the struggle with infectious disease - carleton … · and antigenic shift & drift virus...
TRANSCRIPT
![Page 1: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/1.jpg)
The Struggle with Infectious Disease
Lecture 5
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Influenza
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Influenza
• Infectious disease of birds and mammals
• Caused by the RNA virus of the family Orthomyxoviridae
• Symptoms: chills, fever, sore throat, muscle pain, headache, coughing
• Confused with flu-like illness, “stomach flu”
![Page 4: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/4.jpg)
Influenza • Primary route of infection
is through the air via aerosols
• Secondary route through infected surfaces
• Inactivated by sunlight, disinfectants and detergents
• 500,000 deaths annually worldwide (estimate)
• 3-5 million severe illness
![Page 5: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/5.jpg)
Influenza Virus
• Spherical in shape Outside:
Haemagglutanin Neuraminidase
Inside: 8 fragments of RNA
In between: Envelope Matrix
![Page 6: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/6.jpg)
Influenza Virus
• Three types of influenza – A: Rapid onset, more
severe, causes death – B: Longer onset, less
severe – C: Does not infect people
• Classification is based on Hemagglutinin and Neuraminidase
• 16 HA and 9N – H1,2,3 & N1,2 common
![Page 7: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/7.jpg)
Influenza virus has a lot of hosts!
![Page 8: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/8.jpg)
How does influenza virus cause us ill
• Upper respiratory tract infections: local infections may cause mild symptoms
• Lower respiratory tract infections (lungs): fever, cough, dizziness, or even neurological symptoms etc.
• Cytokine storms: exceedingly inflammatory reactions (cytokine storms), particularly in the lung.
![Page 9: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/9.jpg)
Influenza Infection
![Page 10: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/10.jpg)
Seasonal vs Pandemic flu
Why do we keep getting influenza?
1. Seasonal flu is caused by antigenic drift (small antigenic changes of hemagglutinin; but neuraminidase can also contribute to the antigenic drift).
2. Pandemic flu caused by antigenic Shift, ie., much more dramatic change in the hemagglutinin (and also neuraminidase, although neuraminidase is not as important as hemagglutinin).
3. The antigentic drift and shift is caused by the inherent property of virus replication enzymes (error-prone), segmented genes of the virus (predisposed to gene reconbination) and also immune pressure!
![Page 11: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/11.jpg)
Pandemic Influenza
• Caused by a virus that has shifted so we have no immunity
![Page 12: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/12.jpg)
1918 “Spanish” flu pandemic
• Most deadly, ~ 500 million people infected.
• ~40-60 million deaths. • Avian H1N1 virus • Cytokine-storm might
significantly contribute to the death.
• Origin is uncertain
![Page 13: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/13.jpg)
1918 Pandemic
• More died than were killed in the entire WW1
• Some died of pneumonia
• ~50% died from ‘cytokine storm’ preventing breathing
![Page 14: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/14.jpg)
1918 Pandemic
• We do know what the virus looked like – Sequenced virus from
victims
• We don’t know what made it so dangerous
• We can’t yet predict the severity of a subtype
![Page 15: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/15.jpg)
2009 H1N1 pandemic flu • Relatively mild but spread
globally in a very rapid fashion (due to travel).
• Also H1N1 (a hybrid virus with genes from human, avian and swine).
• Young people appears to have “violent reactions”.
• Old people born before 1960 apparently have some antibodies against the virus.
• Affected ~25% wordwide
![Page 16: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/16.jpg)
Flu Vaccine
• Vaccine is the best way to provide protection
• Due to multiple hosts and antigenic shift & drift virus changes rapidly
• We have not found an ‘invariant’ portion of virus
![Page 17: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/17.jpg)
Influenza vaccines: challenges • Virus cause annual
epidemic is often of unpredictable function.
• Each year, 6 months before the flu season, the seeds must be selected.
• Selection of seeds is more of a guesswork (based on last year’s surveillance data).
• Mismatch can occur.
![Page 18: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/18.jpg)
![Page 19: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/19.jpg)
Influenza
![Page 20: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/20.jpg)
Influenza
• Infectious disease of birds and mammals
• Caused by the RNA virus of the family Orthomyxoviridae
• Symptoms: chills, fever, sore throat, muscle pain, headache, coughing
• Confused with flu-like illness, “stomach flu”
![Page 21: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/21.jpg)
Influenza • Primary route of infection
is through the air via aerosols
• Secondary route through infected surfaces
• Inactivated by sunlight, disinfectants and detergents
• 500,000 deaths annually worldwide (estimate)
• 3-5 million severe illness
![Page 22: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/22.jpg)
Influenza Virus
• Spherical in shape Outside:
Haemagglutanin Neuraminidase
Inside: 8 fragments of RNA
In between: Envelope Matrix
![Page 23: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/23.jpg)
Influenza Virus
• Three types of influenza – A: Rapid onset, more
severe, causes death – B: Longer onset, less
severe – C: Does not infect people
• Classification is based on Hemagglutinin and Neuraminidase
• 16 HA and 9N – H1,2,3 & N1,2 common
![Page 24: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/24.jpg)
Influenza virus has a lot of hosts!
![Page 25: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/25.jpg)
How does influenza virus cause us ill
• Upper respiratory tract infections: local infections may cause mild symptoms
• Lower respiratory tract infections (lungs): fever, cough, dizziness, or even neurological symptoms etc.
• Cytokine storms: exceedingly inflammatory reactions (cytokine storms), particularly in the lung.
![Page 26: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/26.jpg)
Influenza Infection
![Page 27: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/27.jpg)
Seasonal vs Pandemic flu
Why do we keep getting influenza?
1. Seasonal flu is caused by antigenic drift (small antigenic changes of hemagglutinin; but neuraminidase can also contribute to the antigenic drift).
2. Pandemic flu caused by antigenic Shift, ie., much more dramatic change in the hemagglutinin (and also neuraminidase, although neuraminidase is not as important as hemagglutinin).
3. The antigentic drift and shift is caused by the inherent property of virus replication enzymes (error-prone), segmented genes of the virus (predisposed to gene reconbination) and also immune pressure!
![Page 28: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/28.jpg)
Pandemic Influenza
• Caused by a virus that has shifted so we have no immunity
![Page 29: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/29.jpg)
1918 “Spanish” flu pandemic
• Most deadly, ~ 500 million people infected.
• ~40-60 million deaths. • Avian H1N1 virus • Cytokine-storm might
significantly contribute to the death.
• Origin is uncertain
![Page 30: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/30.jpg)
1918 Pandemic
• More died than were killed in the entire WW1
• Some died of pneumonia
• ~50% died from ‘cytokine storm’ preventing breathing
![Page 31: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/31.jpg)
1918 Pandemic
• We do know what the virus looked like – Sequenced virus from
victims
• We don’t know what made it so dangerous
• We can’t yet predict the severity of a subtype
![Page 32: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/32.jpg)
2009 H1N1 pandemic flu • Relatively mild but spread
globally in a very rapid fashion (due to travel).
• Also H1N1 (a hybrid virus with genes from human, avian and swine).
• Young people appears to have “violent reactions”.
• Old people born before 1960 apparently have some antibodies against the virus.
• Affected ~25% wordwide
![Page 33: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/33.jpg)
2014 Vaccine Mismatch
• So what went wrong
• Or did it?
![Page 34: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/34.jpg)
Flu Vaccine
• Vaccine is the best way to provide protection
• Due to multiple hosts and antigenic shift & drift virus changes rapidly
• We have not found an ‘invariant’ portion of virus
![Page 35: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/35.jpg)
Influenza vaccines: challenges • Virus cause annual
epidemic is often of unpredictable function.
• Each year, 6 months before the flu season, the seeds must be selected.
• Selection of seeds is more of a guesswork (based on last year’s surveillance data).
• Mismatch can occur.
![Page 36: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/36.jpg)
![Page 37: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/37.jpg)
Current influenza vaccines
• Trivalent: currently H1N1 and H3N2 (both are type A virus derived vaccines) and type B (Victoria lineage).
• Vaccines are produced in eggs. • Then purified by ultracentrifugation and
filtration. • The viruses are then killed by chemicals such
as formaldehyde and detergents
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Limitations of current flu vaccines
• Has to be re-made each year (vaccine only induce short-term protection).
• The seeds can be wrong (guesswork is wrong). • Mismatch between the vaccine seeds and actual
circulating strains can occur, resulting in attenuated or non-protection!
• Some people are allergic to eggs. • Adverse reactions: very rare such as location
injection site reaction. Extremely rare is neurological disorder (Guillain-Barre syndrome )
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How to improve the vaccines
• Adjuvants: Several oil-in-water adjuvants, including MF59 and AS03, have significantly enhanced immune responses in healthy adult vaccine recipients to inactivated influenza A/H5N1 or H1N1.
• These adjuvants may also broaden the spectrum of immune protection (multiple subtyes of virus).
• The adjuvants may spare antigens: good for pandemic preparation.
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Live attenuated virus-based vaccine (flu-mist)
• Intransal administration of live “attenuated” virus: mimic viral infection.
• It “may” induce broader immune responses.
![Page 44: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/44.jpg)
Treatment
• Only treatment for viral infections is anti-viral medication
• Can’t ‘kill’ a virus like a bacteria
• Treatments disrupt the process
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Antivirals – where they work to stop virus during the viral life cycle?
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Limitations with antiviral
• Drug resistant strains can occur very fast; it was reported in one study that over 90% of H1N1 swine virus studied in one cohort become resistant to Tamiflu.
• Cannot prevent infection but only shorten duration of illness and lessen the symptoms.
• Ongoing Debate on its real benefit.
![Page 47: The Struggle with Infectious Disease - Carleton … · and antigenic shift & drift virus changes rapidly • We have not found an ‘invariant’ portion of virus . Influenza vaccines:](https://reader031.vdocuments.site/reader031/viewer/2022022021/5ba01bd309d3f259468c2d92/html5/thumbnails/47.jpg)
New research on treatment
• Antibody therapy: Monoclonal antibodies (humanized or human antibodies).
• Only in experiment animal studies. • Expensive to produce. • Plasma or antisera from convalescent people
could be useful – only experimental stages or limited data from very small number of people.
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Vaccines produced in systems other than eggs
• Produced in mammalian cells: grow the virus in mammalian cells instead of eggs. Vaccines may be better resemble the actual antigenic epitopes of the viruses?
• Produced in plants: such as rice or tobacco. • Produced as virus-like particle (devoid of nucleic
acids, thus non-infectious). It may induce better immune responses.
• NON OF THE ABOVE HAVE DEMONSTRATED CLEAR ADVANTAGES OVER THE EGG-DERIVED VACCINES (except avoidance of egg-allergy?)
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New approaches: interior proteins as antigens
• Using interior virus proteins as antigens. • These antigens are nucleoproteins or matrix
proteins. They are > 90% conserved potential good vaccine candidates
• But they are weak immunogens. • Most of time, such antigens are inducing non-
neutralizing antibodies.
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Universal vaccines
• Some sequences in HA are very conserved. • But they are comprised of very short peptide
sequences. • So they are Not immunogenic. • Must be engineered to allow better
recognization by the host. • Only at very early stages – laboratory studies.
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Other new approaches
• Using viral vectors such as adenoviral vector.
• Using moleculatr adjuvants to improve vaccines (such as CD40 ligand or ligand for Toll-like receptors); these molecular adjuvants improve immune responses.