The Immunology of COVID-19 Flashcards

Question

For vaccines, vaccine efficacy (VE) can be calculated in the same way:

Answer 1

VE = 1 – (IRvaccinated/IRnon-vaccinated)=1-IRR

Answer 2

* Determining neutralising antibody titres requires an **experimental** system that allows precise detection of infection relative to **antibody** levels.

Answer 3

* 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.

Answer 4

“Neutralizing antibody levels are **highly** predictive of immune protection from **symptomatic** SARS-CoV-2 infection”

Answer 5

* Mutations occur in all SARS-C0V-2 proteins, however, those in the **Spike** 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.

Answer 6

Mutations occur in all SARS-C0V-2 proteins, however, those in the Spike 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.

Answer 7

* A large proportion of new cases are of the Indian variant * It is estimated that 20,000 individuals arrived from India after the Indian variant (B.1.617) was first detected in the UK (The Times, 16 May 2021 ). * This may explain why a large proportion of cases are now caused by this variant or sub-variants arising from it. * The Indian variant appears easier to transmit, however, vaccines appear to work albeit with somewhat **lower** efficacy * The easing of lock-down, however, is likely to contribute to the recent increase in cases of whichever variant.

Answer 8

* A large proportion of new cases are of the Indian variant * It is estimated that 20,000 individuals arrived from India after the Indian variant (B.1.617) was first detected in the UK (The Times, 16 May 2021 ). * This may explain why a large proportion of cases are now caused by this variant or sub-variants arising from it. * The Indian variant appears easier to transmit, however, vaccines appear to work albeit with somewhat lower efficacy * The easing of lock-down, however, is likely to contribute to the recent increase in cases of whichever variant.

Answer 9

* 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.

Answer 10

* 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.

Answer 11

* Continuous antibody production requires antigen **persistence** * The **gut** epithelium may act as a reservoir for SARS-CoV-2 (as in HIV) * **GI**-Symptoms occur in 30-70% of infections * **GI** infection associated with lower mortality (attenuating effect?) * SARS-CoV-2 RNA is found in stools * **GI** infection may be self limiting (mostly no live virus isolated from stools) * SARS-CoV-2 may affect and change the gut virome (reduced diversity) with wide-ranging effects on immunity and therapeutic potential * This is mostly uncharted territory……

Answer 12

* Continuous antibody production requires antigen persistence * The gut epithelium may act as a reservoir for SARS-CoV-2 (as in HIV) * GI-Symptoms occur in **30-70**% of infections * GI infection associated with lower **mortality** (attenuating effect?) * SARS-CoV-2 RNA is found in **stools** * GI infection may be self **limiting** (mostly no live virus isolated from stools) * SARS-CoV-2 may affect and change the gut **virome** (reduced diversity) with wide-ranging effects on immunity and therapeutic potential * This is mostly uncharted territory……

Answer 13

The gut epithelium may act as a **reservoir** for SARS-CoV-2 (as in HIV)

Answer 14

* The gut **epithelium** may act as a reservoir for SARS-CoV-2 (as in HIV) * GI-Symptoms occur in **30-70**% of infections * GI infection associated with lower **mortality** (attenuating effect?) * SARS-CoV-2 RNA is found in **stools** * GI infection may be **self limiting** (mostly no live virus isolated from stools) * SARS-CoV-2 may affect and change the gut **virome** (reduced diversity) with wide-ranging effects on immunity and **therapeutic** potential

Answer 15

* 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 * The majority of T-cells is thought to be in the **gut** * There are many unconventional T-cells and a whole spectrum of T-cells that are increasingly innate-like (discussing these is beyond the scope of this lecture, we mention them in the mucosal immunology lecture)

Answer 16

* 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 testing of selected peptides is increasingly becoming the industry standard

Answer 17

* 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 testing of selected peptides is increasingly becoming the industry standard

Answer 18

* Some peptides recognised by T-cells in SARS-CoV-1 infection, the infection causing the 2002/2003 SARS 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

Answer 19

* CD4 T-cells recognise essentially **all** SARS-CoV-2 proteins. * **Significant** differences between unexposed and exposed individuals were found for spike, NCAP, VME, VEMP, ORF3b, and NSP3a

Answer 20

T-cells: CD8 T-cell responses peak around day 30 and **decline** over time (COV-19)

Answer 21

T-cells: CD8 T-cell responses peak around day 30 and **decline** over time (COV-19)

Answer 22

* So far, follow-up has been too short to provide definite answers on the decline of T-cell immunity over time. It is normal for T-cell responses (like antibody responses) to **contract** over time. * **Memory** T-cell 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

Answer 23

* No evidence so far that variants critically affect T-cell **immunity** * Large numbers of **epitopes** appear to be recognised across all proteins with mutations unlikely to affect all epitopes * Strong T-cell epitopes were found in the fusion peptide II (FP II) region of the **spike** protein. FP II shows very little variation across strains of SARS-CoV-1/2, MERS and HCoVs indicating mutations may harm the virus * T-cell **responses** may be critical in preventing severe disease even if antibodies fail to prevent infection or cell-to-cell spread

Answer 24

* There is **limited** evidence for associations of HLA-type and COVID-19 severity at this time * Due to the huge **polymorphisms** of the HLA locus, very large studies will be required in future to prove or disprove significant HLA-associations * If found, such associations may inform vaccine strategies

Answer 25

* There is limited evidence for associations of HLA-type and COVID-19 severity at this time * Due to the huge polymorphisms of the HLA locus, very large studies will be required in future to prove or disprove significant HLA-associations * If found, such associations may inform **vaccine** strategies

Answer 26

* HLA/Disease associations can be based on T-cell recognition of peptides presented by HLA-molecules * May explain the role of biogeographical ancestry in disease **susceptibility** * Recently published results suggest that the presence of HLA-A\*0201 and HLA-A\*0301 are associated with a **lower** risk, but HLA-A\*0101 with a **higher** risk of death in older people (\>60 years)

Answer 27

* Some underlying diseases associated with fatal COVID-19 outcome may represent immunological risk factors, others simply weaken the patient

Answer 28

* Some underlying diseases associated with fatal COVID-19 outcome may represent immunological risk factors, others simply weaken the patient

Answer 29

* Some immunological aspects of known risk factors (work in progress) * **Age**: reduced innate and adaptive immunity, reduced B-cell and T-cell receptor repertoires (‘immunosenescence’), thymic involution, fewer naïve T-cells, 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 * **Genetic** background: HLA-type, polymorphisms in genes regulating inflammation, vitamin D binding protein variants (e.g. less free Vit D in black people), vitamin D-deficiency, and many more

Answer 30

* Some immunological aspects of known risk factors (work in progress) * Age: reduced innate and adaptive immunity, reduced B-cell and T-cell receptor repertoires (‘**immunosenescence**’), thymic **involution**, fewer **naïve** T-cells, 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 * Genetic background: **HLA**-type, polymorphisms in genes regulating inflammation, vitamin D binding protein variants (e.g. less free Vit D in **black** people), vitamin **D**-deficiency, and many more

Answer 31

* Currently licenced vaccines in the UK * Astra Zeneca **(2 shots)** * Pfizer/Biontech **(2 shots)** * Moderna **(2 shots)** * Johnson& Johnson **(single shot)** * Following an extremely successful vaccine campaign in the UK * almost **25** million have been vaccinated fully * almost 40 million had one shot

Answer 32

* Currently licenced vaccines in the UK * **Astra Zeneca** (2 shots) * Pfizer/Biontech (2 shots) * **Moderna** (2 shots) * Johnson& Johnson (single shot) * Following an extremely successful vaccine campaign in the UK * almost 25 million have been vaccinated fully * almost **40** million had one shot

Answer 33

* (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 * Note: Vaccines may also use inactivated virus (Sinovac) but are not (yet) licenced in the UK

Answer 34

* (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 * Note: Vaccines may also use **inactivated** virus (Sinovac) but are not (yet) licenced in the UK

Answer 35

* RNA vaccines use **messenger** RNA (mRNA) in order to achieve the production of relevant proteins of a **pathogen** in host cells. Just as a reminder, RNA is composed of adenine (A), cytosine (C), guanine (G), and uracil (U). RNA vaccines are not integrated into the recipient’s **genome**. In order to reach the inside of a cell, mRNA needs to be stabilised and packaged. Protein will be expressed in the injected tissues (i.e. muscle cells) * Stability is achieved by * A specially modified Nucleotide positioned at the 5’ end (Cap) * A poly (A) tail * Composition and structure of the 3’ untranslated regions (3’UTR) contribute to intracellular mRNA stability.

Answer 36

* RNA vaccines use messenger RNA (mRNA) in order to achieve the production of relevant proteins of a pathogen in host cells. Just as a reminder, RNA is composed of adenine (A), cytosine (C), guanine (G), and uracil (U). RNA vaccines are not integrated into the recipient’s genome. In order to reach the inside of a cell, mRNA needs to be stabilised and packaged. Protein will be expressed in the injected tissues (i.e. muscle cells) * Stability is achieved by * A specially modified **Nucleotide** positioned at the **5**’ end (Cap) * A poly (A) tail * Composition and structure of the **3**’ untranslated regions (3’UTR) contribute to intracellular mRNA stability.

Answer 37

* RNA vaccines use messenger RNA (mRNA) in order to achieve the production of relevant proteins of a pathogen in host cells. Just as a reminder, RNA is composed of adenine (A), cytosine (C), guanine (G), and **uracil** (U). RNA vaccines are not integrated into the recipient’s genome. In order to reach the inside of a cell, mRNA needs to be stabilised and packaged. Protein will be expressed in the injected tissues (i.e. muscle cells) * Stability is achieved by * A specially modified Nucleotide positioned at the 5’ end (Cap) * A **poly** (A) tail * Composition and structure of the 3’ **untranslated** regions (3’UTR) contribute to intracellular mRNA stability.

Answer 38

* Cell entry is achieved by packaging in **liposomes**. These are fragile and may be damaged and destroyed by **shaking**. * In the beginning, the mRNA vaccines were treated with extreme care. Doses were drawn up immediately prior to **administration** and a fair number of doses was discarded as a **precaution** e.g. after dropping syringes. * In some countries the guidance for the Pfizer/Biontech vaccine, for example, has been adjusted a little bit, to the extent that vaccine doses can be drawn up centrally and transported by car to vaccine centres.

Answer 39

* Cell entry is achieved by packaging in **liposomes**. These are **fragile** and may be **damaged** and destroyed by shaking. * In the beginning, the mRNA vaccines were treated with extreme care. Doses were drawn up immediately prior to administration and a fair number of doses was discarded as a precaution e.g. after dropping syringes. * In some countries the guidance for the Pfizer/Biontech vaccine, for example, has been adjusted a little bit, to the extent that vaccine doses can be drawn up centrally and transported by car to vaccine centres.

Answer 40

* Advantages: * **Safety**: no pathogen particles or inactivated pathogen, non-infectious, not integrated into host genome, RNA strand degraded once the protein is made. * **Efficacy**: reliable immune response * **Production**: can be produced more rapidly, is standardised, improved response speed in emerging outbreaks * Appear to have fewer and/or less severe side-effects than **conventional** vaccines * Disadvantages: * High cost (so far) * Logistic issues (low storage temperature, fragile)

Answer 41

* Advantages: * Safety: no pathogen particles or inactivated pathogen, non-infectious, not integrated into host **genome**, RNA strand **degraded** once the protein is made. * Efficacy: **reliable** immune response * Production: can be produced more rapidly, is standardised, improved response speed in emerging outbreaks * Appear to have fewer and/or less severe side-effects than conventional vaccines * Disadvantages: * High **cost** (so far) * Logistic issues **(low storage temperature, fragile)**

Answer 42

* 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

Answer 43

* 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

Answer 44

* 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 could be useful to prepare individuals for dealing with the infection (trained immunity)

Answer 45

* 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 could be useful to prepare individuals for dealing with the infection **(trained immunity)**

Answer 46

* Infection induces robust B and T-cell responses * **Cross**-reactivity with **common cold** coronaviruses exists but but we do not know if it is only protective or could also be harmful * 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 risk * New **vaccines** accommodating **variants** are being developed

Answer 47

* Infection induces robust B and T-cell responses * Cross-reactivity with common cold coronaviruses exists but but we do not know if it is only protective or could also be harmful * 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 risk * New vaccines accommodating variants are being developed

The Immunology of COVID-19 Flashcards

(72 cards)