Immunology

An ancient conflict between hosts and pathogens has driven the innate and adaptive arms of immunity. Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that can be leveraged therapeutically. The humoral response to SARS-CoV-2 infection has been the focus of intense research, and the role of the innate immune system has received significantly less attention. Here, we review current knowledge of the innate immune response to SARS-CoV-2 infection and the various means SARS-CoV-2 employs to evade innate defense systems. We also consider the role of innate immunity in SARS-CoV-2 vaccines and in the phenomenon of long COVID.

Published in Cell. Mol. Immunology (Nov. 20, 2023):

https://doi.org/10.1038/s41423-023-01104-y 

The glycosylation of viral envelope proteins can play important roles in virus biology and immune evasion. The spike (S) glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) includes 22 N-linked glycosylation sequons and 17 O-linked glycosites. Here, we investigated the effect of individual glycosylation sites on SARS-CoV-2 S function in pseudotyped virus infection assays and on sensitivity to monoclonal and polyclonal neutralizing antibodies. In most cases, removal of individual glycosylation sites decreased the infectiousness of the pseudotyped virus. For glycosylation mutants in the N-terminal domain (NTD) and the receptor binding domain (RBD), reduction in pseudotype infectivity was predicted by a commensurate reduction in the level of virion-incorporated spike protein.

Notably, the presence of a glycan at position N343 within the RBD had diverse effects on neutralization by RBD-specific monoclonal antibodies (mAbs) cloned from convalescent individuals. The N343 glycan reduced overall sensitivity to polyclonal antibodies in plasma from COVID-19 convalescent individuals, suggesting a role for SARS-CoV-2 spike glycosylation in immune evasion. However, vaccination of convalescent individuals produced neutralizing activity that was resilient to the inhibitory effect of the N343 glycan.

Preprint at bioRxiv (June 30, 2023):

 https://doi.org/10.1101/2023.06.30.547241 

Epstein-Barr virus (EBV) reactivation resulting from the inflammatory response to coronavirus infection may be the cause of previously unexplained long COVID symptoms—such as fatigue, brain fog, and rashes—that occur in approximately 30% of patients after recovery from initial COVID-19 infection. The first evidence linking EBV reactivation to long COVID, as well as an analysis of long COVID prevalence, is outlined in a new long COVID study published in the journal Pathogens.  "We ran EBV antibody tests on recovered COVID-19 patients, comparing EBV reactivation rates of those with long COVID symptoms to those without long COVID symptoms," said lead study author Jeffrey E. Gold of World Organization. "The majority of those with long COVID symptoms were positive for EBV reactivation, yet only 10% of controls indicated reactivation." The researchers began by surveying 185 randomly selected patients recovered from COVID-19 and found that 30.3% had long term symptoms consistent with long COVID after initial recovery from SARS-CoV-2 infection. This included several patients with initially asymptomatic COVID-19 cases who later went on to develop long COVID symptoms.

The researchers then found, in a subset of 68 COVID-19 patients randomly selected from those surveyed, that 66.7% of long COVID subjects versus 10% of controls were positive for EBV reactivation based on positive EBV early antigen-diffuse (EA-D) IgG or EBV viral capsid antigen (VCA) IgM titers. The difference was significant (p < 0.001, Fisher's exact test). "We found similar rates of EBV reactivation in those who had long COVID symptoms for months, as in those with long COVID symptoms that began just weeks after testing positive for COVID-19," said coauthor David J. Hurley, Ph.D., a professor and molecular microbiologist at the University of Georgia. "This indicated to us that EBV reactivation likely occurs simultaneously or soon after COVID-19 infection." The relationship between SARS-CoV-2 and EBV reactivation described in this study opens up new possibilities for long COVID diagnosis and treatment. The researchers indicated that it may be prudent to test patients newly positive for COVID-19 for evidence of EBV reactivation indicated by positive EBV EA-D IgG, EBV VCA IgM, or serum EBV DNA tests. If patients show signs of EBV reactivation, they can be treated early to reduce the intensity and duration of EBV replication, which may help inhibit the development of long COVID. "As evidence mounts supporting a role for EBV reactivation in the clinical manifestation of acute COVID-19, this study further implicates EBV in the development of long COVID," said Lawrence S. Young, Ph.D., a virologist at the University of Warwick, and Editor-in-Chief of Pathogens. "If a direct role for EBV reactivation in long COVID is supported by further studies, this would provide opportunities to improve the rational diagnosis of this condition and to consider the therapeutic value of anti-herpesvirus agents such as ganciclovir."

Original findings published in Pathogens (June 10, 2021):

https://doi.org/10.3390/pathogens10060763

COVID-19, caused by SARS-CoV-2, can involve sequelae and other medical complications that last weeks to months after initial recovery, which has come to be called Long-COVID or COVID long-haulers. This systematic review and meta-analysis aims to identify studies assessing long-term effects of COVID-19 and estimates the prevalence of each symptom, sign, or laboratory parameter of patients at a post-COVID-19 stage. LitCOVID (PubMed and Medline) and Embase were searched by two independent researchers. All articles with original data for detecting long-term COVID-19 published before 1st of January 2021 and with a minimum of 100 patients were included. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. Heterogeneity was assessed using I2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed.

A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included. The follow-up time ranged from 15 to 110 days post-viral infection. The age of the study participants ranged between 17 and 87 years. It was estimated that 80% (95% CI 65-92) of the patients that were infected with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). All meta-analyses showed medium (n=2) to high heterogeneity (n=13). In order to have a better understanding, future studies need to stratify by sex, age, previous comorbidities, severity of COVID-19 (ranging from asymptomatic to severe), and duration of each symptom. From the clinical perspective, multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.

Preprint available in medRxiv (Jan. 30, 2021):

https://doi.org/10.1101/2021.01.27.21250617 

Cytokine Storm Cytokine storm, a life-threatening disorder involving cytokine elevations and immune-cell hyperactivation, has various causes and is characterized by constitutional symptoms

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. 

NIH-funded study suggests need to boost CD8+ T cell response after infection. The magnitude and quality of a key immune cell’s response to vaccination with two doses of the Pfizer-BioNTech COVID-19 vaccine were considerably lower in people with prior SARS-CoV-2 infection compared to people without prior infection, a study has found. In addition, the level of this key immune cell that targets the SARS-CoV-2 spike protein was substantially lower in unvaccinated people with COVID-19 than in vaccinated people who had never been infected. Importantly, people who recover from SARS-CoV-2 infection and then get vaccinated are more protected than people who are unvaccinated. These findings, which suggest that the virus damages an important immune-cell response, were published today in the journal Immunity. The study was co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and led by Mark M. Davis, Ph.D. Dr. Davis is the director of the Stanford Institute for Immunity, Transplantation and Infection and a professor of microbiology and immunology at Stanford University School of Medicine in Palo Alto, California. He is also a Howard Hughes Medical Institute Investigator. Dr. Davis and colleagues designed a very sensitive tool to analyze how immune cells called CD4+ T cells and CD8+ T cells respond to SARS-CoV-2 infection and vaccination. These cells coordinate the immune system’s response to the virus and kill other cells that have been infected, helping prevent COVID-19.

The tool was designed to identify T cells that target any of dozens of specific regions on the virus’s spike protein as well as some other viral regions. The Pfizer-BioNTech vaccine uses parts of the SARS-CoV-2 spike protein to elicit an immune response without causing infection. The investigators studied CD4+ and CD8+ T-cell responses in blood samples from three groups of volunteers. One group had never been infected with SARS-CoV-2 and received two doses of the Pfizer-BioNTech COVID-19 vaccine. The second group had previously been infected with SARS-CoV-2 and received two doses of the vaccine. The third group had COVID-19 and was unvaccinated. The researchers found that vaccination of people who had never been infected with SARS-CoV-2 induced robust CD4+ and CD8+ T-cell responses to the virus’ spike protein. In addition, these T cells produced multiple types of cell-signaling molecules called cytokines, which recruit other immune cells—including antibody-producing B cells—to fight pathogens. However, people who had been infected with SARS-CoV-2 prior to vaccination produced spike-specific CD8+ T cells at considerably lower levels—and with less functionality—than vaccinated people who had never been infected. Moreover, the researchers observed substantially lower levels of spike-specific CD8+ T cells in unvaccinated people with COVID-19 than in vaccinated people who had never been infected. Taken together, the investigators write, these findings suggest that SARS-CoV-2 infection damages the CD8+ T cell response, an effect akin to that observed in earlier studies showing long-term damage to the immune system after infection with viruses such as hepatitis C or HIV. The new findings highlight the need to develop vaccination strategies to specifically boost antiviral CD8+ T cell responses in people previously infected with SARS-CoV-2, the researchers conclude.  

Research published (March 15, 2023) in Immunity:

https://doi.org/10.1016/j.immuni.2023.03.005 

5 juillet 2021 Une équipe de scientifiques internationaux a récemment identifié des anticorps ultrapuissants anti-coronavirus 2 (SRAS-CoV-2) anti-syndrome respiratoire aigu sévère provenant de donneurs convalescents. Les anticorps sont capables de neutraliser une large gamme de variantes du SRAS-CoV-2, même à des concentrations sous-nanomolaires. De plus, les combinaisons de ces anticorps réduisent le risque de générer des mutants d'échappement in vitro. L'étude a été publiée le 13 août 2021 dans la revue Science. https://www.science.org/doi/full/10.112 ... ce.abh1766 Sur le fond Le coronavirus 2 du syndrome respiratoire aigu sévère (SRAS-CoV-2), l'agent pathogène responsable de la maladie à coronavirus 2019 (COVID-19), est un virus à ARN simple brin enveloppé de sens positif appartenant à la famille des bêta-coronavirus humains. La glycoprotéine de pointe sur l'enveloppe virale est composée de deux sous-unités S1 et S2. Dont, la sous-unité S1 se lie directement au récepteur de l'enzyme de conversion de l'angiotensine 2 (ACE2) de la cellule hôte via le domaine de liaison au récepteur (RBD) pour initier le processus d'entrée virale. La majorité des anticorps thérapeutiques contre le SRAS-CoV-2 ont été conçus sur la base de la séquence de protéine de pointe native trouvée dans la souche Wuhan originale du SRAS-CoV-2. Ainsi, de nouvelles variantes virales avec de multiples mutations de la protéine de pointe peuvent probablement développer une résistance contre ces anticorps. Dans ce contexte, des études ont montré que les anticorps développés en réponse aux vaccins COVID-19 actuellement disponibles ont moins d'efficacité pour neutraliser les nouvelles variantes préoccupantes (COV) du SRAS-CoV, notamment B.1.1.7, B.1.351, P1 et B.1.617.2. Dans la présente étude, les scientifiques ont isolé et caractérisé des anticorps anti-pic RBD de patients guéris du COVID-19. Identification des anticorps Les anticorps ont été isolés de quatre donneurs convalescents infectés par la souche Washington-1 (WA-1) du SRAS-CoV-2. La séquence de pointe dans la souche WA-1 est similaire à la séquence de pointe dans la souche originale de Wuhan. Les cellules B isolées à partir d'échantillons de sang provenant de donneurs ont été triées pour l'identification des anticorps. Cela a conduit à l'identification de quatre anticorps neutralisants puissants ciblant le pic RBD. Ces anticorps ont montré une forte affinité pour le pic SRAS-CoV-2 même à des concentrations nanomolaires. Pour déterminer si les anticorps hautement puissants pouvaient bloquer l'ACE2 - la liaison aux pointes, des tests d'interférométrie par compétition ACE2 et de liaison à la surface cellulaire ont été effectués. Les résultats ont révélé que sur 4 anticorps, deux liés aux RBD en « position haute » et deux liés aux RBD en « position basse ». De plus, trois anticorps sur quatre bloquaient directement l'interaction RBD - ACE2, et un inhibait indirectement l'interaction par encombrement stérique - le ralentissement des réactions chimiques dû à l'encombrement stérique. Neutralisation médiée par les anticorps Tous les anticorps expérimentaux ont montré une puissance significativement plus élevée dans la neutralisation des variants contenant la mutation D614G que la souche WA-1. Une analyse plus poussée avec des particules lentivirales pseudotypées avec des variantes à pointes a indiqué que les anticorps maintiennent une puissance élevée pour neutraliser un ensemble diversifié de 10 variantes à pointes. Il est important de noter que trois des quatre anticorps expérimentaux ont montré une grande efficacité pour neutraliser 13 variantes circulantes préoccupantes/intéressantes du SRAS-CoV-2, notamment B.1.1.7, B.1.351, B.1.427, B.1.429, B.1.526, P.1, P.2, B.1.617.1 et B.1.617.2. Analyse structurale et fonctionnelle des anticorps Des analyses au microscope cryoélectronique des structures du complexe anticorps-antigène ont révélé que deux anticorps avec le pouvoir de neutralisation le plus élevé se lient à la protéine de pointe avec tous les RBD en « position haute ». D'autres analyses structurelles ont révélé que les modes de liaison à l'épitope des anticorps sont responsables d'un pouvoir neutralisant élevé contre les COV du SRAS-CoV-2. La capacité de liaison et de neutralisation des anticorps a été affectée négativement par trois mutations de pointe, dont F486R, N487R et Y489R. Résistance aux anticorps Une pression de sélection d'anticorps a été appliquée à la souche WA-1 pour identifier les mutations potentielles d'échappement qui peuvent apparaître au cours de l'infection virale. La pression de sélection positive a été appliquée en incubant le virus avec des concentrations croissantes des anticorps pour déclencher la résistance aux anticorps. Dans deux des anticorps les plus puissants, l'un était affecté négativement par une seule mutation F486S et l'autre était affecté par les mutations F486L, N487D et Q493R. Cependant, la mutation Q493R a montré un impact négligeable sur la liaison et la neutralisation. Une analyse plus poussée a révélé que ces mutations d'échappement sont principalement absentes dans les variantes virales circulantes, indiquant l'absence de pression de sélection. En effectuant plusieurs cycles de sélection à l'aide de traitements combinés avec deux anticorps, il a été observé que les combinaisons d'anticorps pourraient réduire le risque d'acquisition de mutations d'échappement et le développement ultérieur de variantes virales résistantes. Source: News Medical et merci à QcLiLi, dans Twitter En référence à "Wang L. 2021. Anticorps ultrapuissants contre des variantes diverses et hautement transmissibles du SRAS-CoV-2. Sciences". -- -- --

Scientists across the world are closely tracking the spread of mutations in the coronavirus and investigating whether they could render current vaccines less effective. SARS-CoV-2 is no Ferrari among viruses when it comes to mutations. Scientists reckon that its 30,000-base RNA genome acquires around two single-letter mutations a month, a rate around half as fast as influenza and one-quarter the rate of HIV. But allowed to multiply and jump from body to body for more than a year, SARS-CoV-2 has inevitably flourished into a genetically diverse tree branching into countless different variants.  Many variants—defined by a specific assortment of mutations—are relatively unremarkable. But scientists have been keeping a close watch on three rapidly spreading variants—first identified in the UK, South Africa, and Brazil—which harbor an unusual constellation of mutations. They all share a mutation called N501Y that affects the receptor binding domain (RBD) of the spike protein, which the virus uses to clasp onto human cells’ receptors and enter them. That mutation replaces SARS-CoV-2’s 501st amino acid, asparagine, with tyrosine, potentially allowing it to bind more tightly to ACE2 receptors, studies in cells and animal models suggest. By itself, that mutation isn’t unusual, but the variants possess an exceptionally large number of other mutations, some also on the spike protein. Substantive changes to a virus’ behavior, such as heightened transmissibility, are likely the result of multiple mutations rather than individual ones, molecular epidemiologist Emma Hodcroft of the University of Bern tells The Atlantic.  The observation that similar mutations have appeared in three independent variants, and the fact that they are spreading, makes scientists suspect that they may have an evolutionary edge. “They have multiple, eight to ten, mutations in the spike protein all stacked up at once—that suggests that there [is] a lot of evolution and adaption of the protein happening,” Daniel Jones, a molecular pathologist at the Ohio State University, tells The Scientist. “The concern being that since that’s the target of vaccinations and . . . the target for antibody [therapies] like the Regeneron cocktail, for instance, that it might be the beginning of a virus that could evade antibody therapy and/or vaccine coverage.”

SARS-CoV-2 mutations’ effects on transmissibility

It’s often in a virus’ interest to become more transmissible so it can spread and replicate more quickly. Earlier in the pandemic, a spike protein mutation known as D614G—which is widely believed to have made the virus more transmissible—surged to dominance around the world, notes virologist John Moore of Weill Cornell Medical College. Epidemiological data suggest that the B.1.1.7 variant, a descendant of the D614G lineage first identified in the UK that has spread to other parts of the world, also has heightened transmissibility. Eight of the 17 mutations it has recently accumulated are in the spike protein, which could feasibly have an effect on ACE2 binding and virus replication. Hypothetically, if a virus can bind more tightly to the body’s ACE2 receptors, it could be more capable of establishing an infection once it gets into the body and/or of generating more viral particles in the upper respiratory tract, making it easier to transmit to other people, particularly during the presymptomatic stage, explains Theodora Hatziioannou, a virologist at the Rockefeller University in New York. She adds that in her view, it’s hard to definitively ascribe case surges, including the current one in the UK, to single factors such as increased transmissibility, over other driving factors, such as what she sees as ineffective lockdown policies. “I’m not saying that [increased] transmissibility is out of the question. I’m just saying it’s extremely hard to prove.” In South Africa, epidemiologists have estimated that the new variant there, B.1.351 (also known as 501Y.V2), is around 50 percent more contagious compared with dominant lineages, based on its rapid spread, according to The Wall Street Journal. In Brazil, it’s too early to conclude whether a variant now circulating there, called P.1, is inherently more transmissible. First reported on January 12 in the state of Amazonas, it’s been associated with a devastating surge in cases in Manaus, a city where researchers had previously estimated that 75 percent of residents had already been infected with SARS-CoV-2. But it’s still unclear whether properties of the virus itself are contributing to the surge, says virologist Paola Resende of the Oswaldo Cruz Institute in Rio de Janeiro. “In Brazil, we can see a lot of parties, we can see the pubs crowded, and people are on the streets not wearing masks. I think this behavior of the population is the main reason [for] the increase.”

Evading the immune system

Our immune system—and, in particular, antibodies—is a powerful evolutionary force on viruses. Some pathogens such as influenza, and maybe also common cold-causing coronaviruses, mutate their proteins toward new shapes to avoid being targeted by antibodies that would normally prevent them from infecting cells, a process known as antigenic drift. A study recently posted as a preprint to bioRxiv by Hatziioannou and her colleagues suggests that the RBD mutations present in the B.1.351 variant are due to antigenic drift. The team passaged a model virus bearing the dominant SARS-CoV-2 spike protein in the presence of individual neutralizing antibodies extracted from people who had received either the Moderna or Pfizer/BioNTech vaccine. Depending on which antibody they were cultured with, the viruses would gradually adopt a single mutation—either E484K, K417N, and N501Y—which are present in B.1.351. That suggests that “the virus is mutating in these positions to avoid antibodies,” Hatziioannou says. Such antibody-escape mutations don’t necessarily mean that the virus will cause more severe disease or entirely outwit the immune response, she cautions. There are other parts of the immune system to help clear the virus. There’s no evidence so far to suggest that the variants identified in South Africa or Brazil are more lethal. Based on an analysis of several datasets, scientists in the UK suggested last week there’s a “realistic possibility” that B.1.1.7 is deadlier than previous strains, but experts say it’s still too early to draw that conclusion. Another concern is about whether people who have overcome mild infections with older variants could become reinfected with a new one. Nobody that I know has been losing a moment of sleep over the UK variant from a vaccine-efficacy perspective.....

Home/Newsroom/Q&A Detail/Coronavirus disease (COVID-19): Herd immunity, lockdowns and COVID-19 Coronavirus disease (COVID-19): Herd immunity, lockdowns and COVID-19 15 October 2020 | Q&A What is ‘herd immunity’? ‘Herd immunity’, also known as ‘population immunity’, is a concept used for vaccination, in which a population can be protected from a certain virus if a threshold of vaccination is reached. Herd immunity is achieved by protecting people from a virus, not by exposing them to it. Vaccines train our immune systems to create proteins that fight disease, known as ‘antibodies’, just as would happen when we are exposed to a disease but – crucially – vaccines work without making us sick. Vaccinated people are protected from getting the disease in question and passing it on, breaking any chains of transmission. Visit our webpage on COVID-19 and vaccines for more detail. With herd immunity, the vast majority of a population are vaccinated, lowering the overall amount of virus able to spread in the whole population. As a result, not every single person needs to be vaccinated to be protected, which helps ensure vulnerable groups who cannot get vaccinated are kept safe. The percentage of people who need to have antibodies in order to achieve herd immunity against a particular disease varies with each disease. For example, herd immunity against measles requires about 95% of a population to be vaccinated. The remaining 5% will be protected by the fact that measles will not spread among those who are vaccinated. For polio, the threshold is about 80%. Achieving herd immunity with safe and effective vaccines makes diseases rarer and saves lives. Find out more about the science behind herd immunity by watching or reading this interview with WHO’s Chief Scientist, Dr Soumya Swaminathan. Attempts to reach ‘herd immunity’ through exposing people to a virus are scientifically problematic and unethical. Letting COVID-19 spread through populations, of any age or health status will lead to unnecessary infections, suffering and death. The vast majority of people in most countries remain susceptible to this virus. Seroprevalence surveys suggest that in most countries, less than 10% of the population have been infected with COVID-19. We are still learning about immunity to COVID-19. Most people who are infected with COVID-19 develop an immune response within the first few weeks, but we don’t know how strong or lasting that immune response is, or how it differs for different people. There have also been reports of people infected with COVID-19 for a second time.          Until we better understand COVID-19 immunity, it will not be possible to know how much of a population is immune and how long that immunity last for, let alone make future predictions. These challenges should preclude any plans that try to increase immunity within a population by allowing people to get infected. Although older people and those with underlying conditions are most at risk of severe disease and death, they are not the only ones at risk. Finally, while most infected people get mild or moderate forms of COVID-19 and some experience no disease, many become seriously ill and must be admitted into hospital. We are only beginning to understand the long-term health impacts among people who have had COVID-19, including what is being described as ‘Long COVID.’ WHO is working with clinicians and patient groups to better understand the long term effects of COVID-19.   Read the Director-General’s opening remarks at the 12 October COVID-19 briefing for a summary of WHO’s position. Most people who are infected with COVID-19 develop an immune response within the first few weeks after infection. Research is still ongoing into how strong that protection is and how long it lasts. WHO is also looking into whether the strength and length of immune response depends on the type of infection a person has: without symptoms (‘asymptomatic’), mild or severe. Even people without symptoms seem to develop an immune response. Globally, data from seroprevalence studies suggests that less 10% of those studied have been infected, meaning that the vast majority of the world’s population remains susceptible to this virus. For other coronaviruses – such as the common cold, SARS-CoV-1 and Middle East Respiratory Syndrome (MERS) – immunity declines over time, as is the case with other diseases. While people infected with the SARS-CoV-2 virus develop antibodies and immunity, we do not yet know how long it lasts.  Watch this conversation with Dr Mike Ryan and Dr Maria Van Kerkhove for more information on immunity. Large scale physical distancing measures and movement restrictions, often referred to as ‘lockdowns’, can slow COVID‑19 transmission by limiting contact between people. However, these measures can have a profound negative impact on individuals, communities, and societies by bringing social and economic life to a near stop. Such measures disproportionately affect disadvantaged groups, including people in poverty, migrants, internally displaced people and refugees, who most often live in overcrowded and under resourced settings, and depend on daily labour for subsistence. WHO recognizes that at certain points, some countries have had no choice but to issue stay-at-home orders and other measures, to buy time. Governments must make the most of the extra time granted by ‘lockdown’ measures by doing all they can to build their capacities to detect, isolate, test and care for all cases; trace and quarantine all contacts; engage, empower and enable populations to drive the societal response and more. WHO is hopeful that countries will use targeted interventions where and when needed, based on the local situation. WHO TEAM WHO Headquarters (HQ) Related