Jennifer Taylor

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Tuberculosis A Major Killer Worldwide and the
Vaccines to Stop It

• Jennifer Taylor
• Colorado State University
• Fort Collins, CO

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TB is an ancient disease
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Colorado once a haven for TB patients

• Fresh air
• Year-round sunshine
• Low humidity
• Higher elevations

Symptom relief
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Sanatariums sprouted in Colorado
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Heliotherapy and fresh air
Patients lay in beds pushed out on the porches of
the Texas Building of the Jewish Consumptives'
Relief Society for sun heliotherapy treatment for
tuberculosis. 
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The Current Situation

• 1 person infected per second
• 1/3 people on the planet are infected
• Kills nearly 1.8 million per year
• TB is a leading cause of death in HIV patients.
• Multidrug-resistant (MDR) and extensively
  drug-resistant (XDR) strains of TB are found
  throughout the world.
• Despite being one of the most widely used
  vaccines in the world today, the TB vaccine (BCG)
  has had no apparent impact on the TB pandemic.

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Mycobacterium tuberculosis

• Robert Koch in 1882
• Waxy cell wall
• Acid-fast bacillus
• Slow growing

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Tuberculosis the disease

• Spread through air
• Coughing, sneezing, talking, singing
• Usually a pulmonary infection
• Can infect other organs
• Potts Disease (spine)
• Miliary TB (dissemination)
• Symptoms
• Cough (3 weeks)
• Chest pain
• Coughing up blood
• Weakness and fatigue
• Weight loss
• No appetite
• Night sweats
• Fever

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Diagnosis of TB

• PPD test (Mantoux Skin Test)
• QuantiFERON TB Gold Test
• Chest X-ray
• Microbiology
• Sputum smears
• Culturing the bacteria

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Treatment
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Multi-Drug Resistant (MDR) and Extremely Drug
Resistant (XDR) Mtb
Is Man Made

• Drugs are toxic, so people dont always complete
  therapy.
• Wrong dose
• Wrong length of time prescribed
• Full drug supply unavailable
• Poor quality drugs

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BCG and Why We Need a New Vaccine

• Bacille Calmette-Guerin (BCG)
• 1908 Sub-cultured a virulent strain of M.
  tuberculosis every 3 weeks for 13 years until it
  was attenutated.

• 1921 high-risk infant protected
• Most widely distributed vaccine in the world
• Protects babies and children
• Protective efficacy varies in adults by 0-80.
• Interferes with the diagnostic PPD test

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Granuloma The Hallmark of TB

• M. tuberculosis bacilli are inhaled
• Bacilli infect alveolar macrophages
• Infected macrophages recruit cells
• Activated T cells wall off the infection

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Pathogenesis of Granuloma Formation
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Protection against Mtb

• Cellular immunity is required
• HIV patients highly susceptible
• CD4 KO mice
• IFN-gamma KO mice
• CD8 KO mice
• B cells do not seem to protect

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2 Camps of TB Vaccine Development

• Replace BCG
• Unlikely due to widespread use, low cost, safety
  record
• Focus on recombinant BCG and attenuated Mtb
• Boost BCG

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TB Vaccine Candidates in Clinical Trials
Barker, LF, et al. Current Opinion in Immunology
2009, 21331338
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CSU-NIH Contract for TB Vaccine Development

• Provide the most relevant data to move a vaccine
  candidate forward using currently available
  animal models.
• Animal models mouse and guinea pig

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Infectious Disease Research ComplexBiosafety
Level 3 FacilitiesCSU
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Immunology Suite and the Aerosol Delivery System
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Animal Models in Tuberculosis Research

• Short-term mouse model
• Protection data
• Immunological analysis of vaccine candidates
• Long-term guinea pig model
• Survival data
• Protection data
• Immunological data?

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Short-Term Mouse Model
Low dose aerosol virulent M. tuberculosis
Vaccinate
Immune response
4 weeks
30 days
C57BL/6
Viable count
Immune response to vaccination
Colony Form Units
ELISpot
Flow cytometry
ELISA
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Guinea Pig Model

• Disease and survival experiment
• Develop classical granulomas similar to humans
  with active tuberculosis
• As lung tissue necrosis progresses, begin to lose
  weight and die of tuberculosis similar to humans

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Long-term guinea pig model
Low dose aerosol virulent M. tuberculosis
Monitor
Vaccinate
10 weeks
Hartley
Hartley guinea pigs Vaccinate Challenge with low
dose aerosol Monitor for survival and pathology
BCG
Saline
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Guinea Pig Pathology vs. Colony Forming Units
Saline
BCG
Mean Log10 CFU
Days post infection
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Future

• Develop post-vaccination immune profile that can
  be correlated with outcome after infection
• Identify additional correlates of protection
• Increased numbers of guinea pig reagents has
  allowed for increased studies of the
  immunological of vaccines

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Acknowledgments

• TB Vaccine Testing and Reagent Materials Contract
  
• Angelo Izzo
• Ajay Grover, PhD
• Jolynn Troudt
• Andrew Keyser
• Kimberly Arnett
• Linda Izzo
• NIH NIAID HHSN266200400091c