Viral pandemics Influenza and Coronaviruses Flashcards
What are three required characteristics for a virus to become a pandemic?
Novel antigenicity
Replicates efficiently in human cells.
Transmit efficiently between people.
Name 6 viruses with pandemic potential
Influenza
SARS-CoV-2
Nipah
West Nile Virus
Dengue
Zika
What influenza pandemics have occurred in the past century?
1918 Spanish Flu: 50m dead
1957 Asian Flu: 2m dead
1968 Hong Kong Flu: 1m dead
2009 Swine Flu: 200,000 dead
What are the most common subtypes of influenza causing disease in humans?
Influenza A (H1)
Influenza A (H3N2)
Influenza B
Describe the structure of Influenza
Enveloped virus
-ve sense segmented (8) RNA genome
Haemagglutinin (HA) + Neuraminidase (NA) spikes
What is the function of Haemagglutinin spikes?
Binds sialic acid receptors, allows virus entry.
Endosomal-viral envelope fusion= release
Strains named after this structure e.g. H5N1=HA5, NA1
What is the function of Neuraminidase spikes?
Cleaves sialic acid residues allowing exit of virions from the host cell, disrupts mucin barrier.
Why is influenza predominantly a respiratory disease?
It is activated by human airway tryptase found in lung tissue
What is the natural reservoir of influenza A viruses?
A. Pigs
B. Chickens
C. Ducks
D. Tigers
C. Ducks
How do influenza pandemics occur?
they cross over from animals (humans have no ability to recognise these viruses)
How must avian-origin influenza mutate to infect humans?
To replicate efficiently in human airway: change in polymerase activity
Transmit through air between people: change in hemagglutinin spike protein interaction + binding to cells
Which protein in human cells can support influenza replication?
ANP32: essential host cofactors that support influenza polymerase activity.
How can influenza polymerase utilise shorter mammalian ANP32?
Mutation in PB2 subunit.
Polymerase adaptation to mammals achieved by single amino acid change in PB2 E627K.
Describe the influenza life cycle
HA binds to Sialic Acid receptors (SA-R) on human URT cells + human tryptase cleaves HA to allow entry
Acidity of the endosome triggers a fusion event by which it releases its genome into the cell
Genome then travels to nucleus + takes over host factors to drive transcription + translation
New viral products produced (proteins + genome) assemble at surface of cell + bud off
What is antigenic drift?
Accumulation of point mutations (Due to error prone RNA polymerases) changes the nature of the antigen over time (drift)
What is antigenic shift?
Recombination of genomic segments of 2 co-infecting flu strains→ leads to rapid potentially whole antigenic change for a viral strain (shift)
Potentially allows exchange of RNA segments between human + animal strains
What needs to change in order for virus to successfully infiltrate humans?
Incoming virus needs to penetrate mucus + infect epithelial cells.
What contributes to incompatibility of avian-origin influenza virus with human respiratory tract?
Low acidic pH of URT followed by neutral pH of LRT
What does influenza bind to once through the mucous? What is the difference in humans and birds? What does this mean for the virus?
Sialic acid
Humans: linked to rest of sugar chain by alpha 2-6 linkage
Birds: linked to rest of sugar chain by alpha 2-3 linkage
Needs mutation in haemagglutinin protein to change shape of receptor binding pocket
Why is influenza A currently incompatible with human-human transmission?
Avian influenza HA must adapt for transmission in humans by acquiring affinity for human receptors (alpha 2-6).
Influenza entry + release of genetic material is pH dependent + HA protein is pH sensitive.
What are the potential responses used to manage pandemics?
Non pharmaceutical: Lock down, Social distancing
Antiviral drugs
Vaccines
Are antiviral medications for influenza used together or separately?
Antiviral medications for influenza are NOT licensed to be used together (like HAART).
What is sialic acid derived from?
Neuraminidic acid
What is neuraminidase?
New particles leaving cell are covered in HA
Virus doesn’t want to latch back onto sialic acid on this cell as host cell immune response is to kill itself
Virus encodes enzyme: Neuraminidase
Neuraminidase cuts sialic acid off original cell surface to prevent reattachment
How do neuraminidase inhibitors work?
Prevent neuraminidase cutting off sialic acid
Virus sticks to + re-enters old cell
Replication is halted
What are examples of neuraminidase inhibitors?
Oseltamivir
Zanamivir
What do new influenza antivirals target?
Polymerase acidic protein endonucleases.
What is an example of a polymerase acidic protein endonuclease inhibitor?
Baloxavir
The influenza vaccine given to those at greater risk of complications from flu in the UK is:
A. A live attenuated virus.
B. A purified fraction containing HA and NA of an inactivated virus.
C. A purified HA protein expressed in insect cells.
D. An immunoglobulin fraction from sera of immune patients.
B. A purified fraction containing HA + NA of an inactivated virus
What are the two types of influenza vaccine given in the UK?
Inactivated vaccine
Live attenuated vaccine
What are features of the inactivated influenza vaccine?
Split or subunit HA rich
Given to those at risk
Short term strain specific immunity mediated by antibody to HA head, stops binding + entry
What are features of the live attenuated influenza vaccine?
Cold adapted virus limited to URT
Given to children
Broader more cross reactive immunity inc. cellular response (strong T cell response)
What is the major influenza viral antigen?
Haemagglutinin
What is the structure of a influenza spike protein (HA)?
All subtypes look completely different- very ‘plastic’ head
Can completely change key amino acids our immune systems sees
Every year looks different to antibodies: ATM cant make a universal vaccine because they induce antibodies that see this ‘head region’
Where do most broadly neutralising Abs (bnAb) target?
HA stalk/ stem
Stem/ stalk= is more conserved
If you could induce antibodies to recognize this region of the virus, a universal vaccine could be possible- antibodies would see all types of flu
To which parts of HA do current influenza vaccines generate a response?
Current vaccines generate specific Ab responses raised against immunodominant HA1 epitopes at 5 antigenic sites (Sa, Sb, Ca1, Ca2, Cb).
What are coronaviruses?
RNA genomes, single stranded +ve sense RNA, very large genomes.
Enveloped virions. 100nm
Nidovirales: A nested set of mRNAs from one large genome
Which coronaviruses have caused disease in humans?
OC43, 229E, NL-63 + HKU-1 cause 20-30% common colds
SARS + MERS are zoonotic
What do SARS and SARS-CoV2 bind to?
Angiotensin Converting Enzyme 2
Where is SARS CoV2 thought to have come from?
Bats/ Pangolins
Harbour 100s of coronaviruses, which recombine
Can transmit to intermediate host/ directly to humans
Describe the time course of SARS CoV2 infection
Infected through airborne route
Replication in URTI + LRTI (predilection URT)
Start to be ill with cold ~5d
Turning point at 8d with immune response
OR
Dissemination into deeper lung, more vigorous immune response (cytokine storm)
What causes the severe effects of coronavirus?
Virus dissemination
Immunopathology
A COVID patient in ITU is most likely to benefit from:
A. Kaletra, a combination of lopinavir and ritonavir usually used to treat HIV.
B. Hydroxychloroquine, an antimalarial.
C. Remdesivir a nucleoside analogue.
D. Dexamethasone, a steroid.
D. Dexamethasone, a steroid.
Why is dexamethasone used in COVID patients on ventilation?
Cheap + extensively used steroid.
RECOVERY trial found Dex was effective in those receiving oxygen or ventilated.
Reduced deaths in illest cohort by 1/3.
Now standard of care in UK
Beneficial in patients with cytokine storm squashing immune system
Worse prognosis if suppress immune system if it is reacting itself
Which monoclonal antibodies have been trialed against COVID?
Regeneron
Sotrovimab
Which small molecule antivirals have been trialed against COVID?
Molnupiravir: Targets polymerase, nucleoside analogue.
Paxlovid: Targets protease.
Why is the COVID vaccine not effective against the Omicron variant?
Omicron has a large number of Spike mutations that affect antibody neutralization.
Antibodies can’t recognise binding site
