The Struggle with Infectious Disease

Lecture 5

Nonspecific Response

University of Illinois at Chicago http://www.uic.edu/classes/bios/bios100/lecturesf04am/lect23.htm

Internal System

• Detects foreign cells – Self identification

molecules

• Marks foreign cells – Antibodies

• Destroys foreign cells and removes them – Variety of techniques

depending on type of invader

Influenza

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”

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

Influenza Virus

• Spherical in shape Outside:

Haemagglutanin Neuraminidase

Inside: 8 fragments of RNA

In between: Envelope Matrix

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

Influenza virus has a lot of hosts!

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.

Influenza Infection

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!

Pandemic Influenza

• Caused by a virus that has shifted so we have no immunity

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

Unknown Origins

• Appears to have started in both North and South Hemispheres ~simultaneously

• 3 waves separated by months (weeks)

• Infected humans and pigs simultaneously

• No obvious source of virus in birds or pigs Taubenberger, J; Morens D (2006). "1918 Influenza: the mother of all

pandemics". Emerg Infect Dis 12 (1): 15–22.

1918 Pandemic

• More died than were killed in the entire WW1

• Some died of pneumonia

• ~50% died from ‘cytokine storm’ preventing breathing

• Unusual age distribution for mortality

• “W” curve with peak around 30 years

• May be related to 1890 epidemic (uncertain)

Taubenberger, J; Morens D (2006). "1918 Influenza: the mother of all pandemics". Emerg Infect Dis 12 (1): 15–22.

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

1918 Pandemic

• H1N1 virus • Infected pigs and

resortment lead H3N2 – Foundation for current

circulating strains – Source of concerns with

‘species jump’

• H2N2 (Asiatic Flu) of 1957 was an exception

Burying victims North River, Newfoundland, Archives of Canada

1919 Poster “If treated it gets better right away”

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

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

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.

Influenza Virus

• Spherical in shape Outside:

Haemagglutanin Neuraminidase

Inside: 8 fragments of RNA

In between: Envelope Matrix

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

Influenza virus has a lot of hosts!

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.

Influenza Infection

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!

Shift vs Drift

Antigenic Drift • Accumulation of mutations

in the genes that code for antigen binding sites

• Results in sites that cannot be inhibited by previous antibodies

Antigenic Shift • Two or more viruses or viral

strains combine to form a new subtype having a mixture of the surface antigens of the original strains

• Specific case of reassortment

What is a Gene

• A gene is a section of DNA that can be related to a heritable trait e.g. hair colour, blood type

• They vary in length but seem to be of the order of 1000 base pairs

• First described in 1972

Protein Synthesis

• DNA contains a great many genes • Genes provide the codes for synthesising

proteins • Proteins are the foundation of biological

structures

Anatomy of a Gene

National Institute of Allergy and Infectious Diseases NIAID

Pandemic Influenza

• Caused by a virus that has shifted so we have no immunity

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

1918 Pandemic

• More died than were killed in the entire WW1

• Some died of pneumonia

• ~50% died from ‘cytokine storm’ preventing breathing

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

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

http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm

2009 Pandemic

• Groups at Increased Risk of Severe Influenza (2009 H1N1)

• Most impacted populations – Children, young adults – Persons with underlying chronic medical conditions

(e.g. chronic lung disease, heart disease, immunosuppression, neurological and neurodevelopment diseases)

– Pregnant women – Indigenous populations

Unusual Age Distribution

0

5

10

15

20

25

0-17 18-64 65+

Median Deaths/100k pH1N1

Average Deaths/100k 1990-1999

Mortality rate per 100,000 separated by age group for 2009 H1N1 Pandemic and Average influenza related deaths for the period 1990-1999. http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm

2009 Pandemic

Race/Ethnicity Influenza Season 2009 2009-10

White, non-Hispanic 3.0 16.3

Black, non-Hispanic 10.9 29.7

Hispanic 8.2 30.7 Asian/Pacific Islander 8.1 12.5

American Indian/Alaska Native

4.1 32.7

2009: April 15 - August 31, 2009 2009-10: September 1, 2009 - January 26, 2010

Age-adjusted and Season-specific 2009 H1N1 Influenza-related Hospitalization Rates (per 100,000) by race & ethnicity – Emerging Infections Program, 2009-10, CDC, Atlanta, USA

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

Influenza vaccines: challenges • Virus causing 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.

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

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 )

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.

Live attenuated virus-based vaccine (flu-mist)

• Intransal administration of live “attenuated” virus: mimic viral infection.

• It “may” induce broader immune responses.

Treatment

• Only treatment for viral infections is anti-viral medication

• Can’t ‘kill’ a virus like a bacteria

• Treatments disrupt the process

Antivirals – where they work to stop virus during the viral life cycle?

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.

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.

Vaccines produced in systems other than eggs

• Produced in mammalian cells: grow the virus in mammalian cells instead of eggs. Vaccines may 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.

• NONE OF THE ABOVE HAVE DEMONSTRATED CLEAR ADVANTAGES OVER THE EGG-DERIVED VACCINES (except avoidance of egg-allergy?)

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.

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

recognition by the host. • Only at very early stages – laboratory studies.

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.

2014 Vaccine Mismatch

• So what went wrong

• vH1N1 reassortment of H1N1 California and H3N2 (matrix protein)

• Or did it?

Current Issues

• Does vaccination increase likelihood of catching the flu in the following year?

• S.E. Ohmit et.al. Clinical Infectious Diseases 2014:58(3):319-27.