seminar 302 2014

Influenza A virus – From biology to vaccines

• Samita AndreanskyDepartments of Microbiology and

Immunology, Pediatrics and Medicine

Influenza kills 20-30,000 Americans each year. About 40,00 die in road accidents

Young and Elderly are most vulnerable

1918 Spanish Flu Approx 20-40 million deaths

America’s deaths from influenza were greater than the number of U.S. servicemen killed in any war

Series10

100

200

300

400

500

600

700

800

900

Civil WWI 1918-19 WWII Korean Vietnam War Influenza War War

Thousands

0

900

• The influenza virus is a upper respiratory tract infection caused by one of the influenza virus pathogens (Type A, B, or C).

• Although it is called a respiratory disease, it affects the whole body, making you feel sick all over.

http://www.nlm.nih.gov/medlineplus/ency/imagepages/17237.htm

Where does Influenza virus acts on the body

Virus – Host Interaction

Virus Attachment Protein: Hemagglutinin

Host receptor : Sialic Acid

viralzone.expasy.org

Host receptor specificity

• Tiny droplets that come from a person’s mouth and nose when they cough and sneeze.

• • Touching objects

contaminated with particles from an infected person’s nose and throat.

http://www.lungusa.org/diseases/c&f02/influenza.html#what

Transmission from person to person by:

• Symptoms begin 1-4 days after infection. • You can spread the flu before your symptoms start and

3-4 days after your symptoms appear. • The following symptoms of the flu can vary depending

on the type of virus, a person’s age and overall health:– Sudden onset of chills and fever (101 – 103 degrees F)– Sore throat, dry cough – Fatigue, malaise – Terrible muscle aches, headaches– Diarrhea– Dizziness

Symptoms

• A bacterial “superinfection” can develop when the influenza virus infects the lungs.

• The result? – The bacteria that live in the nose and throat can descend to the lungs

and cause bacterial pneumonia. • Who is most at risk?

– People over 50, infants, those with suppressed immune function or chronic diseases.

• Other complications include bronchitis, sinusitis and ear infections.

http://www.ecureme.com/atlas/version2001/atlas.asp

Complications of Flu

Influenza A virus

• Nucleic acid : RNA

• Enveloped virus

• Viral family: Orthomyxoviridae

• Three types• A, B, C

Influenza viruses are small.Average eukaryotic cells is 10,000 nm in diameter (10 microns) 100 times bigger than the influenza virus diameter

Different Species – Different Genes

A/Fujian/411/2002 (H3N2)

NeuraminidaseHemagglutini

n

Type of nuclearmaterial

Virustype

Geographicorigin

Strainnumber

Year of isolation

HA and NA

substrain

Virus Nomenclature

Serotypes in humans

HA 1-16NA 1-9

Drift and Shift generates new viruses

Evolutionary Survival Strategy for the virus

Host immune response : Clears the infection

Our Immune System is like an army

www.avaara.com

•Gradual Change• Due to point mutations in HA and NA• Occurs in both A and B viruses

DRIFT

old neuraminidase new neuraminidase

Drift

http://www.biotech.ubc.ca/db/TEACH/BANK/

PPT/flu2.ppt

•Eight-member Gene Teams” with each member being a separate Player•Promiscuity of the virus – they can give away genes and acquire new segments

Shift – Reassortment of genes

•Occurs through assortment of genes• Sudden change and cause for pandemics• Occurs only in influenza A viruses• We have no pre-existing immunity

Deaths

20% were 10 years old or under

64% were 25 years old or under

87% were 35 years old or under

Median Age 16-20 years old

Avian H5N1 Virus jumped species

2009 Swine H1N1 Flu “You have killed us all”

Death - 17,770 people in 213 countries in 2009

1918 1957 1968 1977 19971998/9

2003

H1

H1H3

H2

H7H5H5

H9

SpanishInfluenza

AsianInfluenza

RussianInfluenza

AvianInfluenza

Hong KongInfluenza

Timeline of influenza infection

2014

Swine H1

“The pandemic clock is ticking, we just don’t know what time it is”

E. Marcuse

• Inactivated vaccine• (generates only antibody response)

• Live attenuated vaccine (generates both antibody and T cell responses)

Annual

Cornerstone of Prevention

Immunology 101

Host response to viral infection

• Antibodies against Hemagglutinin

• CD8 T cells lyse infected cells

• CD4 T cells

surveillance

select strains

prepare reassortants

standardize antigen

assign potency

review/license

formulate/test/package

vaccinate

WHO/CDC)

WHO/CDC/FDA

CDC/FDA

FDA

FDA

FDA

manufacturers

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

clinic

Vaccine Production

Cell SubstratePreparation

Remove Cells,Purify Virus

Infect &Incubate

InactivateVirus

Influenza Vaccine Production

• Selection of strains difficult and time consuming

• Annual, seasonal production

• Technical process, specialized facilities

• Lack of cross protection against antigenic variants Long term protection uncertain ??

• Relatively high cost

• Annual vaccine administration is required26

Constraints of Vaccine Production

Pre-pandemic: Vaccine Planning

• Definition: Vaccines developed against influenza viruses that are currently circulating in animals and that have the potential to cause a pandemic in humans

• Rationale: might provide priming or “limited protection” against pandemic strain Goal: Reduce morbidity or mortality Might not reduce number of viral infections

• Problem: Which vaccine strains, and when should it be given?

27

Despite . . . – Expanded global and national surveillance – Better healthcare, medicines, diagnostics– Greater vaccine manufacturing capacity

New risks:– Increased global travel and commerce– Greater population density– More elderly and immunosuppressed– More daycare and nursing homes– Bioterrorism

Pandemic Flu Today