Characteristics of a pathogen
- 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
Zoonotic spill over
- 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
Coronavirus
- ssRNA
- Outside - spike protein - used to attach to cells
- Alpha corona
○ Not very bad - like cold - Beta corona
○ SARS
○ MERS
COVID 19
SARS outbreak
- Found in china
- Limited outbreak
○ Only 8098 cases
○ Transmission only occurred when symptoms occurred
Transmission to hospital care
- Limited outbreak
MERS outbreak
- 2400 cases 900 deaths
- Bats to camel (intermediate)
Camel to human
- Bats to camel (intermediate)
SARS like symptoms covid 19
- Linked to wet market Wuhan, china
- Primary viral pneumonia leading to respiratory failure
By end of jan 2020 - 2761 cases
- Primary viral pneumonia leading to respiratory failure
Where did SARS-COV2 (covid19) come from
- Bats - reservoir
- Pangolin - close relation to human covid 19
Not intermediate
- Pangolin - close relation to human covid 19
How did it infect cells
- 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
- Conformational change when bind to cell
Spike protein
- 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
Symptoms and transmission
- 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
Infection induces robust immune response
- 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
Key phases
- 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
Cytokine storm
- 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
- Unregulated release
Infectivity
- 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
Remdesivir
○ Designed to target polymerase by original SARS virus
○ Inhibition of RNA replication
○ Used for patients in hospitalisation
Intravenously - not readily accessible
hydroxychloroquine
No statistical data for hydroxychloroquine use bad clinical trial
Ivermectin
○ Horse de wormer
No evidence
Anti-IL6 receptor agonist
○ Effective for reducing severity ○ Anti-inflammatory □ Corticosteroids also present anti-inflammatory - Not preventative Treats symptoms
Novel vaccine platform - subunit
○ 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
Novel vaccine platform - astraZeneca
§ 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
Does immunity wane
- 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
Variants of concern
UK - alpha strain
South Africa - beta strain
Brazil - gamma strain
India - delta strain
In comparing variants
- 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
The future of living with covid
- 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
- Vaccine hesitancy
