Coronaviridae family, which are viruses that cause respiratory infections of varying severity. The cellular host factors and pathways co-opted by SARS-CoV-2 and other coronaviruses in the execution of their life cycles remain ill-defined. To develop an extensive compendium of host factors required for infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-OC43, HCoV-NL63, and HCoV-229E), we performed parallel genome-scale CRISPR knockout screens. These screens uncovered multiple host factors and pathways with pan-coronavirus and virus-specific functional roles, including major dependency on glycosaminoglycan biosynthesis, SREBP signaling, and glycosylphosphatidylinositol biosynthesis, as well as an unexpected requirement for several poorly characterized proteins. We identified an absolute requirement for the VTT-domain containing protein TMEM41B for infection by SARS-CoV-2 and all other coronaviruses. This human Coronaviridae host factor compendium represents a rich resource to develop new therapeutic strategies for acute COVID-19 and potential future coronavirus spillover events. Preprint available in bioRxiv (October 8, 2020): https://doi.org/10.1101/2020.10.07.326462
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Juan Lama
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In the current COVID-19 pandemic a key unsolved question is the duration of acquired immunity in recovered individuals. The recent emergence of SARS-CoV-2 precludes a direct study on this virus, but the four seasonal human coronaviruses may reveal common characteristics applicable to all human coronaviruses. We monitored healthy subjects over a time span of 35 years (1985-2020), providing a total of 2473 follow up person-months, and determined a) the time to reinfection by the same seasonal coronavirus and b) the dynamics of coronavirus antibody depletion post-infection. An alarmingly short duration of protective immunity to coronaviruses was found. Reinfections occurred frequently at 12 months post-infection and there was for each virus a substantial reduction in antibody levels as soon as 6 months post-infection. Preprint Available (June 16, 2020): https://doi.org/10.1101/2020.05.11.20086439 Article published in Nat. Medecine (Sept. 14, 2020): https://doi.org/10.1038/s41591-020-1083-1
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