Pandemics

Question 1

What hosts exist in flu pandemics?

Answer 1

Humans
Birds
Dogs
Rats
Mammals

Question 2

What is Tropism in influenza?

Answer 2

Influenza virus infection causes respiratory disease because:
• The influenza virus requires activation by host cell proteases that are only expressed in the respiratory tract
• Virus enters cell using sialic acid receptors on cells, binding to haemagglutinin
• Enters cell and replicates using host cell machinery

Question 3

What is the replication cycle of influenza?

Answer 3

attachment, penetration, uncoating, replication, assembly, and virion release

Question 4

How does bird flu infect humans?

Answer 4

• Cleavage in human airway/lung by Clara Tryptase
• Host range barriers prevent frequent infection of humans with avian influenza. Antibodies bind to HA on the outer layer of virus, therefore preventing entry into the cell. However, HA constantly changes due to antigenic drift.
• Infection of humans with unadapted avian influenza viruses can lead to hypercytokinaemia.

Question 5

What pathology is caused by avian flu?

Answer 5

The alveolar spaces are filled with a mixed mononuclear/neutrophilic infiltrate, the alveolar walls are thickened, and the septae are edematous. In later stages there is a fibroproliferative response with collagen deposition in the alveolar walls

Question 6

Why is the large number of bird flus that exist not a problem?

Answer 6

• Since 1997 a number of avian influenza viruses have infected humans, often with high case fatality BUT they have not led to pandemics because they do not transmit through the air between people

Question 7

What is influenza virus shift?

Answer 7

• DNA has H and N segments
• Reassortment of DNA leads to antigenic shift (recombination)
• Ie H3N2 and H5N1 recmobine to make mutant virus – there are 256 combinations of possible RNA recombinations
• Some of these are not viable, some are not good at infecting, but some can cause pandemics

Question 8

What are barriers in humans?

Answer 8

• Avian influenza viruses can infect human lower airway but NOT URT using a2,3SA receptors
• Lack of infection in URT cells, or appropriate cells type in upper airway cells may explain lack of transmission of avian influenza from human to human
• Adaptation for transmission through air occurs in other genes such as polymerase, NA and elsewharee in HA can increase replication, stability and spread.

Question 9

What are the requirements of a pandemic?

Answer 9

• A pandemic virus will have novel antigenicity.
• A pandemic virus will replicate efficiently in human airway.
• A pandemic virus will transmit efficiently between people.

Question 10

What are the big flu pandemics?

Answer 10

• 1918 influenza virus and all subsequent human viruses of 20th century have PB2 627K .
• Human H5N1 and H7N9 infections associated with severe disease carry PB2 E627K mutation.
• Avian influenza viruses co-opt ANP32A to support RNA replication but cannot utilize shorter mammalian ANP32 homologues unless they mutate PB2

Question 11

How do pandemics happen?

Answer 11

Question 12

Which strains have occurred in the past century?

Answer 12

Question 13

How does flu transmission occur?

Answer 13

• Birds grown in farms can transmit easily
• Regarding human transmission,
  
  • Aerosol transmitted
  • Through droplets, mainly in shared air spaces
  • Through formites (hand to hand to nose)
• Mucus is a strong infection barrier – but viral neuroaminidase counters it
• Efficiency of receptor binding and virion stability also determine the pandemic potential

Question 14

What is Swine flu?

Answer 14

• Influenza virus also circulates in pigs (H1/3)
  
  • H1N1 swine influenza spread globally over a few weeks
  • Nearly 9000 hospitalizations in the UK, more than 800 deaths
  • Globally 200,000 deaths

Question 15

What is the history of swine flu?

Answer 15

• Seropositivity in London and Birmingham >40% in children by September 2009 (Miller et al. 2010)
• Case fatality ~ 0.02%
• Mild disease in majority of cases.
• 50% of those hospitalized were previously healthy (FLUCIN Thorax 2010).
• Elderly were relatively spared because People alive in 1920-1940 had been infected with antigenically similar virus to pH1N1 2009 (Spanish flu H1N1).
• pH1N1 in the UK 2009; spread by children in schools in the first wave. Third wave worst.

Question 16

What are severe outcomes linked to swine flu?

Answer 16

• High dose, route of exposure
• Mutant virus (D225G mutation in HA associated with 25% fatal cases in Norway)
• Bacterial superinfection (Odds ratio of 125 after other factors accounted for in Argentinian study)
• Co morbidity: Asthma, pregnancy, obesity, diabetes
• Genetic predisposition: IFITM3 mutation; ethnic bias
• Genetic determinants of influenza susceptibility: Loss of IFITM3 linked with severe influenza.

Question 17

What are the antivirals useful for flu pandemics?

Answer 17

• Three or four different antiviral drugs already exist for influenza, and are licensed for use in the clinic. However unlike HAART for HIV we don’t use them together.
• Amantadine
  
  • Targets M2 ion channel
  • Single amino acid mutation in M2 (S31N) renders virus resistant
  • Does not work against influenza B or pH1N1 or seasonal H3N2
• Neuraminidase inhibitors and mode of administration:
  
  • NA cleaves SA on cell that they infected to prevent all other viral cells from binding to it
  • Tamiflu (oseltamivir) oral
  • Relenza (zanamivir) inhaled or iv formulation
  • Peramivir iv
• In adults oseltamivir reduced time to first alleviation of symptoms by 16.8 hours, in children by 29 hours.
• “no evidence.. to use these drugs to prevent serious outcomes in annual influenza and pandemic influenza outbreaks….”

Question 18

What is drug resistance?

Answer 18

• Emergence of drug resistant variants in immunocompromised
• Therefore only used in prophylaxis, given half doses

Question 19

Aare flu vaccines useful?

Answer 19

• Vaccines (3 month lag phase)
  
  • Influenza is best controlled using vaccines but
  • There will be no specific matched vaccine for a novel pandemic virus in the short term (takes 3 month)
  • In use today
    
    • Trivalent or quadrivalent inactivated vaccine
      
      • Split or subunit- HA rich
      • Short term strain specific immunity mediated by antibody to HA head:
    • Live attenuated vaccine, also tri or quadrivalent (against H1, H3, B yamagata and B victoria (common seasonal flus)
      
      • Cold adapted virus limited to urt
      • Given to those at risk (children)
      • Broader more cross reactive immunity including cellular response

Question 20

Should healthcare workers get vaccines?

Answer 20

Yes

• More than 1 million HCWs have direct patient care and all are offered influenza vaccines.
• 2012/13 year the uptake rate for seasonal vaccine was 44.5%.
• Flu vaccine does not give you flu.
• A person infected with influenza virus is contagious before they know they are infected.
• By not getting flu vaccine you put your vulnerable patients at risk.

Question 21

What are pandemic vaccine stages?

Answer 21

• Inactivated vaccines to novel HA proteins require adjuvant to generate a robust immune response
• Novel oil-in-water adjuvants used in monovalent vaccines AS03 Pandemrix: Narcolepsy!
  
  • Untimely siesta. The autoimmune concept of H1N1-related narcolepsy involves four stages (3).
  • (A) Stage I: Preferentially in HLA-DQB1*06:02+ individuals, anti-H1N1 vaccination triggers formation of antibodies that bind to the viral NP and hypocretin receptor 2.
  • (B) Stage II: After perforation of the blood-brain barrier, the antibodies leak into the brain tissue.
  • (C) Stage III: Antibodies bind to the hypocretin receptor 2 on the surface of neurons and disrupt signaling either by direct blockade or by secondary depletion of hypocretin formation.
  • (D) Stage IV: Disrupted hypocretin signaling results in clinical narcolepsy.

Question 22

What are whole cirus vaccines?

Answer 22

• Whole virus vaccines produced in Vero cells immunogenic without adjuvant Celvapan

Question 23

Who should get what vaccines?

Answer 23

Give adults inactivated vaccine : much more specific, give on seasonal basis

Give CHILD live attenuate as it gives much more broad immunity! .

Question 24

500,000 people die each year from seasonal influenza. The number of deaths from COVID worldwide since January 2020 is

1. 60 million
2. 6 million
3. 600,000
4. 60,000

Answer 24

6 million

Question 25

What is a coronavirus?

Answer 25

* RNA genomes, single stranded positive sense RNA, very large genomes… 30kb! * Enveloped virions. 100nm * Nidovirales- a nested set of mRNAs from one large genome * Seven coronaviruses have infected humans: * OC43, 229E, NL-63 and HKU-1 cause 20-30% common colds * SARS and MERS are zoonotic .

Question 26

How does SARS bind to cells?

Answer 26

ACE2

Question 27

The most likely origin of SARS CoV2 is: 1. Wild waterfowl 2. Horseshoe bats 3. Created in a laboratory 4. Pangolins

Answer 27

Horseshoe bats

Question 28

Where has it come from?

Answer 28

* Bats harbour hundreds of different coronaviruses, most discovered by huge sequencing exercises after SARS. * These viruses recombine. * Animals in live markets or farms can act as secondary hosts. * CoV with 96% similarity to SARS CoV2 has been found in pangolins. * CoV with 99% similarity found in bats in Laos

Question 29

What is the time course for SARS and COVID19?

Answer 29

Question 30

What are the outcomes of COVID?

Answer 30

Question 31

A COVID patient in ITU is most likely to benefit from 1. Kaletra, a combination of lopinavir and ritonavir usually used to treat HIV 2. Hydroxychloroquine, an antimalarial 3. Remdesivir a nucleoside analogue 4. Dexamethasone, a steroid

Answer 31

Dexamethasone, a steroid

Question 32

Why is dexamethasone good?

Answer 32

* Cheap and 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.

Question 33

What drugs can be used?

Answer 33

mAbs: Regeneron, Sotrovimab Small molecule antivirals: Molnupiravir: targets polymerase, nucleoside analogue Paxlovid: targets protease

Question 34

What is the COVID vaccine?

Answer 34

mRNA vaccines encoding stabilized spike

Question 35

What is the most common variant?

Answer 35

- Omicron has now displaced Delta variant around the world - Omicron is less well controlled by current vaccines - Omicron is associated with less severe disease (Wolter et al. Lancet 2022)

Question 36

Omicron has a large number of Spike mutations that affect antibody neutralization

Answer 36

Omicron has a large number of Spike mutations that affect antibody neutralization