3 to 5

million
Severe
illness

250,000 to
500,000
deaths

3 to 5 million
Severe illness

Outline
1. Introduction
2. Innate Immune Response
3. Adaptive Immune Response
4. Evading

5. Vaccination

1. Introduction

Family of Orthomyxoviridae
3 types
Influenza A virus
Pandemic
Influenza B virus

Epidemic

Influenza C virus

Respiratory
diseases

Spanish flu (1918-1920)

50-100 million deaths (subtype of H1N1)

Hong Kong flu (1968-1969)

35,000 deaths (H3N2)

Asian flu (1956-1958)

4 million deaths (H2N2)

18
11

http://www.cdc.gov/flu/images/h1n1/3D_Influenza_transparent_key_pieslice_lrg.gif

2. Innate
response to
influenza virus

Recognize pathogens through PAMPs

(pathogen-associated molecular patterns)

- Body recognizes unique molecules of

microorganism that are not associated with
human cells
(carbohydrates, proteins, lipids, nucleic acids)
- PAMPs recognized by PRRs (pathogen
recognition receptors)

3 classes of PRRs:
-

Retinoic acid inducible gene-I (RIG-I)

Found in most cell types in cytosol
Recognize ssRNA bearing 5 triphosphate
Induction of type I interferons

- Toll-like receptors (TLR-7)

Recognize genomic RNA in endosomes of dendritic cells
Both live & killed virus can induce type I IFN through TLR-7
Plays important role in development of adaptive immunity
-NOD-like receptors (NLRP3)
Inflammasome senses damaged cells
Involve an increase in disease tolerance

Induction of type I interferons &

proinflammatory cytokines
- Infected epithelial cells produce type I interferons (IFN-/)
- PAMP-PRR interactions (TLR-7) induce macrophages & immature DCs at
site of infection to produce:
+ Type I interferons
+ Proinflammatory cytokines (IL-1, IL-6, IL-12, TNF- )
+ Chemokines (MIP-1alpha/beta, MCP-1, IL-8)
- Leads to amplification of the inflammatory response.

Type I interferons (INF/)

Bind to IFNR triggers antiviral functions in the cell
-> Protect uninfected cells from virus infection

Induce the influx and activation of NK cells

-> Kill infected epithelial cells before virus release
Upregulate MHC class I expression
-> Make cells better targets for lysis

Role of natural killer cell

- Can directly recognize & bind virus-infected cells
through receptors
Natural cytotoxicity receptors (NKp46) recognizes HA
- Activated NK cells:
+ Produce a variety of cytokines (INF-gamma), chemokines
+ Important bridge between innate and adaptive immunity

Roles of dendritic cells

- 2 subsets:

CONVENTIONAL DENDRITIC
CELLS (CDC)
+ Main function: antigen
presentation
+ Response to virus in TLRindependent manner

PLASMACYTOID DENDRITIC CELLS

(PDC)
+ Main function: IFN-type I
producing cells
+ Ability to retain RNA & DNA in TLRcontaining endosomes
-> better interaction of viral nucleic
acid and TLR

- DCs are central to initiation and regulation of adaptive immune

response

3. Adaptive
Immunity

Humoral Immunity
1. Viral HA:
Ab directed to globular head of HA => sterilize immunity to
virus infection.
Ab block receptor-mediated endocytosis.

Humoral immunity
2. Viral NA:
Ab interfere with the last phase of viral replication cycle
NA-specific Abs do not neutralize the virus
Limit the viral spread & shorten duration of illness.
contribute to clearance of virus-infected cells

Cellular Immunity
1. CD4+ T cells
Associated with MHC class II

a. Th2: produce IL-4, IL-5, IL-13

=> promote activation of B cells
b. Th1: produce IFN-, IL-2
=> promote CTL response

Cellular immunity
2. CD8+ T Cells

Activated after recognition of viral epitopes with MHC class

I
=> Subsequently mature into CTLs

3. Regulatory T cells and Th17 cells

a. Tregs: balances the immune response

=>control CD4+ T cells an CTL responses

b. Th17 cells: produce IL-6
=> inhibit the effect of Tregs & promote T
helper responses

4. How influenza virus

escapes from
immunity?

Escape from innate immunity

NS1 protein inhibits type I Interferon

Other proteins interfere with host responses (PB1, PB2, PA)

Escape from Humoral Immune

Response
ANTIGENIC DRIFT
Small changes, happend continually
Produce viruses with same antigenic
properties
Small changes accumulated
antigenic difference

ANTIGENIC SHIFT
Abrupt, major changes in influenza A

Results in new influenza A subtype

(different hemagglutinin,
neuraminidase)

People are lack of protection against

the new virus

http://www.organicbestchoices.com/page/333070235

Escape from cellular immune

response
Evade recognition by virus-specific T cells:
Viruses with large DNA genome: encode proteins interfering with
antigen processing, presentation pathways

RNA viruses : + evade recognition by T cells

+ selective pressure exerted by virus-specific T cells

http://www.mdpi.com/1999-4915/4/9/1438/htm

5. Influenza
Virus
Vaccination

Influenza Virus
Vaccination
Annual Vaccination
Can be trivalent or quadrivalent vaccine:
One influenza type A subtype H1N1 virus strain
One influenza type A subtype H3N2 virus strain
One or two influenza type B virus strains

Can be an injection or a nasal spray.

Time for Influenza Virus

Vaccination
Influenza Virus Vaccination should begin ideally by
October.

Should continue to be offered throughout the flu

season

How Influenza Virus Vaccine

Works
Take about two weeks after vaccination
Activate the immune system to provide antibodies
against influenza virus
For the first time of vaccination, 2 doses are
needed. From second time, 1 dose is enough.

Who should get influenza

virus vaccination each year
Children aged 6 months until their 5th birthday
Pregnant women

People 50 years old

People of any age with chronic medical conditions
People living in long-stay facilities
People who live with or care for those at high risk for
complications from flu

Types of Influenza Virus

Vaccine
Inactivated vaccine:
Intramuscular
Split virus and subunit types
Duration of immunity of 1 year or less

Live attenuated vaccine:

Intranasal
Using the technique of cold-adaptation
Duration of immunity at least 1 year

Who should not be vaccinated

with live attenuated influenza
vaccine
Children < 2 years of age

Who should not be vaccinated

with live attenuated influenza
vaccine
Children < 2 years of age

Who should not be vaccinated

with live attenuated influenza
vaccine
Children < 2 years of age
People 50 years old
People with a medical condition that places them at high risk for
complications from influenza
Children < 5 years old with a history of recurrent wheezing
Children or adolescent taking aspirin

People with a history of Guillain-Barr syndrome

Pregnant women
People with a severe allergy to chicken eggs or any of the nasal spray
vaccine components.

Syndrome after vaccination

Begin within 6-12 hours and persists for 1-2 days
Fever
Malaise
Headache
Arthralgia
Myalgia
Guillain-Barr syndrome (GBS)
Immediate allergic reaction

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