SARS coV2

Question 1

Characteristics of a pathogen

Answer 1

• Introduction of a virus into human circulation with no pre-existing immunity
  
  • Sudden onset
  • Rapid global spread, fast human to human transmission
    Get waves of infection, increasing virulence

Question 2

Zoonotic spill over

Answer 2

• Jump of a virus from an animal to a host is called a spill over
  As humans and animals come closer together - the chance of spill over event increases

Question 3

Coronavirus

Answer 3

• ssRNA
  
  • Outside - spike protein - used to attach to cells
  • Alpha corona
    ○ Not very bad - like cold
  • Beta corona
    ○ SARS
    ○ MERS
    COVID 19

Question 4

SARS outbreak

Answer 4

• Found in china
  
  • Limited outbreak
    ○ Only 8098 cases
    ○ Transmission only occurred when symptoms occurred
    Transmission to hospital care

Question 5

MERS outbreak

Answer 5

• 2400 cases 900 deaths
  
  • Bats to camel (intermediate)
    Camel to human

Question 6

SARS like symptoms covid 19

Answer 6

• Linked to wet market Wuhan, china
  
  • Primary viral pneumonia leading to respiratory failure
    By end of jan 2020 - 2761 cases

Question 7

Where did SARS-COV2 (covid19) come from

Answer 7

• Bats - reservoir
  
  • Pangolin - close relation to human covid 19
    Not intermediate

Question 8

How did it infect cells

Answer 8

• Spike protein
  ○ Binds to ACE2 (high affinity for ACE2)
  
  • Conformational change when bind to cell
    ○ Allow entry of virus into cell
    ○ Cleave protein to allow conformational change
    Furin (host protease) –> cleavage peptide

Question 9

Spike protein

Answer 9

• In spike protein there is a S1 subunit
  ○ Receptor-binding domain in S1 subunit
  
  • Cleavage proteins between S1 and S2
  • There are differences from bat to pangolin and human residue in receptor-binding domain ACE2 receptors
    ○ Adaptation from a mammalian host
  • Polybasic cleavage site is unique to humans
    ○ Not found in bats or pangolin
    Suggests further adaptation for the purpose of human to human transmission

Question 10

Symptoms and transmission

Answer 10

- Unique symptoms
		○ Shortness of breath
			§ Result of respiratory syndrome
		○ Loss of taste
	- Transmitted through water droplets
		○ Hygiene initiatives
		○ Social distance
		○ Transmission through asymptomatic infection
	- Affects all age groups
		○ No pre-existing immunity
		○ Symptoms are most severe in young adults and mature
Weird for healthy young adults

Question 11

Infection induces robust immune response

Answer 11

• Both b and t cell response
  
  • Inflammatory response in most severe compared to asymptomatic- over representation (high inflammatory)
  • 20% infections require hospitalisations
    ○ Of those 1 in 20 require ICU
    40-50% mortality in ICU patients

Question 12

Key phases

Answer 12

- Presymptomatic
		○ Infection of ACE2- expressing nasal epithelial cells in upper respiratory tract
	- Early phase
		○ Exhibit pneumonitis
	- Late phase -  severe
		○ Cytokine storm
			§ Overactive inflammation
			§ Breakdown of epithelial cells
Necrosis

Question 13

Cytokine storm

Answer 13

• Cytokines are mediates for immune signalling
  
  • Unregulated release
    ○ Many designed for inflammation signalling
    ○ With unregulation it doesn’t treat but rather triggers the disease
  • With regulated response
    ○ There is a resolution a fall of cytokine release after appropriate mediation
  • There is no resolution with storm (duration)
  • The cytokines mobilise neutrophils, macrophages and effector cells
    ○ Effector cells perturb tissue homeostasis
    § Epithelial failure
    § Leaking
  • Inability to resolve inflammation leads to lung damage
    Prolonged type IFNa/b/gamma reduce proliferation of lung epithelial cells, impacts regen

Question 14

Infectivity

Answer 14

• Wuhan strain: R0 = 2.5
  
  • MERS - R0<1
  • Even with low R0 - large proportion of population perceptible
    ○ Exponential infection
    ○ 100 ppl –> 250 –> 625 –> 1500
  • Social distancing
    ○ Limiting ability to spread reduces R0
  • Immunization
    Large number vaccinated chance of spread reduced - no. of susceptible reduced

Question 15

Remdesivir

Answer 15

○ Designed to target polymerase by original SARS virus
○ Inhibition of RNA replication
○ Used for patients in hospitalisation
Intravenously - not readily accessible

Question 16

hydroxychloroquine

Answer 16

No statistical data for hydroxychloroquine use bad clinical trial

Question 17

Ivermectin

Answer 17

○ Horse de wormer

No evidence

Question 18

Anti-IL6 receptor agonist

Answer 18

○ Effective for reducing severity
		○ Anti-inflammatory
				□ Corticosteroids also present anti-inflammatory
	- Not preventative
Treats symptoms

Question 19

Novel vaccine platform - subunit

Answer 19

○ Molecular clamp technology
§ Put clamp (peptide sequence) on spike protein from hiv virus
§ Maintains no cleavage - no conformational change
Also tested positive for hiv antibodies = problem

Question 20

Novel vaccine platform - astraZeneca

Answer 20

§ Chimpanzee adenovirus construction and put spike protein in
§ 70-80% efficacy against asymptomatic infection
§ 100% efficacy against severe covid19 require hospitalisation
§ Side effects
□ Thrombosis
® Chance of getting 1 in 200-300 thousand
Chance in dying 1 in 1,000,000
Chance of dying from covid 1 in 500

Question 21

Does immunity wane

Answer 21

• Antibody times did slow
  
  • Level of symptoms always lower
  • Even with waning memory b and t cells maintained long term
    People with severe covid can lose cd4 help

Question 22

Variants of concern

Answer 22

UK - alpha strain
South Africa - beta strain
Brazil - gamma strain
India - delta strain

Question 23

In comparing variants

Answer 23

• Alpha change in spike protein
  
  • antigenic drift
  • Beta mutated cleavage site
  • Delta completely different set of mutations
    ○ Binds more effectively to ACE2
    ○ Changes to cleavage site
    ○ More transmissible
    ○ Becomes the dominant strain
    § Increases R0 to ~6
    § More severe
    No significant drop in vaccine efficacy

Question 24

The future of living with covid

Answer 24

• Require high proportion of vaccination
  
  • Vaccine hesitancy
    ○ Clear communication
  • Emergence of new variants
    ○ New variant is immune to vaccinated
    ○ Need booster shots
    Development of new vaccines