Transcript Ole Lund Classical Vaccines

Classical Vaccines
Ole Lund
Vaccination
• Vaccination
• Administration of a substance to a person with the purpose of
preventing a disease
• Traditionally composed of a killed or weakened micro organism
• 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.
Edward Jenner. Vaccine trials
The arm of Sarah Nelmes, a dairy maid, who had contracted cowpox.
Jenner used material from her arm to vaccinate an eight year old boy,
James Phipps. (1798).
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 was 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
Effectiveness of vaccines
1958 start of small pox
eradication program
Vaccines Today
• Vaccines have been made for only 34 of the more than
400 known pathogens that are harmful to man (<10%).
• 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
• Many vaccine products of today are short lived
• Maintained cool and last < 1 year
• The cost for developing new vaccine is estimated to be
close to 500 million us $,
• and the time span from development to the vaccine
marked is between 10 and 30 years
R&D Productivity is Down Because of Increased
Costs and Decreased Success Rates
NME: New Molecule entries
Industry R&D Expense
($Billions)
No. of NME Approvals
1
Source: PhRMA, FDA, Lehman Brothers
Example: Live Influenza Vaccine
The First 36 years
John Maassab
describes cold
adapted influenza
viruses
First human
studies
Four-year
efficacy study
FDA VRBPAC
Review - #2
Aviron
formed
FDA VRBPAC
Review - #1
Licensure
First
FluMisttm trial
1967
1976
1985 1989
1995
2003
By 2002, 25 separate influenza strains in over 28,000 people tested as CAIV reassortants
Johnson
1963 - 69
Nixon
1969 - 74
Ford
1974 - 77
Carter
1977 - 81
Reagan
1981 - 89
Bush
1989 - 93
William C. Gruber, M.D. VP, Global Clinical Research Wyeth Vaccines Research June 17, 2005
Clinton
1993 - 01
Bush, “W”
2001-
6/17/03
Live Influenza Vaccine – FluMist®
Development Time
Development Costs
Price
Launched
1967-2003 ( 36 years)
>> $1 Billion (3 companies)
$45/dose
2003/04 season
Projected sales
>50M doses
Manufactured in ‘03
5M doses in 1st season
Sold in ’03/04
<1M doses
Impact on public health yet to be determined
William C. Gruber, M.D. VP, Global Clinical Research Wyeth Vaccines Research June 17, 2005
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
• Cannot repeat vaccination (boost)
Subunit Vaccines
• Definition: Vaccine composed of a purified antigenic determinant
that is separated from the virulent organism.
• Advantages
• Relatively easy to produce (not live)
• Create a better-tolerated vaccine that is free from whole
microorganism cells
• The vaccine may be purified
• Selecting one or a few proteins which confer protection
• Disadvantages
• Induce little CTL
• Viral and bacterial proteins are not produced within cells
Subunit Vaccines: Polysaccharides
• Definition: A vaccine containing purified capsular polysaccharide
antigen from the most common infectious types of Streptococcus
pneumoniae, used to immunize against pneumonococcal disease.
• 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
• Definition: A substance that has been treated to destroy its toxic
properties but that retains the capacity to stimulate production of
antitoxins, used in immunization.
•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
• That is “Does not work in primates”
Epitope based vaccines
• Advantages (Ishioka et al. [1999]):
• More potent
• Better control
• Induce subdominant epitopes (e.g. against tumor antigens
where there is tolerance against dominant epitopes)
• Target multiple conserved epitopes in rapidly mutating
pathogens like HIV and Hepatitis C virus (HCV)
• Designed to break tolerance
• 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
• Immunity acquired by the transfer of antibodies from another
individual, as through injection or placental transfer to a fetus (The
outbreak, Dustin Hoffman)
• 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
•Hanta virus
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
responses.
existing
immunity
or
induce
immune
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 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
Allergy vaccines
• 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 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