Influenza: Vaccines & Neuraminidase Inhibitors

Question 1

Outline influenza virus structure (orthomyxovirus, components 2 & envelope proteins 3).

Answer 1

Orthomyxovirus: single strand enveloped RNA which recognises sialic acid receptors.

Important viral components:
1. Antigenic: Hemagglutinin (H), Neuraminidase (N), vRNA
2. Non-structural protein

Envelope Proteins:
1. Hemagglutinin (HA) functions in attachment & penetration
2. Neuraminidase (NA) cleaves sialic acid from glycoconjugates facilitating elution of progeny virions from infected cells
3. M2 functions in uncoating & virus maturation

Question 2

How do the envelope proteins work in the replication cycle - 2

Answer 2

1. Hemagglutinin is required for attaching the influenza virus to the cells surface
2. Neuraminidase is required for the efficient release of new virions from infected cells

Question 3

What are the 2 domains of haemagglutinin structure?

Answer 3

1. Globular head - this bind to the cell surface receptor of sialic acid,
2. Fibrous stem.

Question 4

What is the function of neuraminidases - 2

Answer 4

1. An enzyme that breaks down the sialic acid receptor on the cell surface (pathogens use these to facilitate infection/propagation)
2. Once sialic acid is removed from the receptor by Neuraminidase, the Haemagglutinin protein is no longer bound.

Question 5

What is the innate influenza infection response - 3

Answer 5

1. NFkB transcription leads to pro-inflammatory cytokine expression of TNFalpha, IFNbeta & IL-8.
2. The chemokines & cytokines produced increase inflammatory responses by attracting NK, B & T cells to the infection site.
3. These cells continue to produce more inflammatory cytokines to keep the Th1 response cycle going.

Question 6

Long term influenza infection response - 3

Answer 6

1. IFNy boosts chemokine gene expression, macrophage activation, antigen presentation & continual development of the specific immune system.
2. Th2 response, T cell stimulation, Antigen Presentation, B Cell maturation.
3. Antigen-specific IgG production - long term protection against similar strains.

Question 7

Antigenic drift - 3

Answer 7

1. Gradual accumulation of amino acid mutations allows the hemagglutinin to escape neutralizing antibodies
2. Epidemic strains of influenza are thought to have changes in three or more antigenic sites
3. Antigenic drift results in reduced ability of circulating antibodies to recognise the ‘new’ virus. e.g. Seasonal Influenza.

Question 8

Seasonal & Pandemic Influenza - 4

Answer 8

Seasonal Influenza:
1. Most common, variant of a previous strain.
2. Can anticipate likely strain to emerge & prepare vaccines in preparedness
3. Most of the population will have at least partial immune protection
Pandemic Influenza
4. Typically a new strain

Question 9

How does pandemic influenza come about - 6

Answer 9

1. Antigenic shift causes genetic shuffling, so new genes encode different Haemagglutinin or Neuraminidase subtypes.
2. Often occurs in animal hosts which are co-infected with multiple strains of influenza.
3. New strain of virus forms, often originating from another species.
4. No immune history, so no natural protection,
5. Can’t predict nature of strain or when it will emerge
6. Little distinction between healthy & those at risk

Question 10

Neuraminidase inhibitors - 4

Answer 10

1. Competitive inhibitors compete with the natural receptors for access to the neuraminidase site.
2. Active against all strains of influence & all serotypes.
3. Structure is more complex & specific, so there are less S/Es & off-target effects.
4. e.g. Oseltamivir and Zanamivir

Question 11

Zanamivir - 4

Answer 11

1. Inhalational delivery of dry powered drug (5 mg per package) in a lactose carrier using a Diskhaler.
2. Approved for treatment of influenza A & B among those aged ≥ 7 years
3. Excreted unchanged by kidney
4. Best given within 48hrs of symptom onset

Question 12

Oseltamivir - 6

Answer 12

1. Orally administered: 75 mg tablets & syrup for children.
2. Treatment & prophylaxis of influenza A & B.
3. Treatment ≥1 year & Chemoprophylaxis ≥ 13 years.
4. Absorption of pro-drug oseltamivir is high following de-esterification in the gut, liver, & blood.
5. Active drug has serum half-life of 8-10 hours, is excreted unchanged by the kidney.
6. Best given within 48hrs of symptom onset

Question 13

Seasonal influenza management - 3

Answer 13

1. Vaccines are 1st line.
2. When strain differs from predicted, the vaccines may provide limited protection, but Anti-viral drugs become important for treatment & management
3. Can result in small epidemic outbreaks as as result.