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Vaccines
Vaccination
•Vaccination
•Administration of a substance to a person with the purpose of
preventing a disease
•Traditionally composed of a killed or weakened microorganism
•Vaccination works by creating a type of immune response that enables
the memory cells to later respond to a similar organism before it can
cause disease
Early History of Vaccination
•Pioneered India and China in the 17th century
•The tradition of vaccination may have originated in India in AD 1000
•Powdered scabs from people infected with smallpox was used to
protect against the disease
•Smallpox was responsible for 8 to 20% of all deaths in several
European countries in the 18th century
•In 1721 Lady Mary Wortley Montagu brought the knowledge of these
techniques from Constantinople (now Istanbul) to England
•Two to three percent of the smallpox vaccinees, however, died from the
vaccination itself
•Benjamin Jesty and, later, Edward Jenner could show that vaccination
with the less dangerous cowpox could protect against infection with
smallpox
•The word vaccination, which is derived from vacca, the Latin word for
cow.
Early History of Vaccination II
•In 1879 Louis Pasteur showed that chicken cholera weakened by
growing it in the laboratory could protect against infection with more
virulent strains
•1881 he showed in a public experiment at Pouilly-Le-Fort that his
anthrax vaccine was efficient in protecting sheep, a goat, and cows.
•In 1885 Pasteur developed a vaccine against rabies based on a live
attenuated virus
•A year later Edmund Salmon and Theobald Smith developed a (heat)
killed cholera vaccine.
•Over the next 20 years killed typhoid and plague vaccines were
developed
•In 1927 the bacille Calmette-Guérin (BCG vaccine) against tuberculosis
vere developed
Vaccination since WW II
•Cell cultures
•Ability to grow cells from higher organisms such as vertebrates in
the laboratory
•Easier to develop new vaccines
•The number of pathogens for which vaccines can be made have
almost doubled.
•Many vaccines were grown in chicken embryo cells (from eggs), and
even today many vaccines such as the influenza vaccine, are still
produced in eggs
•Alternatives are being investigated
Vaccination Today
•Vaccines have been made for only 34 of the more than 400 known
pathogens that are harmful to man.
•Immunization saves the lives of 3 million children each year, but that 2
million more lives could be saved if existing vaccines were applied on a
full-scale worldwide
Human Vaccines
against pathogens
Immunological Bioinformatics, The MIT press.
Categories of Vaccines
•Live vaccines
•Are able to replicate in the host
•Attenuated (weakened) so they do not cause disease
•Subunit vaccines
•Part of organism
•Genetic Vaccines
•Part of genes from organism
Live Vaccines
•Characteristics
•Able to replicate in the host
•Attenuated (weakened) so they do not cause disease
•Advantages
•Induce a broad immune response (cellular and humoral)
•Low doses of vaccine are normally sufficient
•Long-lasting protection are often induced
•Disadvantages
•May cause adverse reactions
•May be transmitted from person to person
Subunit Vaccines
•Relatively easy to produce (not live)
•Induce little CTL
•Viral and bacterial proteins are not produced within cells
•Classically produced by inactivating a whole virus or bacterium
•Heat
•Chemicals
•The vaccine may be purified
•Selecting one or a few proteins which confer protection
•Bordetella pertussis (whooping cough)
•Create a better-tolerated vaccine that is free from whole
microorganism cells
Subunit Vaccines: Polysaccharides
•Polysaccharides
•Many bacteria have polysaccharides in their outer membrane
•Polysaccharide based vaccines
•Neisseria meningitidis
•Streptococcus pneumoniae
•Generate a T cell-independent response
•Inefficient in children younger than 2 years old
•Overcome by conjugating the polysaccharides to peptides
•Used in vaccines against Streptococcus pneumoniae and
Haemophilus influenzae.
Subunit Vaccines: Toxoids
•Toxins
•Responsible for the pathogenesis of many bacteria
•Toxoids
•Inactivated toxins
•Toxoid based vaccines
•Bordetella pertussis
•Clostridium tetani
•Corynebacterium diphtheriae
•Inactivation
•Traditionally done by chemical means
•Altering the DNA sequences important to toxicity
Subunit Vaccines: Recombinant
•The hepatitis B virus (HBV) vaccine
•Originally based on the surface antigen purified from the blood of
chronically infected individuals.
•Due to safety concerns, the HBV vaccine became the first to be
produced using recombinant DNA technology (1986)
•Produced in bakers’ yeast (Saccharomyces cerevisiae)
•Virus-like particles (VLPs)
•Viral proteins that self-assemble to particles with the same size as
the native virus.
•VLP is the basis of a promising new vaccine against human
papilloma virus (HPV)
•Merck
•In phase III
For more information se: http://www.nci.nih.gov/ncicancerbulletin/NCI_Cancer_Bulletin_041205/page5
Genetic Vaccines
•Introduce DNA or RNA into the host
•Injected (Naked)
•Coated on gold particles
•Carried by viruses
•vaccinia, adenovirus, or alphaviruses
•bacteria such as
•Salmonella typhi, Mycobacterium tuberculosis
•Advantages
•Easy to produce
•Induce cellular response
•Disadvantages
•Low response in 1st generation
Epitope based vaccines
•Advantages(Ishioka et al. [1999]):
•Can be more potent
•Can be controlled better
•Can induce subdominant epitopes (e.g. against tumor antigens
where there is tolerance against dominant epitopes)
•Can target multiple conserved epitopes in rapidly mutating
pathogens like HIV and Hepatitis C virus (HCV)
•Can be designed to break tolerance
•Can overcome safety concerns associated with entire organisms or
proteins
•Epitope-based vaccines have been shown to confer protection in animal
models ([Snyder et al., 2004], Rodriguez et al. [1998] and Sette and
Sidney [1999])
Passive Immunization
•Antibodies harvested from infected patients or animals are then used to
protect against disease [Marshall et al., 2003]
•Used in special cases against many pathogens:
•Cytomegalovirus
•Hepatitis A and B viruses
•Measles
•Varicella
•Rubella
•Respiratory syncytial virus
•Rabies
•Clostridium tetani
•Varicella-zoster virus
•Vaccinia
•Clostridium botulinum
•Corynebacterium diphtheriae
Polytope optimization
•Successful immunization can be obtained only if the epitopes encoded
by the polytope are correctly processed and presented.
•Cleavage by the proteasome in the cytosol, translocation into the ER by
the TAP complex, as well as binding to MHC class I should be taken into
account in an integrative manner.
•The design of a polytope can be done in an effective way by modifying
the sequential order of the different epitopes, and by inserting specific
amino acids that will favor optimal cleavage and transport by the TAP
complex, as linkers between the epitopes.
Polytope starting configuration
Immunological Bioinformatics, The MIT press.
Polytope optimization Algorithm
• Optimization of of four measures:
1. The number of poor C-terminal cleavage sites of epitopes
(predicted cleavage < 0.9)
2. The number of internal cleavage sites (within epitope cleavages
with a prediction larger than the predicted C-terminal cleavage)
3. The number of new epitopes (number of processed and
presented epitopes in the fusing regions spanning the epitopes)
4. The length of the linker region inserted between epitopes.
• The optimization seeks to minimize the above four terms by use of
Monte Carlo Metropolis simulations [Metropolis et al., 1953]
Polytope final configuation
Immunological Bioinformatics, The MIT press.
Therapeutic vaccines
• Vaccines to treat the patients that already have a disease
• Targets
• Tumors
• AIDS
• Allergies
• Autoimmune diseases
• Hepatitis B
• Tuberculosis
• Malaria
• Helicobacter pylori
• Concept
• suppress/boost existing immunity or induce immune responses.
Cancer vaccines
• Break the tolerance of the immune system against tumors
• 3 types
1. Whole tumor cells, peptides derived from tumor cells in vitro, or
heat shock proteins prepared from autologous tumor cells
2. Tumor-specific antigen–defined vaccines
3. Vaccines aiming to increase the amount of dendritic cells (DCs)
that can initiate a long-lasting T cell response against tumors.
• Therapeutic cancer vaccines can
responses in humans with cancer
induce
antitumor
immune
• Antigenic variation is a major problem that therapeutic vaccines
against cancer face
• Tools from genomics and bioinformatics may circumvent these
problems
Se also: http://cis.nci.nih.gov/fact/7_2.htm
Allergy vaccines
• Increasing occurrence of allergies in
industrialized countries
• The traditional approach is to
vaccinate with small doses of purified
allergen
• Second-generation
vaccines
under
development
based
recombinant technology
are
on
• Genetically engineered Bet v 1
vaccine can reduce pollen-specific
IgE memory response significantly
• Example of switching a “wrong”
immune response to a less harmful
one.
Figure by Thomas Blicher.
Therapeutic Vaccines against
Persistent Infections
• For example for preventing HIV-related disease progression
• Most of the first candidate HIV-1 vaccines were based entirely or partially
on envelope proteins to boost neutralizing antibodies
• Envelope proteins are the most variable parts of the HIV genome
Vaccines composed of monomeric gp120 molecules induce antibodies
that do not bind to trimeric gp120 on the surface of virions
• A number of recent vaccines are also designed to induce strong cellmediated responses.
• Escapes from CTL responses are associated with disease progression
and high viral loads
• Some CTL epitopes escape recognition quickly because they are not
functionally constrained, others might need several compensatory
mutations because they are in functionally or structurally constrained
regions of HIV-1
Vaccines Against Autoimmune
Diseases
• Multiple sclerosis
• T cells specific for mylein basic protein (MBP) can cause inflammation
of the central nervous system.
• The vaccine uses copolymer 1 (cop 1), a protein that highly
resembles MBP. Cop 1 competes with MBP in binding to MHC class II
molecules, but it is not effective in inducing a T cell response
• On the contrary, cop 1 can induce a suppressor T cell response
specific for MBP, and this response helps diminish the symptoms of
multiple sclerosis
• A vaccine based on the same mechanisms is developed for myasthenia
gravis
More information:
http://www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm,
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12667659&query_hl=4
Vaccines Market
• The vaccine market has increased fivefold from 1990 to 2000
• Annual sales of 6 billion euros
• Less than 2% of the total pharma market.
• Major producers (85% of the market)
• GlaxoSmithKline (GSK), Merck, Aventis Pasteur, Wyeth, Chiron
• Main products (>50% of the market)
• Hepatitis B, flu, MMR (measles, mumps, and rubella) and DTP
(diphtheria, tetanus, pertussis)
• 40% are produced in the United States and the rest is evenly split
between Europe and the rest of the world [Gréco, 2002]
• It currently costs between 200 and 500 million US dollars to bring a new
vaccine from the concept stage to market [André, 2002]
More information:
Gréco, 2002
André, 2002
Trends
• From
• Whole live and killed organisms
• Problems
• Adverse effects
• Production
• To
• Subunit vaccines
• Genetic vaccines
• Challenges
• Enhance immunogenecity
Prediction of antigens
• Protective antigens
• Functional definition (phenotype)
• Which antigens will be protective (genotype)?
• They must be recognized by the immune system
• Predict epitopes (include processing)
• CTL (MHC class I)
•
http://www.cbs.dtu.dk/services/NetCTL/
• Helper (MHC class II)
•
http://mail1.imtech.res.in/raghava/hlapred/index.html
• Antibody
•
http://www.cbs.dtu.dk/services/BepiPred/
More Links: http://www.cbs.dtu.dk/researchgroups/immunology/webreview.html
Function and conservation
• Some of the epitopes must exist in the wild type
• Conservation
•
http://www.ncbi.nlm.nih.gov/BLAST/
• Function
• When is it expressed?
• Where is it trafficked to?
• SecretomeP
Non-classical and leaderless secretion of eukaryotic proteins.
SignalP
Signal peptide and cleavage sites in gram+, gramand
eukaryotic
amino
acid
sequences.
TargetP
Subcellular
location
of
proteins:
mitochondrial,
chloroplastic, secretory pathway, or other.
• Expression level?
Selection of antigens
• Epitopes
• Polytope
• Proteins
• Helper epitopes
• Does it contain any
• Can they be added
• Hide epitopes
• Immunodominant and variable ones
NIH project
Description of whole project:
http://www.cbs.dtu.dk/researchgroups/immunology/EpitopeDiscovery/
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0030091
Pathogen
HLA binding
Elispot
Influenza
X
X
Variola major (smallpox) vaccine strain
X
X
Yersinia pestis
X
Francisella tularensis (tularemia)
X
LCM
X
Lassa Fever
X
Hantaan virus (Korean hemorrhagic fever virus)
X
Rift Valley Fever
X
Dengue
X
Ebola
X
Marburg
X
Multi-drug resistant TB (BCG vaccine)
X
Yellow fever
X
Typhus fever (Rickettsia prowazekii)
X
West Nile Virus
X
X
Acknowledgements
Immunological Bioinformatics
group, CBS, Technical University
of Denmark (www.cbs.dtu.dk)
Morten Nielsen
HLA binding
Claus Lundegaard
Data bases, HLA binding
Anne Mølgaard
MHC binding
Mette Voldby Larsen
CTL prediction
Pernille Haste Andersen
B cell epitopes
Sune Frankild
Databases
Jens Pontoppidan
Linear B cell epitopes
Collaborators
IMMI, University of Copenhagen
Søren Buus
MHC binding
Mogens H Claesson
CTL
La Jolla Institute of Allergy and Infectious
Diseases
Allesandro Sette
Epitope DB
Leiden University Medical Center
Tom Ottenhoff
Tuberculosis
Michel Klein
Ganymed
Ugur Sahin
Genetic library
University of Tubingen
Stefan Stevanovic
MHC ligands
INSERM
Peter van Endert
Tap
University of Mainz
Hansjörg Schild
Proteasome
Schafer-Nielsen
Claus Schafer-Nielsen Peptides