T1 L21. The immunology of COVID-19 (FK).pptx

COVID-19: Essential Immunology Module 204 Prof Florian Kern 2023-05-12 Lecture Overview • • • • • • • • • SARS-CoV-2 and related viruses Genome structure & protein expression General interaction with the immune system Innate immunity B-cells and antibodies T-cells High-risk groups and Immunity V...

COVID-19: Essential Immunology Module 204 Prof Florian Kern 2023-05-12 Lecture Overview • • • • • • • • • SARS-CoV-2 and related viruses Genome structure & protein expression General interaction with the immune system Innate immunity B-cells and antibodies T-cells High-risk groups and Immunity Vaccines currently in use (principles) ‘Long COVID’ 2 SARS-CoV-2 and related viruses: SARS and common cold Orthocoronaviridae Sub- Genus fami ly Betacoronavirus Alpha-CoV Sub-genus Sarbecovirus Species SubDiseas specie e s SARS-CoV-2 SARS-CoV-1 Merbecovirus MERS-CoV Embecovirus HCoV HKU1 Betacoronav HCoV irus 1 OC43 Setracovirus HCoV NL63 Duvinacoronavi HCoV E229 rus SARS SARS MERS C.cold C.cold C.cold C.cold 3 SARS-CoV-2 and related viruses: basics SARS-CoV-2 is a positive-sense, single-stranded RNA virus • Infects vertebrates and invertebrates • Replication and gene expression occurs in the cytoplasm of the host cell • Can use host cell proteins during replication and gene expression • Express structural proteins separately from non-structural 4 SARS-CoV-2 and related viruses: cell entry ACE2 = angiotensin converting enzyme 2 5 SARS-CoV-2 and related viruses: target tissues and symptoms Important target tissues Lung – pneumocytes (pneumonia) Vasculature – vasculitis (contributing to thrombotic events) Gut – epithelial cells, lymphocytes (diarrhea, pain, loos of appetite) CNS – vasculitis (confusion) Muscle – fatigue/weakness, myalgia Naso and oropharynx (sensory neuroepithelium) – loss of smell and taste Tissue tropism is largely determined by ACE2 expression 6 SARS-CoV-2 and related viruses: animals • Horseshoe bats harbour the bat coronavirus RaTG13 which exhibits 97.4% amino acid identity with SARS-CoV-2 in the Spike protein • But bats don’t seem to get sick from coronaviruses • Bats have higher body temperature of about 39 C (related to heir ability to fly), this might work a bit like a fever. • They also have a mutation in STING (Stimulator of Interferon Genes). This is the main adaptor in several DNA-sensing pathways. The mutation makes it less potent, so that less interferon is being produced. • This reduces inflammation doi: 10.1002/vms3.359 7 Genome structure & protein expression The genome translates into about 30 expressed proteins. Major proteins are • the spike protein or (S-protein) • the envelope (E) protein • the membrane protein (M-protein) and • The nucleocapsid protein (N-protein) • The size of the genome is about 30kb (HIV 9.2 kb, CMV 230 kb) 8 Genome structure & protein expression • List of SARS-CoV-2 proteins/size Shor t E Full name Envelope small membrane protein length in AA 75 M Membrane protein 222 N Nucleocapsid protein 419 S Spike glycoprotein 1273 Size corresponds to the relative number of potential B-cell and T-cell epitopes 9 General interaction with the immune system: overview Innate immunity is our first line defence against pathogens and its proper functioning may be a crucial contributor to asymptomatic courses of COVID-19. Is there a way of improving innate immunity? There is no classic memory by way or training cells with specific receptors but ‘trained immunity’ has been described: 11 Science, 22 APRIL 2016 • VOL 352 ISSUE 628 Innate immunity Innate Immunity: How can it be trained? infection or vaccination oi: 10.1126/science.aaf1098 training programs histone modificationDNA methylation micro RNA modulation long non-coding RNA expression possible outcomes adaptive states maladaptive states tolerance/limitation of tissue damageimmune response failure (Immunoparalys innate immunity maturation hyperinflammation Non-specific protection atherosclerosis 12 Trained immunity • Trained immunity is the result of ‘firing up’ immunity by stimuli/events that stimulate the same innate immune cells that are required to protect us from infection • This could be recent vaccination even if completely unrelated to the infectious agent that is dealt with more effectively as a result • It could also be the result of a recent infection • It may be achievable by vaccine adjuvants alone or by other substances like plant lectins. • The fact that in older people innate immunity is often reduced may be one reason why older people are more likely to have severe COVID-19 13 B-cells and antibodies: blocking entry 14 B-cells and antibodies: timeline “Serologic responses to SARS-CoV-2 infection among hospital staff with mild disease in eastern France” Time from onset of symptoms (days) 13–20 (n = 29) 21–27 (n = 83) ≥28 Total (n = 48) P value (Chi2) Rapid test IgM 26 (89.7) 75 (90.4) 141 40 (83.3) (88.1) 0.47 Rapid test IgG 14 (48.3) 59 (71.1) 41 (85.4) 114 (71.2) 0.002 test IgG doi:Rapid 10.1016/j.ebiom.2020.102915 27 (93.1) 80 (96.4) or IgM 46 (95.8) 153 (95.6) 0.76 15 A study in health care workers in 2020 provided an estimate of protection by antibodies over 7 months. 12541 individuals were tested at baseline. Of 11364 individuals (90.6%) who were seronegative for anti-spike antibody at baseline • 223 had a new pos PCR test during follow-up • Their risk was estimated to be 1.09 per 10,000 days at risk Of 1265 who were seropositive for anti-spike antibody at baseline. • 2 were reinfected during the study (new positive PCR) • Their overall risk was estimated at 0.13 per 10,000 days at risk Following adjustment for covariates, an incidence rate ratio (IRR) of 0.12 was calculated. This translates into an efficacy of 88%. 16 https://www.nejm.org/do/10.1056/ B-cells and antibodies: protective efficacy The same calculations were carried out with respect to the presence of anti-nucleocapsid protein-specific IgG antibodies (anti-NCAP) or both. The IRRs were: 0.11 for the presence of anti-NCAP IgG This translates into an efficacy of 89% For vaccines, vaccine efficacy (VE) can be calculated in the same way: VE = 1 – (IRvaccinated/IRnon-vaccinated)=1IRR 17 https://www.nejm.org/do/10.1056/ B-cells and antibodies: protective efficacy B-cells and antibodies: neutralising titres Determining neutralising antibody titres requires an experimental system that allows precise detection of infection relative to antibody levels. 18 Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection Longitudinal data on neutralising antibody titres (serum dilutions) shows a decline of neutralising capacity and allows an estimate of the duration of protection if the levels required for protection are know. 19 an, Science 2021, 10.1126/science.abf4063 B-cells and antibodies: timeline of decay B-cells and antibodies: the concern with variants Spike: (L5F*), T95I, D253G, (S477N*), (E484K*), D614G, B.1.526 (NY) (A701V*) Spike: D80G, 144del, F157S, L452R, D614G, (T791I*), B.1.526.1 (NY) (T859N*), D950H B.1.617 (india) Spike: L452R, E484Q, D614G Spike: (T95I), G142D, E154K, L452R, E484Q, D614G, B.1.617.1 (India) P681R, Q1071H B.1.617.2 Spike: T19R, (G142D), 156del, 157del, R158G, L452R, (India/UK) T478K, D614G, P681R, D950N B.1.617.3 (India) Spike: T19R, G142D, L452R, E484Q, D614G, P681R, D950N Mutations occur in all SARS-C0V-2 proteins, however, those in the Spike P.2 (Brazil) Spike: E484K, (F565L*), D614G, V1176F protein are most concerning because the development of therapeutics has -focused on the Spike protein. This is because the Spike protein is crucial for viral entry into cells. 20 B-cells and antibodies: Therapeutics • Therapeutic antibodies recognising the Spike protein are administered to individuals with COVID-19 to avoid serious disease courses. • Treatment with REGN-COV2 resulted in a statistically significant reduction in the time-weighted average daily change from baseline in viral load (log10 copies/mL) from day 1 through day 7. T (European Medicines Agency, EMA/142650/2021) • Can be given (also subcutaneously) to household members for protection. It reduced the rate of symptomatic infection by 81% between day 0 and 29. 21 • Continuous antibody production requires antigen persistence • The gut epithelium may act as a reservoir for SARS-CoV2 (as in HIV) • GI-Symptoms occur in 30-70% of infections • SARS-CoV-2 RNA is found in stools 22 http://dx.doi.org/10.1136/gutjnl-2021-324622 B-cells and antibodies: antibody persistence and antigen T-cells: basics (reminder) • Conventional, alpha/beta T-cells are involved in immune response coordination and killing of infected cells (they are your ‘standard’ CD4 and CD8 T-cells) • They are essential for the defence against viruses and other intracellular agents 23 T-cells: proteins, peptides, epitopes • Conventional CD4 and CD8 T-cells recognise antigenic peptides in the context of class-II and class-I MHC molecules, respectively (’epitopes’) • The MHC locus is our most polymorphic gene locus (diversity supporting survival) • SARS-CoV-2 provides a multitude of potentially recognised peptides that could be useful in testing and vaccines. Testing all of these would be costly and labour intensive. • Epitope prediction (although not perfect yet) followed by 24 T-cells: the search for the best target proteins/epitopes • Some peptides recognised by T-cells in SARS-CoV-1 infection, the infection causing the 2002/2003 SARS Proteome overlap SARS-CoV-1 epidemic, were identified in the past • Some of them occur identically in SARS-CoV-2 • There also is some homology between the common cold coronaviruses (OC43, E229, NL63, HKU1) and SARS-CoV-2 Common cold CoV SARS-CoV-2 25 T-cells: recognition of SARS-CoV-2 peptide pools CD4 T-cells recognise essentially all SARSCoV-2 proteins. Significant differences between unexposed and exposed individuals were found for spike, NCAP, VME, doi: 10.1038/s41586-020-2598-9 (2020) 26 VEMP, ORF3b, and 27 an, Science 2021, 10.1126/science.abf4063 T-cells: CD4 T-cell responses peak around day 30 and decline over time (natural infection) 28 an, Science 2021, 10.1126/science.abf4063 T-cells: CD8 T-cell responses peak around day 30 (natural infection) and decline over time T-cells: immunity over time • It is normal for T-cell responses (like antibody responses) to contract over time. • Memory T-cells remain and will respond quickly if there is a new infection • Protective levels of memory T-cells are not known, this is an area that is not well understood with respect to any infection • The most important T-cell targets may be different in different individuals (this is related to HLA-type) 29 • No evidence so far that variants critically affect T-cell immunity, not even the latest Omicron variants • Large numbers of epitopes appear to be recognised across all proteins with mutations unlikely to affect all epitopes • T-cell responses may be critical in preventing severe disease even if antibodies fail to prevent infection or cell-to-cell spread 30 i.org/10.1101/2021.04.01.21252379 T-cells: concerns about variants Immunity in high-risk groups Some underlying diseases associated with fatal COVID19 outcome may represent immunological risk factors, 31 Immunity in high-risk groups: immunology • Age: reduced innate and adaptive immunity, reduced B-cell and T-cell receptor repertoires (‘immunosenescence’), thymic involution, fewer naïve Tcells, more memory T-cells • Obesity: large numbers of pro-inflammatory cells in fatty tissue, increased leptin secretion promoting decreased numbers of regulatory T-cells and regulatory T-cell function • Diabetes: strongly glycosylated Ig are more pro-inflammatory • Vascular disease: damaged endothelium (vasculopathy): risk of DIC and thrombotic events 32 Vaccines: general information Most frequently used vaccines in the UK • Pfizer/Biontech (2 shots) • Moderna (2 shots) • Astra Seneca (2 shots) • Johnson& Johnson (single shot) Following an extremely successful vaccine campaign in the UK • almost 50 million have been vaccinated fully (74%) • 140 million doses have been given 33 Vaccine principles (1) RNA/liposomes • Pfizer/Biontech: BNT162b2 contains RNA that encodes an optimized full-length SARS-CoV-2 spike protein. • Moderna: mRNA-1273 encodes a stabilized SARS-CoV-2 spike protein. (2) DNA/viral vectors • Oxford/Astra Zeneca: AZD122 contains a weakened version of a chimpanzee common cold adenovirus that contains DNA coding for the SARS-CoV-2 spike protein. • Johnson& Johnson: Ad26.COV2.S is an adenovirus vector (Ad26) that contains DNA encoding the SARS-CoV-2 spike protein (3) Recombinant SARS-CoV-2 spike protein plus adjuvant • Novavax: Nuvaxovid, adjuvant: Matrix-M from soapbark 34 Long COVID • Persistent symptoms beyond 12 weeks from acute disease • May include extreme tiredness (fatigue), shortness of breath, chest pain or tightness, problems with memory and concentration ("brain fog"), and many additional symptoms (see e.g. NHS website*) • May be linked to viral (antigen) persistence • Bears striking similarity with ‘chronic fatigue syndrome’ (CFS) • May result in part from CNS affection (‘Psychoneuroimmunology’) • May result from persistent pro-inflammatory reprogramming of B-cells and T-cells with long-lasting effects on a range of organ systems • Changes in gut microbiome/virome may also contribute *www.nhs.uk/conditions/coronavirus-covid-19/long-term-effects-of- 35 Summary I • The immune response to COVID-19 is complex, but not necessarily more complex than that to other virus infections • Both innate and adaptive immunity are important • It may be that innate immunity alone can clear the virus in asymptomatic cases, which would explain why some individuals do not form antibodies or only have low antibody levels • Innate immunity may be deficient in patients with a severe clinical course • Drugs/agents that stimulate the early innate immune response may prepare individuals for dealing with the infection (trained immunity) 36 Summary II • Infection induces robust B and T-cell responses • Cross-reactivity with common cold coronaviruses exists and appears to increase vaccine effects • All licenced vaccines induce strong B-cell and T- cell responses • Cross-reactivity is thought to explain why vaccines can achieve unexpected levels of immunity with just one shot • Viral variants so far do not appear to put vaccine success at serious risk • New vaccines accommodating wild type and variants have been developed 37 Learning objectives • SARS-CoV-2: virus size, (very) basic genome organisation, size of proteome • The particular role of the spike protein • Composition of the immune response to SARS-CoV-2 • The role of innate immunity to SARS-CoV-2 • Trained immunity and its difference to immune memory • Main structural B and T-cell response targets in SARS-CoV-2 • Why viral mutants could affect immunity/vaccine success and how • The basic difference between RNA, DNA, and conventional vaccines • Basic epidemiological concepts: incidence risk ratio and efficacy 38 • THANK YOU FOR YOUR ATTENTION • Questions and feedback: [email protected] 39