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
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
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
Are able to replicate in the host
Attenuated (weakened) so they do not cause disease
Part of organism
Part of genes from organism
Able to replicate in the host
Attenuated (weakened) so they do not cause disease
Induce a broad immune response (cellular and humoral)
Low doses of vaccine are normally sufficient
Long-lasting protection are often induced
May cause adverse reactions
May be transmitted from person to person
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
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
Many bacteria have polysaccharides in their outer membrane
Polysaccharide based vaccines
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
Responsible for the pathogenesis of many bacteria
Toxoid based vaccines
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)
In phase III
For more information se: http://www.nci.nih.gov/ncicancerbulletin/NCI_Cancer_Bulletin_041205/page5
Introduce DNA or RNA into the host
Coated on gold particles
Carried by viruses
vaccinia, adenovirus, or alphaviruses
bacteria such as
Salmonella typhi, Mycobacterium tuberculosis
Easy to produce
Induce cellular response
Low response in 1st generation
Epitope based vaccines
Advantages( Ishioka et al. ) :
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.  and Sette and Sidney )
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:
Hepatitis A and B viruses
Respiratory syncytial virus
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:
The number of poor C-terminal cleavage sites of epitopes (predicted cleavage < 0.9)
The number of internal cleavage sites (within epitope cleavages with a prediction larger than the predicted C-terminal cleavage)
The number of new epitopes (number of processed and presented epitopes in the fusing regions spanning the epitopes)
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 .
Vaccines to treat the patients that already have a disease
suppress/boost existing immunity or induce immune responses.
Break the tolerance of the immune system against tumors
Whole tumor cells, peptides derived from tumor cells in vitro, or heat shock proteins prepared from autologous tumor cells
Tumor-specific antigen–defined vaccines
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 induce antitumor immune responses in humans with cancer
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
Increasing occurrence of allergies in industrialized countries
The traditional approach is to vaccinate with small doses of purified allergen
Second-generation vaccines are under development based on recombinant technology
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 cell-mediated 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
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
The vaccine market has increased fivefold from 1990 to 2000
More Links: http://www.cbs.dtu.dk/researchgroups/immunology/webreview.html
Function and conservation
Some of the epitopes must exist in the wild type
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+, gram- and eukaryotic amino acid sequences. TargetP Subcellular location of proteins: mitochondrial, chloroplastic, secretory pathway, or other.
Selection of antigens
Does it contain any
Can they be added
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 X West Nile Virus X Typhus fever (Rickettsia prowazekii) X Yellow fever X X Multi-drug resistant TB (BCG vaccine) X Marburg X Ebola X Dengue X Rift Valley Fever X Hantaan virus (Korean hemorrhagic fever virus) X Lassa Fever X LCM X Francisella tularensis (tularemia) X Yersinia pestis X X Variola major (smallpox) vaccine strain X X Influenza Elispot HLA binding Pathogen
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