Perspective in Vaccine Development

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Perspective in Vaccine Development

• Prasit Palittapongarnpim, M.D.

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Major Breakthrough in Medicine

• Anesthesia allowing surgery
• Vaccination leading to massive decrease of
  mortality and population growth
• Antibiotics and chemotherapy
• Gene/cell therapy?

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Topics

• Importance of vaccines.
• Microbiological perspectives
• Development perspectives
• Vaccine production and marketing.

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Why do we need to develop and produce vaccines?

• Social reasons
• Supply in emergency situations Influenza
• Securing continuously adequate supply BCG
• Non-existing vaccines dengue
• Supplying locally-needed vaccines melioidosis,
  leptospirosis
• Financial reasons are usually poor.
• Limiting the expense on vaccines
• Profit-making

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Smallpox
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Smallpox
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Development of Vaccines which diseases should be
targets?

• Microbiological perspectives
• Developmental perspectives
• RD management perspectives
• Public Health perspectives
• Financial perspectives

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Development of Vaccines which diseases should be
targets?
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Microbiological Perspectives
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It is less difficult to develop vaccines for
pathogens with all following properties

• Complete immunity after natural infection is
  known.
• Pathogens have an Achilles tendon single or a
  few protective antigens (virulence factors), such
  as
• Bacterial toxins
• Bacterial adhesins, e.g., filamentous
  hemagglutinin of B. pertussis.
• Receptor binding ligands of viruses e.g., HA of
  influenza virus
• The antigens are proteins.
• Protection is mediated mainly by antibodies
  (e.g., in vivo-significant neutralizing
  antibodies).
• Extracellular bacteria.
• Pathogens are of a single or very few serotypes.

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Diseases caused entirely by a single or a few
toxins.

• Diphtheria diphtheria toxin.
• Tetanus tetanus toxin
• Cholera cholera toxin
• Enterotoxigenic E. coli Heat labile toxin, heat
  stable toxin.
• Scarlet fever, Toxic shock syndrome,
  Staphylococcal scalded skin syndrome, botulism
• Antibiotic associated diarrhea C. difficile
  toxin A.
• Pertussis Pertussis toxin, adenylate cyclase,
  tracheal cytotoxin, lethal toxin.

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Small Intestine Villus with Microvilli (TEM
x66,490)
http//www.pbrc.hawaii.edu/kunkel/gallery/
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http//gsbs.utmb.edu/microbook/ch024.htm
Nelson ET, Clements JD, Finkelstein RA V.
cholerae adherence and colonization in
experimental cholera electron microscopic
studies. Infect Immun 14527, 1976 4000X
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Why is it so difficult to develop effective
cholera toxoids?

• V. cholerae resides directly on intestinal
  epithelial cells, which are the only CTs target.
• The antibodies to toxin needs to be IgA and
  neutralize CT within a very short distance (lt100
  nm).
• Effective vaccines need to direct at colonization
  not to CT.

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It is more difficult to develop vaccines for
pathogens with one or more of the following
properties,

• eventhough, complete immunity after natural
  infection is possible.
• Pathogens are of multiple serotypes.
• Protective antigens are polysaccharides, which
  may stimulate only T cell independent pathway.
• No protective antigens are identified
  Leptospira, Neisseria gonorrhea, TB,
  Burkholderia, other bacteria, fungi, protozoa.
• Intracellular pathogens many viruses,
  Salmonella, TB, Shigella, Burkholderia-Hiding
  from antibodies.
• Requiring cell mediated immunity
• Immunity can be hazardous such as measles, dengue

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Pathogens with multiple serotypes

• Influenza trivalent seasonal vaccines
• Polioviruses 3 serotypes
• Human papillomavirus quadrivalent vaccines.
• Streptococcus pneumoniae gt90 serotypes. Vaccines
  available for 23 serotypes.
• Neisseriae meningitidis
• Dengue viruses 4 serotypes
• Leptospira interrogans gt200 serovars.
• Streptococcus pyogenes gt100 serotypes

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Anti-PRRP (polyribosyl ribitol phosphate),
protective against Haemophilus influenzae
infection, are naturally absent among toddler.
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T-independent Ag
PRP
B cells
IgM
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PRRP

• Undegradable in human (by antigen presenting
  cells)
• Cannot be presented with MHC II
• Repeating structure -directly stimulating
  specific B cells
• Short period of IgM production, no memory

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T-dependent Ag
PRP
Protein
B cells
ILs
IgG
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Pathogens with polysaccharide capsules

• Haemophilus influenzae serotype a-f, only type b
  cause invasive diseases. Its protective antigen
  is PRRP, which is not immunogenic in infant.
  Protein conjugation is needed.
• S. pneumoniae Protein conjugation is very
  helpful
• N. meningitidis Protein conjugation is very
  helpful
• Salmonella typhi Vi capsule. Protein conjugates
  is in clinical trials
• E. coli O157H7 O-specific polysaccharides-protei
  n conjugate on phase III.

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Intracellular Bacterial Pathogens

• Salmonella typhi live-attenuated strain or Vi
  antigen
• Mycobacterium tuberculosis BCG
• Shigella 4 species, 37 serotypes, Shiga toxin.
  Direct cell-cell invasion. Requiring cell
  mediated immunity.

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It is extremely difficult (or impossible) to
develop vaccines against pathogens with the
following properties

• Complete immunity is has never been reported
  Staphylococcus aureus, malaria, HIV.
• Bacteria can hardly be reached by IR
  Helicobacter pylori
• Chronic diseases requiring years of follow up in
  clinical trials phase III TB, HIV, leprosy.

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Developmental Perspectives
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Vaccine Developments

• To ensure that vaccines are effective and safe,
  they need to pass several steps of testing
  broadly classified into 3 stages.
• Discovery
• Preclinical testing
• Clinical trials

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Gold Standard of Efficacy is Clinical Trials
Phase III

• Efficient Phase I and II- Requiring immunological
  markers for efficacy in phase III
• Neutralizing antibodies
• Skin test???
• The immunological markers can be found by
• Correlation with protection in human population.
• Correlation with protection in phase III trials.
• The markers are extremely important if phase III
  trials is long, requiring a big population and
  expensive.
• Diseases without the markers AIDS, malaria, TB,
  S. aureus, H. pylori.

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Animal Testing

• Efficient animal testing require surrogate
  markers that correlate with human immunological
  markers, used in phase I/II trials.
• It may be the equivalent immunological markers,
  such as neutralizing antibodies.
• However, it is rather rare that animal diseases
  are completely equivalent to human diseases.
• Good animal models are very beneficial for
  vaccine development.

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In vitro testing

• Efficient in vitro testing must correlate with
  surrogate animal markers of efficacy, that
  correlate with human immunological markers, used
  in phase I/II trials, that correlate with
  clinical phase III trial.
• In vitro tests are usually designed by basic
  knowledge on pathophysiology with very few
  evidences that they correlate with phase III
  results.

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Management of Vaccine RD

• Stakeholders
• Financing
• Stage-Gate protocols

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Stakeholders in Vaccine RD

• Researchers
• Financers Private, Granting agencies,
  Government, Philanthropic. Financer may change at
  different stages of development
• Product Development Managers NVCO, NSTDA,
  private, GPO
• Promote/Kill,
• Plan,
• Seek budgets, Budgeting,
• Securing infrastructure,
• Recruiting Researchers,
• Intellectual property issues,
• Regulatory issues
• Public

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Financing

• Development of vaccines is a very long and
  expensive process. The most common cause of
  failure is the cessation of financing.
• In many cases, different financers finance at
  different stages
• Discovery-Granting agencies
• Phase III trials- MOPH (in kind)Private

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