Behavioral Objectives for Influenza Lecture

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Behavioral Objectives for Influenza Lecture

• Differentiate genetic shift from genetic drift in
  influenza viruses and how it occurs.
• Discuss how the regulation of influenza vaccine
  differs from the other vaccines discussed in the
  course.
• Discuss the difficulties in producing influenza
  vaccines.
• Discuss the target populations for immunization
  against influenza and the reasons for choosing
  them.

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HIV and Tuberculosis Vaccines
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Behavioral Objectives

• Discuss the reasons why AIDS therapy in developed
  countries fails in developing countries.
• List HIV vaccine designs.
• Discuss any 5 issues confounding HIV vaccine
  development.
• Define MDR TB and XDR TB.
• Describe vaccines (potential or in use) that may
  be used to immunize against TB.

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AIDS/HIV

• Acquired immunodeficiency disease resulting from
  infection with the human immunodeficiency disease
  virus

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AIDS PANDEMIC

• First reported in USA in 1981
• 40 million people living with HIV/AIDS globally
  19 million deaths have already been recorded
• In 2005 UN estimated 5 million new infections,
  with 3.1 million deaths
• 14,000 infected daily worldwide, 95 in low and
  middle income countries. Includes 2000
  children,lt15 years, 12,000 15-49 years of age
  evenly distributed between the sexes
• In USA the number of new HIV infections has not
  decreased over the past 10 years
• More than 40,000 new cases occur in US yearly
  with 50 in people lt than 25 years

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AIDS
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HIV Life Cycle
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Prevention, Diagnosis and Treatment of AIDS
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• for the vast majority of the worlds
  population, long-term treatment with multiple
  drugs is not feasible because of limited
  healthcare resources and the absence of
  health-care infrastructure.

The vaccine book, pg 245
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HIV vaccine designs

• Traditional approaches
• Live attenuated viruses
• Whole inactivated viruses
• Protein vaccination
• New approaches
• Recombinant viruses
• Naked DNA

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Confounding Issues for HIV Vaccine Development

• Virus heterogeneity
• HIV represents a genetically diverse population
  of viruses.
• HIV-1 is the dominant cause of AIDS throughout
  world. Clusters of related viruses grouped into
  clades.
• HIV-2 causes AIDS in West Africa
• During infection in a single individual,
  genetically distinct virus generated.

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• Different routes of transmission mucosal vs
  blood
• Different forms of virus intracellular vs
  cell-free virus
• Nature of immunity to be induced cellular vs
  humoral
• Clinical trials
• Funding etc.,etc.,etc.

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• The primary goal of an HIV vaccine is to reduce
  the incidence of HIV in the population not
  necessarily to protect individuals from HIV
  infection.

David O Connor Sept. 2007
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Tuberculosis
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Mycobacterium tuberculosis
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TRANSMISSION
Aerosols generated by coughing, sneezing and
talking dry to form droplet nuclei. Those (1-5um)
containing 1-3 bacilli are inhaled
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TUBERCULOSIS-THE PROBLEM

• DISEASE STATUS - 2000
• 2 billion people infected world-wide
• 9 million world-wide develop active
  tuberculosis annually 2 million die
• 10 million new cases in 2005 1 billion new
  cases in 2020.
• Emergence of drug resistant Mycobacterium
  tuberculosis

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GLOBAL TUBERCULOSIS

• 98 of cases in developing countries with an
  increase of 3 annually, 33 in southeast Asia,
  10 in African countries
• 80 of cases seen in 22 countries about half in
  5 countries India, China, Indonesia Nigeria and
  Bangladesh
• Not confined to developing countries 70
  increase in former USSR between 1990 and 1995
  with MDR-TB 40 of these cases.

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TUBERCULOSIS IN THE USA

• In 19th century killed more than any other
  disease
• Improvements in nutrition, housing, sanitation
  medical care in first half of 20th century cut
  cases to 20,000
• Further decline in case rates due to effective
  antibiotic therapies in the 40s 50s with lowest
  rates in mid-1980s
• Resurgence peaked in 1992

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• Between 10-15 million have latent TB 10 will
  develop active disease during lifetime.
• 18,371 active cases in 1998.
• In some sectors of US society TB rates now
  surpass those in worlds poorest countries.
• TB transmission occurs in the impoverished,
  malnourished, drug alcohol addicted,
  overcrowded or in poor health.
• Minorities disproportionately affected.

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CONTRIBUTING FACTORS

• Societal issues
• poverty, overcrowding, IMMIGRATION
• Political issues
• war, resettlement, IMMIGRATION
• Health issues
• malnutrition, drug abuse, HIV infection,
  immunosuppression
• Economic issues
• drug costs, health care

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THE PROBLEM OF DRUG RESISTANT TB

• Emergence of drug resistance some 50 years ago.
• Mutation frequencies range from 1 in 105 to 1 in
  108 replications.
• Primary drug resistance to single drug occurs in
  previously untreated cases 9.
• Secondary drug resistance occurs in patient who
  fails to complete course of treatment and
  relapses.
• These selected strains also have spontaneous
  mutations to other drugs-produce MDR-TB in new
  hosts.
• MDR-TB difficult and expensive to treat.
• XDR-TB even worse with higher mortality.

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DRUG RESISTANT TUBERCULOSIS

• Multi-drug resistant TB (MDR TB)
• Resistance to at least isoniazid rifampin.
• Treatment requires use of second-line (SLDs)
  drugs.
• Extensively drug-resistant TB (XDR)
• resistance to isoniazid, rifampin all
  fluoroquinolones and at least 1 of 3 injectable
  2nd line drugs..

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CAUSES OF DRUG RESISTANCE

• Inadequate dosage or treatment with too few
  drugs.
• Lack of compliance
• Patients fail to take medication consistently for
  6-12 months necessary for cure.
• Patients feel better after 3 or 4 weeks
• Drugs have unpleasant side effects
• Addicts sell TB drugs to buy narcotics

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CDC WHO SURVEY OF DRUG RESISTANT M.TB ISOLATES

• 17,690 TB isolates examined during 2000-2004
• 20 MDR
• 2 XDR

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SIGNIFICANCE OF XDR TB

• XDR TB has emerged as a threat to public health
  and TB control, raising concerns of a future
  epidemic of virtually untreatable TB.
• ( MMWR, March 24, 2006)

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CONTROL MEASURES(Case treatment)

• Prompt diagnosis and effective infected
  individuals.
• Prevention of progression of active disease in
  the exposed population.
• Isolation and treatment of active disease caused
  by MDR TB XDR TB cases
• Treating infected individuals with drugs in
  combination (DOTS-directly observed therapy
  strategy).
• Patient education.
• Immunization

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BCG Vaccine

• Current vaccine, bacile Calmette Guerin (BCG), is
  a live attenuated vaccine aimed at protecting
  naïve individuals-introduced in 1923
• Vaccine is an attenuated strain of M. bovis that
  had been passaged for 13 years resulting in the
  depletion of genes. Continued passage in
  subsequent years yielded closely related but
  genetically different substrains of BCG
• 100-150 genes of 4000 present in M.
  tuberculosis
• are now absent from BCG
• 100 million BCG vaccinations given to children
  each year
• will prevent 30,000 cases of tuberculosis
  meningitis during first 5 years of life 11,000
  cases of miliary tuberculosis.
• BCG immunization does not protect adults against
  primary tuberculosis or reactivation
  tuberculosis.

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• ..certain quarters have heavily criticized
  the TB field for the lack of clinical trials to
  date, while pointing to the huge number of HIV
  trials currently running.

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New potential candidate vaccines for tuberculosis

• Candidate Type Source
• MVA-Ag85 Prime boost University of
  Oxford
• rBCG30 Recombinant BCG UCLA
• Mtb72F Fusion protein
  GlaxoSmithKline
• Ag85/ESAT Fusion protein Copenhagen
• ESAT/Ag85 Fusion protein CBER/FDA

Orme I. Vaccines.241,2006
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Questions That Need Answers

• What should vaccines do at the immunological
  level?
• What surrogate clinical markers could be used to
  track vaccine efficacy?
• What mediates resistance in people naturally
  resistant to tuberculosis?
• How can preclinical trails be run in BCG
  immunized populations?
• What is the basis for immunity to primary
  tuberculosis vs reactivation tuberculosis?