Immunity

Natural immunity to SARS-CoV-2 (obtained by infection) and vaccine-generated immunity to SARS-CoV2 are two different paths to immunity.

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When germs, such as bacteria or viruses, invade the body, they attack and multiply.

This invasion, called an infection, is what causes illness. The immune system uses several tools to fight infection. Blood contains red blood cells, for carrying oxygen to tissues and organs, and white or immune cells, for fighting infection. These white cells consist primarily of macrophages, B-lymphocytes and T-lymphocytes:

Macrophages are white blood cells that swallow up and digest germs, plus dead or dying cells. The macrophages leave behind parts of the invading germs called antigens. The body identifies antigens as dangerous and stimulates antibodies to attack them.

B-lymphocytes are defensive white blood cells. They produce antibodies that attack the antigens left behind by the macrophages.

T-lymphocytes are another type of defensive white blood cell. They attack cells in the body that have already been infected.

The first time the body encounters a germ, it can take several days to make and use all the germ-fighting tools needed to get over the infection. After the infection, the immune system remembers what it learned about how to protect the body against that disease.

The body keeps a few T-lymphocytes, called memory cells, that go into action quickly if the body encounters the same germ again. When the familiar antigens are detected,
B-lymphocytes produce antibodies to attack them.

Table of Contents

    The Beauty of Vaccines and Natural Immunity

    Jun 4 Written By Jay Bhattacharya, Sunetra Gupta, and Martin Kulldorff

    As scientists, we have been stunned and disheartened to witness many strange scientific claims made during this pandemic, often by scientists. None is more surprising than the false assertion made in the John Snow Memorandum – and signed by current CDC Director, Rochelle Wolensky – that “there is no evidence for lasting protective immunity to SARS-CoV-2 following natural infection.”

    Natural Infection Confers Protection Against Severe Disease

    It is now well-established that natural immunity develops upon infection with SARS-CoV-2 in a manner analogous to other coronaviruses. While natural infection may not provide permanent infection-blocking immunity, it offers antidisease immunity against severe disease and death that is likely permanent.  Among the millions that have recovered from COVID19, exceedingly few have become sick again.

    Natural infection typically confers better and broader protection, but this comes at a cost to those who are vulnerable to severe illness and death. For those in the vulnerable group, including the elderly and those with chronic disease, it is safer to acquire future protection against the disease via vaccination than by recovering from the disease. 

    At the same time, it makes little sense to ignore the scientific fact that infection does confer long-lasting future protection for the millions of people who have had COVID.

    https://www.smerconish.com/exclusive-content/the-beauty-of-vaccines-and-natural-immunity

    Preexisting and de novo humoral immunity to SARS-CoV-2 in humans

    Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans.

    Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)–reactive antibodies were detectable using a flow cytometry–based method in SARS-CoV-2–uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit.

    By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S–reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2–uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes.

    Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection. https://science.sciencemag.org/content/370/6522/1339

    “I would probably prefer to have natural immunity” — Dr Byram Bridle (Viral Immunologist)

    Dr. Bridle is an associate professor and viral immunologist in the Department of Pathobiology at the University of Guelph. His research interests include developing a better understanding of how the immune system responds to viral infections as well as designing immunotherapies for the treatment of cancers and infectious diseases.

    He is also passionate about teaching immunology and contributing to the training of Canada’s next generation of researchers.

    He gave this talk to the COVID Plan B group which opposes the official narrative of the deadliness of Covid-19 and its continuous new strains, the necessity of the lockdowns and the theory of elimination, and instead proposes treating the coronavirus like the seasonal flu (using vaccines). His slides.

    https://dryburgh.com/byram-bridle-coronavirus-vaccine-concerns/

    Discrete immune response signature to SARS-CoV-2 mRNA vaccination versus infection

    In COVID-19 patients, immune responses were characterized by a highly augmented interferon response which was largely absent in vaccine recipients. Increased interferon signaling likely contributed to the observed dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in immunized subjects. Analysis of B and T cell receptor repertoires revealed that while the majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients clonally expanded cells were primarily circulating memory cells.

    While both infection and immunization elicit robust humoral responses, our analysis revealed dramatic differences in cell composition and transcriptional profiles of circulating immune cells in response to the two different immune challenges.

    Despite heterogeneity in innate immune response, transcriptional analysis of pDCs and M1 macrophages revealed an upregulation of type I IFN production signature in cells from COVID-19 patients. Type I IFN mediates antiviral immunity, drives expression of a number of genes involved in viral clearance, and plays a critical role in the initiation of innate and adaptive immune responses during a viral infection.

    Infection with SARS-CoV-2 potently induced IFN responses, but we did not observe evidence of IFN induction by the BNT162b2 mRNA vaccine.

    COVID-19 patients had a striking expansion of antibody-producing plasmablasts, with evidence of clonal cells in this cluster. However, we did not detect appreciable expansion of plasmablasts in circulation of individuals immunized with SARS-CoV-2 BNT162b2 mRNA vaccine.

    https://www.medrxiv.org/content/10.1101/2021.04.20.21255677v1.full-text

    No point vaccinating those who’ve had COVID-19: Findings of Cleveland Clinic study

    By Dr. Sanchari Sinha Dutta, Ph.D. Jun 8 2021

    Scientists from the Cleveland Clinic, USA, have recently evaluated the effectiveness of coronavirus disease 2019 COVID-19) vaccination among individuals with or without a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

    The study findings reveal that individuals with previous SARS-CoV-2 infection do not get additional benefits from vaccination, indicating that COVID-19 vaccines should be prioritized to individuals without prior infection. The study is currently available on the medRxiv* preprint server.

    https://www.news-medical.net/news/20210608/No-point-vaccinating-those-whoe28099ve-had-COVID-19-Findings-of-Cleveland-Clinic-study.aspx

    An Urgent Message from Professor Sucharit Bhakdi

    The beauty of you natural immune system, how it fights pathogens and the possible catastrophic adverse effects of the covid19 vaccine.

    Your health valuable to you? 17 minutes well spend!

    Stanford study ties milder COVID-19 symptoms to prior run-ins with other coronaviruses

    By BRUCE GOLDMAN
    In COVID-19 patients whose symptoms were mild, Stanford researchers found that they were more likely than sicker patients to have signs of prior infection by similar, less virulent coronaviruses.

    The immune cells in question, called killer T cells, roam through the blood and lymph, park in tissues, and carry out stop-and-frisk operations on resident cells. The study, published online July 1 in Science Immunology, showed that killer T cells taken from the sickest COVID-19 patients exhibit fewer signs of having had previous run-ins with common-cold-causing coronaviruses.

    https://med.stanford.edu/news/all-news/2021/07/stanford-study-ties-milder-covid-19-symptoms-to-prior-run-ins-wi.html

    CD8+ T cells specific for conserved coronavirus epitopes correlate with milder disease in COVID-19 patients

    Abstract
    A central feature of the SARS-CoV-2 pandemic is that some individuals become severely ill or die, whereas others have only a mild disease course or are asymptomatic.

    Here we report development of an improved multimeric αβ T cell staining reagent platform, with each maxi-ferritin “spheromer” displaying 12 peptide-MHC complexes. Spheromers stain specific T cells more efficiently than peptide-MHC tetramers and capture a broader portion of the sequence repertoire for a given peptide-MHC.

    Analyzing the response in unexposed individuals, we find that T cells recognizing peptides conserved amongst coronaviruses are more abundant and tend to have a “memory” phenotype, compared to those unique to SARS-CoV-2. Significantly, CD8+ T cells with these conserved specificities are much more abundant in COVID-19 patients with mild disease versus those with a more severe illness, suggesting a protective role.

    https://immunology.sciencemag.org/content/6/61/eabg5669

    A thread on current understanding of natural immunity to SARS-CoV-2

    By Shane Crotty – Vaccine scientist. Immune system scientist. Professor, La Jolla Institute for Immunology (LJI), a non-profit scientific research institute.

    A thread on current understanding of natural immunity to SARS-CoV-2 🧵

    Immunity to SARS-CoV-2 is a key issue for global society. Natural immunity to SARS-CoV-2 (obtained by infection) and vaccine-generated immunity to SARS-CoV2 are two different paths to immunity.

    Based on our team’s SARS2 immune memory measurements (memory T and B cells
    & antibodies) we predicted natural immunity against serious cases of SARS2 reinfection would last multiple years in most people, against the original SARS2 strain.

    Download the full twitter thread in pdf:

    Study in Sweden: Immunity from infection more effective than from vaccination

    Many studies have confirmed that there is good cross immunity from previous infections with the common corona cold viruses. This is one of the reasons why there is a very high percentage of infections without any symptoms and it is also one of the reasons why children are not affected. Many studies have also confirmed that infections result in strong and very long-lasting immunity from T cells.

    The better immunization by infection is to be expected according to the previous studies. I have put together a comprehensive overview of the most important studies up to and including March 2021 here . A to N on 19 April 20221 ature Immunology appeared he products concerned on the basis of studies of the durability of immunity and shows that the vast majority of infected people develop a robust and long-lasting immunity by T cells. It is shown that immunity arises after asymptomatic infections or mild Covid courses.

    The difference in the number of memory T cells after an asymptomatic or symptomatic infection seems to be of little importance. If someone has survived an infection without symptoms, that person will be even better able to fight off a new infection if specific T cells are already present.

    Original article in German https://tkp.at/2021/05/10/studie-in-schweden-immunitaet-durch-infektion-wirksamer-als-durch-impfung/ Google translate version

    Professor Sunetra Gupta – Herd immunity Presentation
    Your Immune System Evolves to Fight Coronavirus Variants

    Antibodies can change to counter new forms of the shape-shifting virus, research hints
    By Monique Brouillette on March 31, 2021

    “Essentially, the immune system is trying to get ahead of the virus,” says Michel Nussenzweig, an immunologist at the Rockefeller University, who conducted some recent studies that tracked this phenomenon. The emerging idea is that the body maintains reserve armies of antibody-producing cells in addition to the original cells that responded to the initial invasion by SARS-CoV-2, the virus that causes COVID. Over time some reserve cells mutate and produce antibodies that are better able to recognize new viral versions. “It’s really elegant mechanism that that we’ve evolved, basically, to be able to handle things like variants,” says Marion Pepper, an immunologist at the University of Washington, who was not involved in Nussenzweig’s research. Whether there are enough of these cells, and their antibodies, to confer protection against a shape-shifting SARS-CoV-2 is still being figured out.

    Had COVID? You’ll probably make antibodies for a lifetime

    May 2021 – People who recover from mild COVID-19 have bone-marrow cells that can churn out antibodies for decades, although viral variants could dampen some of the protection they offer.

    Many people who have been infected with SARS-CoV-2 will probably make antibodies against the virus for most of their lives. So suggest researchers who have identified long-lived antibody-producing cells in the bone marrow of people who have recovered from COVID-19.

    The study provides evidence that immunity triggered by SARS-CoV-2 infection will be extraordinarily long-lasting. Adding to the good news, “the implications are that vaccines will have the same durable effect”, says Menno van Zelm, an immunologist at Monash University in Melbourne, Australia. https://www.nature.com/articles/d41586-021-01442-9

    A bone-marrow plasma cell (artificially coloured). Such cells, which produce antibodies, linger for months in the bodies of people who have recovered from COVID-19.Credit: Dr Gopal Murti/Science Photo Library

    Covid-19 immunity likely lasts for years, according to a new study.

    A new study shows immune cells primed to fight the coronavirus should persist for a long time after someone is vaccinated or recovers from infection.

    “There was a lot of concern originally that this virus might not induce much memory,” says Shane Crotty, a researcher at the La Jolla Institute for Immunology in California and a coauthor of the new paper. “Instead, the immune memory looks quite good.”
    A study published in August showed that T cells specific to SARS can remain in the blood for at least 17 years, bolstering hopes that covid-19 immunity could last for decades.

    Note: You find the referred study from August further down on this page MIT Technology review

    Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection

    Highlights

    • Most recovered COVID-19 patients mount broad, durable immunity after infection
    • Neutralizing antibodies show a bi-phasic decay with half-lives >200 days
    • Spike IgG+ memory B cells increase and persist post-infection
    • Durable polyfunctional CD4 and CD8 T cells recognize distinct viral epitope regions

    Ending the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2.
    Here, we evaluate 254 COVID-19 patients longitudinally up to 8 months and find durable broad-based immune responses.

    SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. SARS-CoV-2 infection also boosts antibody titers to SARS-CoV-1 and common beta-coronaviruses.

    In addition, spike-specific IgG+ memory B cells persist, which bodes well for a rapid antibody response upon virus re-exposure or vaccination. Virus-specific CD4+ and CD8+ T cells are polyfunctional and maintained with an estimated half-life of 200 days. Interestingly, CD4+ T cell responses equally target several SARS-CoV-2 proteins, whereas the CD8+ T cell responses preferentially target the nucleoprotein, highlighting the potential importance of including the nucleoprotein in future vaccines.

    Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients.
    https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00203-2

    SARS-CoV-2 elicits robust adaptive immune responses regardless of disease severity

    We report broad serological profiles within the cohort, detecting antibody binding to other human coronaviruses. 202(>99%) participants had SARS-CoV-2 specific antibodies, with SARS-CoV-2 neutralization and spike-ACE2 receptor interaction blocking observed in 193(95%) individuals.

    A significant positive correlation (r=0.7804) between spike-ACE2 blocking antibody titers and neutralization potency was observed.

    Further, SARS-CoV-2 specific CD8+ T-cell responses were clear and quantifiable in 95 of 106(90%) HLA-A2+ individuals.

    https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00203-6/fulltext

    Long-lived macrophage reprogramming drives spike protein-mediated inflammasome activation in COVID-19

    Our findings reveal that SARS-CoV-2 infection causes profound and long-lived reprogramming of macrophages resulting in augmented immunogenicity of the SARS-CoV-2 S-protein, a major vaccine antigen and potent driver of adaptive and innate immune-signaling. https://www.embopress.org/doi/full/10.15252/emmm.202114150

    SARS-CoV-2 Spike protein induces IL-1β secretion in macrophages from COVID-19 patients
    SDS–PAGE of the recombinant SARS-CoV-2 spike protein (S-protein).
    SARS-CoV-2 spike binding assay of IgGs isolated from COVID-19 patients (n = 3; red circles) or SARS-CoV-2 naïve individuals (SC-naïve) (n = 2; blue circles).
    Experimental scheme: After PBMCs isolation, CD14+ cells were enriched by positive selection. Subsequently, 5 × 104CD14+ cells/well were seeded and incubated in the presence of M-CSF for 5 days. Differentiated macrophages were stimulated with/without recombinant SARS-CoV-2 spike protein or lipopolysaccharide (LPS) for 4 h. To activate IL-1β secretion nigericin or ATP was added for 2 h. Finally, IL-1β secretion was quantified by ELISA.
    Quantification of IL-1β concentration (pg/ml) in the supernatant of primary macrophage cultures from COVID-19 patients (n = 44; red bars) or SC-naïve individuals (n = 24; blue bars) stimulated with LPS or S-protein (0.1 µg/ml). To activate IL-1β secretion, nigericin was added for 2 h.
    TNF-α (pg/ml) secreted from macrophages derived from SC-naïve and COVID-19 patients as described above. Cells were stimulated with LPS (SC-naïve/COVID-19 n = 4), LPS with nigericin (SC-naïve n = 4; COVID-19 n = 6), S-protein (SC-naïve n = 5; COVID-19 n = 4), S-protein with nigericin (SC-naïve n = 3; COVID-19 n = 4) or left unstimulated (SC-naïve n = 3; COVID-19 n = 4). Significances shown in the 
    Long-lived SARS-CoV-2-specific CD8+ T cells during COVID-19 convalescence

    April 29, 2021 – Protracted yet coordinated differentiation of long-lived SARS-CoV-2-specific CD8+ T cells during COVID-19 convalescence

    The uncertainty about the longevity of the immune response elicited by prior SARS-CoV- 2 infection or vaccination has been a major area of concern as the world tries to exit from the ongoing COVID-19 pandemic. Studies at the start of the pandemic suggesting a short-lived SARS-CoV-2 antibody response brought about widespread concern, but follow-up studies now suggest that infected individuals exhibit a prolonged and evolving humoral immune response 

    In summary, we report an unexpectedly dynamic evolution of Nuc322-331-specific CD8+ T cells during convalescence in PID4103. This evolution was gradual and persistent even up to 6 months after complete symptom resolution. We observed coordination of this response with the CD4+ T cell and antibody responses directed against the same antigen, and found that it was characterized by a progressive diminution of the activation state and polyfunctionality of cells in parallel with increases in their expansion potential. If one assumes similarities to nucleocapsid- specific CD8+ T cells from SARS-CoV-1, then the course of differentiation we describe here may be one that leads to SARS-CoV-2-specific memory CD8+ T cells that can persist for up to 17 years, and perhaps even longer.

    https://www.biorxiv.org/content/10.1101/2021.04.28.441880v1.full Download PDF

    Twelve-month specific IgG response to SARS-CoV-2 receptor-binding domain among COVID-19 convalescent plasma donors in Wuhan

    April 05, 2021
    To investigate the duration of humoral immune response in convalescent coronavirus disease 2019 (COVID-19) patients, we conducted a 12-month longitudinal study through collecting a total of 1,782 plasma samples from 869 convalescent plasma donors in Wuhan, China and tested specific antibody response.

    The results show that positive rate of IgG antibody against receptor-binding domain of spike protein (RBD-IgG) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the COVID-19 convalescent plasma donors exceeded 70% for 12 months post diagnosis.

    RBD-IgG kinetics displayed a gradually downward trend, the titer started to stabilize after 9 months and decreased by 68.1% compared with the 1st month. Moreover, male plasma donors produced more RBD-IgG than female plasma donors and patient age positively correlated with the RBD-IgG titer. A strong positive correlation between RBD-IgG and neutralizing antibody titers was also identified.

    This study is essential for understanding SARS-CoV-2-induced immune memory to develop vaccine and therapeutics.

    In conclusion, this 12-month longitudinal study demonstrates that despite of the downward trend of RBD-IgG response kinetics in COVID-19 convalescent plasma donors, over 70% plasma donors persist to produce RBD-IgG at detectable levels for longer than 1 year post diagnosis, which stably remain at a GMT of approximately 200. In addition, the RBD-IgG titers of male plasma donors are higher than those of female plasma donors at the initial stage of infection, meanwhile, age is positively correlated with the RBD-IgG titers. Furthermore, we confirmed the positive association between RBD-IgG and neutralizing antibody titers. 

    https://www.biorxiv.org/content/10.1101/2021.04.05.437224v1.full

    Lasting immunity found after recovery from COVID-19

    Jan 26, 2021
    After people recover from infection with a virus, the immune system retains a memory of it. Immune cells and proteins that circulate in the body can recognize and kill the pathogen if it’s encountered again, protecting against disease and reducing illness severity.

    This long-term immune protection involves several components. Antibodies—proteins that circulate in the blood—recognize foreign substances like viruses and neutralize them. Different types of T cells help recognize and kill pathogens. B cells make new antibodies when the body needs them.

    All of these immune-system components have been found in people who recover from SARS-CoV-2, the virus that causes COVID-19.
    https://www.nih.gov/news-events/nih-research-matters/lasting-immunity-found-after-recovery-covid-19

    SARS-CoV-2 antibodies provide lasting immunity

    October 13, 2020
    “The latest time-points we tracked in infected individuals were past seven months, so that is the longest period of time we can confirm immunity lasts,” Dr. Bhattacharya said. “That said, we know that people who were infected with the first SARS coronavirus, which is the most similar virus to SARS-CoV-2, are still seeing immunity 17 years after infection. If SARS-CoV-2 is anything like the first one, we expect antibodies to last at least two years, and it would be unlikely for anything much shorter.”

    https://medicalxpress.com/news/2020-10-sars-cov-antibodies-immunity.html

    Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection

    Abstract
    Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.

    https://science.sciencemag.org/content/early/2021/01/06/science.abf4063

    https://science.sciencemag.org/content/371/6529/eabf4063

    Preexisting and de novo humoral immunity to SARS-CoV-2 in humans

    Antibodies predating infection
    Immunological memory after infection with seasonal human coronaviruses (hCoVs) may potentially contribute to cross-protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

    Ng et al. report that in a cohort of 350 SARS-CoV-2–uninfected individuals, a small proportion had circulating immunoglobulin G (IgG) antibodies that could cross-react with the S2 subunit of the SARS-CoV-2 spike protein (see the Perspective by Guthmiller and Wilson).

    By contrast, COVID-19 patients generated IgA, IgG, and IgM antibodies that recognized both the S1 and S2 subunits. The anti-S2 antibodies from SARS-CoV-2–uninfected patients showed specific neutralizing activity against both SARS-CoV-2 and SARS-CoV-2 S pseudotypes.

    A much higher percentage of SARS-CoV-2–uninfected children and adolescents were positive for these antibodies compared with adults.

    This pattern may be due to the fact that children and adolescents generally have higher hCoV infection rates and a more diverse antibody repertoire, which may explain the age distribution of COVID-19 susceptibility.
    https://science.sciencemag.org/content/370/6522/1339

    SARS-CoV-1 neutralizing antibodies can still be detected 12–17 years afterward

    NOVEMBER 17, 2020
    More recent studies have demonstrated that SARS-CoV-1 neutralizing antibodies can still be detected 12–17 years afterward (Guo et al., 2020Tan et al., 2020). Given these lessons, conclusions about the rapid loss of immunity to SARS-CoV-2 are premature and inconsistent

    https://www.cell.com/immunity/fulltext/S1074-7613(20)30445-3

    SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls

    Nature 15 July 2020
    We showed that patients (n = 23) who recovered from SARS (the disease associated with SARS-CoV infection) possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 years after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2. We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19 or contact with individuals who had SARS and/or COVID-19 (n = 37). SARS-CoV-2-specific T cells in uninfected donors exhibited a different pattern of immunodominance, and frequently targeted NSP7 and NSP13 as well as the N protein.  https://www.nature.com/articles/s41586-020-2550-z

    Immune T Cells May Offer Lasting Protection Against COVID-19

    Posted on July 28th, 2020 by Dr. Francis Collins (NIH Director’s Blog)
    Bertoletti’s team recognized that many factors could help to explain how a single virus can cause respiratory, circulatory, and other symptoms that vary widely in their nature and severity—as we’ve witnessed in this pandemic. One of those potential factors is prior immunity to other, closely related viruses.

    SARS-CoV-2 belongs to a large family of coronaviruses, six of which were previously known to infect humans. Four of them are responsible for the common cold. The other two are more dangerous: SARS-CoV-1, the virus responsible for the outbreak of Severe Acute Respiratory Syndrome (SARS), which ended in 2004; and MERS-CoV, the virus that causes Middle East Respiratory Syndrome (MERS), first identified in Saudi Arabia in 2012.

    The researchers gathered blood samples from 36 people who’d recently recovered from mild to severe COVID-19. They focused their attention on T cells (including CD4 helper and CD8 cytotoxic, both of which can function as memory T cells).

    They identified T cells that respond to the SARS-CoV-2 nucleocapsid, which is a structural protein inside the virus. They also detected T cell responses to two non-structural proteins that SARS-CoV-2 needs to make additional copies of its genome and spread. The team found that all those recently recovered from COVID-19 produced T cells that recognize multiple parts of SARS-CoV-2.

    Next, they looked at blood samples from 23 people who’d survived SARS. Their studies showed that those individuals still had lasting memory T cells today, 17 years after the outbreak. Those memory T cells, acquired in response to SARS-CoV-1, also recognized parts of SARS-CoV-2.

    T-cell immunity to SARS-CoV-2

    Immunodominant T-cell epitopes from the SARS-CoV-2 spike antigen reveal robust pre-existing T-cell immunity in unexposed individuals

    The predicted epitopes induced robust T-cell activation in unexposed donors demonstrating pre-existing CD4 and CD8 T-cell immunity to SARS-CoV-2 antigen.

    The T-cell reactivity to the predicted epitopes was higher than the Spike-S1 and S2 peptide pools in the unexposed donors. A key finding of our study is that pre-existing T-cell immunity to SARS-CoV-2 is contributed by TCRs that recognize common viral antigens such as Influenza and CMV, even though the viral epitopes lack sequence identity to the SARS-CoV-2 epitopes.

    In conclusion, our study demonstrates strong pre-existing CD8 T-cell immunity in many unexposed donors contributed by the engagement of cross-reactive TCRs against common CMV and flu antigens. The presence of high-quality cross-reactive TCRs can protect individuals by mounting an early CD8 T-cell response and clearing the virus. Identifying additional immunodominant epitopes in SARS-CoV-2 and their cognate TCRs can become a powerful immune monitoring tool for assessing protective immunity against SARS-CoV-2 in the population.

    Identification of immunogenic epitopes from SARS-CoV-2 by OncoPeptVAC. (A) ROC curves of OncoPeptVAC TCR-binding and netMHCpan-4.1 HLA binding algorithms. A blind dataset of non-immunogenic or immunogenic HLA class-I binding T-cell epitopes from IEDB was used to assess the performance of OncoPeptVAC (cyan). The HLA-binding affinity of the epitopes expressed as percentile rank < 1% was used to assess the performance of netMHCpan-4.1 in predicting true immunogenic epitopes (orange). (B) Separation of immunogenic from non-immunogenic epitopes by OncoPeptVAC score. (C) Separation of immunogenic from non-immunogenic epitopes by HLA-binding percentile rank. (D) Schematic showing the steps used to identify immunogenic epitopes from SARS-CoV-2 proteome. (E) Number of immunogenic epitopes identified in different SARS-CoV-2 antigens. (F) HLA-A, B and C-restricted epitopes from SARS-CoV-2 proteome.

    https://www.nature.com/articles/s41598-021-92521-4

    At least six studies have reported T cell reactivity against SARS-CoV-2.

    It seemed a truth universally acknowledged that the human population had no pre-existing immunity to SARS-CoV-2, but is that actually the case?

    Yet a stream of studies that have documented SARS-CoV-2 reactive T cells in people without exposure to the virus are raising questions about just how new the pandemic virus really is, with many implications.

    Not so novel coronavirus?
    At least six studies have reported T cell reactivity against SARS-CoV-2 in 20% to 50% of people with no known exposure to the virus.

    Understanding the protective value of pre-existing SARS-CoV-2 T cell reactivity “is identical to the situation on vaccines,” said Antonio Bertoletti, professor of infectious disease at Duke-NUS Medical School in Singapore. “Through vaccination we aim to stimulate antibodies and T cell production, and we hope that such induction of immunity will protect … but we need a phase III clinical study to really demonstrate the effect.

    Full article online https://www.bmj.com/content/370/bmj.m3563

    SARS-CoV-2 Variants Still Recognized by T Cells

    March 31, 2021 | Original story from the National Institutes of Health

    When variants of SARS-CoV-2 (the virus that causes COVID-19) emerged in late 2020, concern arose that they might elude protective immune responses generated by prior infection or vaccination, potentially making re-infection more likely or vaccination less effective. To investigate this possibility, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and colleagues analyzed blood cell samples from 30 people who had contracted and recovered from COVID-19 prior to the emergence of virus variants. They found that one key player in the immune response to SARS-CoV-2—the CD8+ T cell—remained active against the virus.

    In their study of recovered COVID-19 patients, the researchers determined that SARS-CoV-2-specific CD8+ T-cell responses remained largely intact and could recognize virtually all mutations in the variants studied. While larger studies are needed, the researchers note that their findings suggest that the T cell response in convalescent individuals, and most likely in vaccinees, are largely not affected by the mutations found in these three variants, and should offer protection against emerging variants. 

    Optimal immunity to SARS-Cov-2 likely requires strong multivalent T-cell responses in addition to neutralizing antibodies and other responses to protect against current SARS-CoV-2 strains and emerging variants, the authors indicate. They stress the importance of monitoring the breadth, magnitude and durability of the anti-SARS-CoV-2 T-cell responses in recovered and vaccinated individuals as part of any assessment to determine if booster vaccinations are needed.  https://www.technologynetworks.com/immunology/news/sars-cov-2-variants-still-recognized-by-t-cells-347278

    Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection

    The results clearly indicate that most of the recovered COVID-19 patients have developed effective T cell memory pools against SARS-CoV-2.

    To assess the SARS-CoV-2-specific T-cell memory, human peripheral blood mononuclear cells (PBMCs) from 90 COVID-19 patients collected between 48–86 days after disease onset were stimulated in vitro for 10 days with peptide pools designed to target the spike glycoprotein (S), membrane glycoprotein (M), nucleocapsid (N), envelope glycoprotein (E) and ORF1ab region of RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. Our data showed that the memory CD4+ and CD8+ T cells of 94.44% and 83.33%, respectively, of the COVID-19 patients successfully underwent expansion

    Here we report virus-specific CD4+ and CD8+ T-cell memory in recovered COVID-19 patients and close contacts.

    We also demonstrate the size and quality of the memory T-cell pool of COVID-19 patients are larger and better than those of close contacts. However, the proliferation capacity, size and quality of T-cell responses in close contacts are readily distinguishable from healthy donors, suggesting close contacts are able to gain T-cell immunity against SARS-CoV-2 despite lacking a detectable infection. Additionally, asymptomatic and symptomatic COVID-19 patients contain similar levels of SARS-CoV-2-specific T-cell memory. https://www.nature.com/articles/s41467-021-22036-z

    Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases

    Open Access Published:January 26, 2021 DOI: https://doi.org/10.1016/j.xcrm.2021.100204

    Alison Tarke, John Sidney, Conner K. Kidd, Jennifer M. Dan, Sydney I. Ramirez, Esther Dawen Yu, Jose Mateus, Ricardo da Silva Antunes, Erin Moore, Paul Rubiro, Nils Methot, Elizabeth Phillips, Simon Mallal, April Frazier, Stephen A. Rawling, Jason A. Greenbaum, Bjoern Peters, Davey M. Smith, Shane Crotty, Daniela Weiskopf, Alba Grifoni, Alessandro Sette

    Highlights
    T-cell responses recognize at least 30–40 epitopes in each donor
    Immunodominance is correlated with HLA binding
    Immunodominant regions for CD4+ T cells have minimal overlap with antibody epitopes
    CD8+ T cell responses depend on the repertoire of HLA class I alleles

    In this study, we report a comprehensive map of epitopes recognized by CD4+ and CD8+ T cell responses across the entire SARS-CoV-2 viral proteome. Importantly, these epitopes have been characterized in the context of a broad set of HLA alleles using a direct ex vivo, cytokine-independent approach.

    Several studies have reported significant pre-existing immune memory to SARS-CoV-2 peptides in unexposed donors.1,3,4,15This reactivity was shown to be associated, at least in some instances, with memory T cells specific for human CCCs cross-reactively recognizing SARS-CoV-2 sequences.3,15 In particular, it was shown that the SARS-CoV-2 epitopes recognized in unexposed donors had significantly higher homology to CCC than SARS-CoV-2 sequences not recognized in unexposed donors. 

    This study presents a comprehensive analysis of the patterns of epitope recognition associated with SARS-CoV-2 infection in a cohort of approximately 100 different convalescent donors spanning a range of peak COVID-19 disease severity representative of the observed distribution in the San Diego area. 
    We are not aware of any study that describes the repertoire of CD4+ and CD8+ T cell epitopes recognized in SARS-CoV-2 infection with a comparable level of granularity or breadth. 

    T-cells Are the Superstars in Fighting COVID-19 

    Sept. 24, 2020
    By Eshani M King, Evidence Based Research in Immunology and Health

    German researchers found that a staggering 81% of individuals had pre-existing T-cells that cross-react with SARS-CoV-2 epitopes. This fits with modelling in May by Imperial College’s Professor Friston, a world authority in mathematical modelling of complex dynamic biological systems, indicating that around 80% and 50% of the German and UK populations, respectively, are resistant to COVID-19.

    https://doctormurray.com/does-the-flu-shot-increase-covid-19-risk/

    T cells target broad range of SARS-CoV-2 epitopes, study shows

    According to the scientists, the new research is the most detailed analysis so far of which proteins on SARS-CoV-2 stimulate the strongest responses from the immune system’s “helper” CD4+ T cells and “killer” CD8+ T cells.

    “We are now armed with the knowledge of which parts of the virus are recognised by the immune system,” said Professor Alessandro Sette, who co-led the new study.

    However, the broad immune response helps and most people have immune cells that can recognise sites other than the receptor binding domain.

    Among the epitopes they uncovered, the researchers identified several additional epitopes on the SARS-CoV-2 S protein. By targeting many vulnerable sites on the S protein, the immune system would still be able to fight infection, even if some sites on the virus change due to mutations. T cells target broad range of SARS-CoV-2 epitopes, study shows

    Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

    An analysis of immune cell responses to SARS-CoV-2 from recovered patients identifies the regions of the virus that is targeted and also reveals cross-reactivity with other common circulating coronaviruses.

    Highlights
    -Measuring immunity to SARS-CoV-2 is key for understanding COVID-19 and vaccine development
    -Epitope pools detect CD4+ and CD8+ T cells in 100% and 70% of convalescent COVID patients
    -T cell responses are focused not only on spike but also on M, N, and other ORFs
    -T cell reactivity to SARS-CoV-2 epitopes is also detected in non-exposed individuals

    Summary
    Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide ‘‘megapools,’’ circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in 70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the antiSARS-CoV-2 IgG and IgA titers. The M, spike, and N proteins each accounted for 11%–27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a, and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted.

    Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in 40%–60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘‘common cold’’ coronaviruses and SARS-CoV-2.

    https://www.cell.com/action/showPdf?pii=S0092-8674%2820%2930610-3

    Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19

    June 29, 2020 – SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19.

    We systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in a large cohort of unexposed individuals as well as exposed family members and individuals with acute or convalescent COVID-19. Acute phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype.

    Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative family members and individuals with a history of asymptomatic or mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits robust memory T cell responses akin to those observed in the context of successful vaccines, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19 also in seronegative individuals.

    https://www.biorxiv.org/content/10.1101/2020.06.29.174888v1.full

    SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition

    T cell immunity is central for the control of viral infections.

    To characterize T cell immunity, but also for the development of vaccines, identification of exact viral T cell epitopes is fundamental. Here we identify and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential 
    T cell epitopes in COVID-19 convalescent and unexposed individuals. SARS-CoV-2-specific peptides enabled detection of post-infectious T cell immunity, even in seronegative convalescent individuals. Cross-reactive SARS-CoV-2 peptides revealed pre-existing T cell responses in 81% of unexposed individuals and validated similarity with common cold coronaviruses, providing a functional basis for heterologous immunity in SARS-CoV-2 infection.

    Diversity of SARS-CoV-2 T cell responses was associated with mild symptoms of COVID-19, providing evidence that immunity requires recognition of multiple epitopes.

    Together, the proposed SARS-CoV-2 T cell epitopes enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for COVID-19.

    https://www.nature.com/articles/s41590-020-00808-x#Sec2

    Highly functional Cellular Immunity in SARS-CoV-2 Non-Seroconvertors is associated with immune protection

    To understand SARS-CoV-2 specific T-cell immunity in the absence of seroconversion, we characterized immunological features of Non-Seroconvertors recovered from infection. Highly functional specific T-cell responses and low immune activation were determinants of immune protection from severe disease.

    Antiviral CD4+ and CD8+ T-cell responses are key in the natural control of viral infections (Noel et al., 2016Pereyra et al., 2010Kiepiela et al., 2007). Emerging data from SARS-CoV-2 animal models support the role of T-cell immunity as a correlate of protection from infection (McMahan et al., 2021) and virus-specific CD4+ and CD8+ T-cell responses are considered key players in the resolution and long-term protection from infection (Peng et al., 2020). The presence of SARS-CoV-2 CD4+ and CD8+ T-cell responses up to 6 months after infection in mild to moderate clinical course and persistent immunological alterations in the memory compartment have been described (Breton et al., 2021Dan et al., 2021). Moreover, protection through pre-existent SARS-CoV-2 cross-reactive CD4+ T cell responses to other coronaviruses in a fraction of individuals has been proposed as a mechanism limiting disease severity (Mateus et al., 2020Sekine et al., 2020).

    These and other studies support the relevance of cellular immunity in the control and prevention of SARS-CoV-2 infection.

    https://www.biorxiv.org/content/10.1101/2021.05.04.438781v1.full

    Immunity to COVID-19 is probably higher than tests have shown

    Published: 2020-08-18
    A new study from Karolinska Institutet and Karolinska University Hospital shows that many people with mild or asymptomatic COVID-19 demonstrate so-called T-cell-mediated immunity to the new coronavirus, even if they have not tested positively for antibodies.

    https://news.ki.se/immunity-to-covid-19-is-probably-higher-than-tests-have-shown

    Research suggests Pfizer-BioNTech COVID-19 vaccine reprograms innate immune responses

    Researchers in The Netherlands and Germany have warned that Pfizer-BioNTech’s coronavirus disease 2019 (COVID-19) vaccine induces complex reprogramming of innate immune responses that should be considered in the development and use of mRNA-based vaccines.

    …  little is known about the broad effects the vaccine may have on the innate and adaptive immune responses.
    … However, they also showed that the vaccine altered the production of inflammatory cytokines by innate immune cells following stimulation with both specific (SARS-CoV-2) and non-specific (viral, fungal and bacterial) stimuli.
    … Cytokine responses to certain stimuli were reduced following vaccination.

    The researchers say that in combination with strong adaptive immune responses, the reprogramming of innate responses could either contribute to a more balanced inflammatory reaction to SARS-CoV-2 infection or a weakened innate immune response.

    The effect of the BNT162b2 vaccination on innate immune responses could also interfere with the responses to other vaccinations, adds the team.

    https://www.news-medical.net/news/20210510/Research-suggests-Pfizer-BioNTech-COVID-19-vaccine-reprograms-innate-immune-responses.aspx

    The BNT162b2 mRNA vaccine against SARS-CoV-2 reprograms both adaptive and innate immune responses

    …Intriguingly, the BNT162b2 vaccine induces reprogramming of innate immune responses as well, and this needs to be taken into account: in combination with strong adaptive immune responses, this could contribute to a more balanced inflammatory reaction during COVID-19 infection, or it may contribute to a diminished innate immune response towards the virus.

    https://www.medrxiv.org/content/10.1101/2021.05.03.21256520v1.full-text

    ONLINE CHAPTER Immunological methods and applications

    The methods and applications described in this chapter will hopefully explain how, in practical terms, one would go about measuring cytokine production by individual T-cell subsets, or antibody production by B-cells, or apoptosis induced by NK cells, and so on.

    https://www.roitt.com/pdf/Online_Chapter.pdf