De Groot Nova Se Immunology Of Vaccines2009

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Information about De Groot Nova Se Immunology Of Vaccines2009

Published on January 29, 2009

Author: AnnieDG

Source: slideshare.net

Brown University University of Rhode Island and EpiVax, Providence RI January 2009 Annie De Groot MD Immunology of Vaccines

Outline Vaccine Research and Development Immunology of Vaccines Some Case Studies: tetanus smallpox polio Emerging infectious diseases Vaccine technology now

Research and Development Leads to Vaccine Production It currently costs between 200 and 500 million US dollars to bring a new vaccine from the concept stage to market But incentives are present: The vaccine market has increased fivefold from 1990 to 2000 Annual sales of 8 billion dollars Less than 2% of the total pharma market but projected to increase Major producers (85% of the market) GlaxoSmithKline (GSK), Merck, Aventis Pasteur, Wyeth, Novartis 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

It currently costs between 200 and 500 million US dollars to bring a new vaccine from the concept stage to market

But incentives are present:

The vaccine market has increased fivefold from 1990 to 2000

Annual sales of 8 billion dollars

Less than 2% of the total pharma market but projected to increase

Major producers (85% of the market)

GlaxoSmithKline (GSK), Merck, Aventis Pasteur, Wyeth, Novartis

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

Drug Development Process Laboratory R+D Pre-IND - Safety/Toxicity -> IND filing Phase I - human safety/toxicity Phase II - efficacy Phase III - extended studies / other drug(s) NDA -> FDA Approval Post-licensure surveillance

2008 Success!: New HPV (Cervical Cancer) Vaccine almost 100% effective!

2007 Failure: Merck Ad5 HIV Vaccine

Merck Ad5 HIV Vaccine

Vaccines are Still Big!! Recent Vaccine R and D News November 16, 2007 - - Pfizer buys Coley for $164M August 15, 2008 - - Pfizer inks vaccine pact with Cytos October 3, 2008 - - Crucell wins $70M to develop new vaccines December 29, 2008 - - Novartis pays $20M for CMV program (AlphaVax) January 7, 2009 - - Wyeth in talks to buy vaccine maker Crucell January 8, 2009 - - GSK unveils $300M vaccines plant . . .

November 16, 2007 - - Pfizer buys Coley for $164M

August 15, 2008 - - Pfizer inks vaccine pact with Cytos

October 3, 2008 - - Crucell wins $70M to develop new vaccines

December 29, 2008 - - Novartis pays $20M for CMV program (AlphaVax)

January 7, 2009 - - Wyeth in talks to buy vaccine maker Crucell

January 8, 2009 - - GSK unveils $300M vaccines plant

. . .

Why Is Vaccine Research and Development Important? Immunization saves the lives of 3 million children each year. 2 million more children could be saved if existing vaccines were applied on a full-scale worldwide Vaccines have been made for only 34 of the more than 400 known pathogens that are harmful to humans. What is not said: The small molecule R and D is not producing many new drugs – vaccines are seen as a “Pipeline solution”.

Immunization saves the lives of 3 million children each year.

2 million more children could be saved if existing vaccines were applied on a full-scale worldwide

Vaccines have been made for only 34 of the more than 400 known pathogens that are harmful to humans.

What is not said: The small molecule R and D is not producing many new drugs – vaccines are seen as a “Pipeline solution”.

Outline Vaccine Research and Development Immunology of Vaccines Some Case Studies: tetanus smallpox polio Emerging infectious diseases Vaccine technology now

What does a vaccine do? . . . Trains the immune system to recognize and fight infection . . . Without requiring exposure to the pathogen

10 Steps to Making A Vaccine Define Disease (Chickenpox vs Smallpox) Define Pathogen (Virus vs Parasite) Is there Immunity (If not you are in trouble) Correlates of Immunity one or many? (Ab? Ag? CMI?) Critical Antigens - one or many? Animal Model? Does it predict protection? Prototype Vaccine - Preclinical Proof Safety and Toxicity, GMP, Stability FDA “IND” Approval Post Clinical Phase Clinical trials (Phase I, II, III) Approval (and indication) Distribution / Acceptance / Access Is there Immunity (If not you are in trouble) 4. Correlates of Immunity one or many? (Ab? Ag? CMI?)

Define Disease (Chickenpox vs Smallpox)

Define Pathogen (Virus vs Parasite)

Is there Immunity (If not you are in trouble)

Correlates of Immunity one or many? (Ab? Ag? CMI?)

Critical Antigens - one or many?

Animal Model? Does it predict protection?

Prototype Vaccine - Preclinical Proof

Safety and Toxicity, GMP, Stability

FDA “IND” Approval

Post Clinical Phase

Clinical trials (Phase I, II, III)

Approval (and indication)

Distribution / Acceptance / Access

Is there Immunity (If not you are in trouble)

4. Correlates of Immunity one or many? (Ab? Ag? CMI?)

Basic Principles of Vaccine Immunology Innate immunity (e.g., macrophages, neutrophils, certain molecules) is the first line of defense. It is fast (usually good-to-go) and usually effective. Adaptive immunity (mediated by B and T cells) can be slow to respond (several days). It is highly effective when the innate immune system cannot fully deal with the threat.

 

Primary response (primary immunization) is relatively: Secondary response (secondary immunization or booster immunization) is relatively: slow (4-7days) small amount of antibody (low concentration of antibody) low affinity antibody IgM first, IgG second (equal amounts of IgM and IgG) fast (2-4 day) large amounts of antibody high affinity antibody mostly IgG

Initial SARS Strain 2nd SARS Strain Initial SARS Strain

Often, a secondary (memory) response is so fast and effective in removing antigens (pathogens), there are few or no symptoms detected by the infected individual (protective immunity). Secondary responses are the reason we do not get certain infectious diseases more than once. Secondary responses also explain why vaccinations work. For vaccinations, instead of immunizing with something that makes you sick, a vaccine contains antigens prime the immune response.

Vaccine strategies: B cells need T help

Macrophages / APC

Two types of T cells: Th and CTL

Th cells provide help to B cells

CTL cells kill virus infected cells

Categories of Vaccines Live attenuated Whole Killed Subunit Epitope-based

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 Epitope-based vaccines Minimal essential information with least cross-reactive material

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

Epitope-based vaccines

Minimal essential information with least cross-reactive material

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

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 anti-viral T cell response (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 Example: HPV Vaccine created from two HPV proteins A self-assembling “particle” made of purified protein that is free from whole microorganism cells

Relatively easy to produce (not live)

Induce little anti-viral T cell response (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

Example: HPV Vaccine created from two HPV proteins

A self-assembling “particle” made of purified protein 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 This approach used in vaccines against Streptococcus pneumoniae and Haemophilus influenzae.

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

This approach 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

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

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

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

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 response to a broad range of proteins and subdominant eptiopes (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]) and De Groot (in Press).

Advantages (Ishioka et al. [1999]):

Can be more potent

Can be controlled better

Can induce response to a broad range of proteins and subdominant eptiopes (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]) and De Groot (in 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.

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 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

Break the tolerance of the immune system against tumors

3 types

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

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.

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.

Outline Vaccine Research and Development Immunology of Vaccines Some Case Studies: tetanus smallpox polio Emerging infectious diseases Vaccine technology now

TETANUS

SMALLPOX

POLIO

Wild Poliovirus, 1988

Wild Poliovirus, 2004

Progress in Polio Eradication New Polio Cases linked to Nigerian Boycott, 2005 10 steps to making a vaccine Pathogen Correlates of immunity Critical antigens Animal model Delivery method Preclinical confirmation FDA Approval Clinical Trial Distribution Acceptance

Pathogen

Correlates of immunity

Critical antigens

Animal model

Delivery method

Preclinical confirmation

FDA Approval

Clinical Trial

Distribution

Acceptance

Wild Poliovirus, 2006

Wild Poliovirus, 2007

Can we Eradicate Polio?

Outline Vaccine Research and Development Immunology of Vaccines Some Case Studies: tetanus smallpox polio Emerging infectious diseases Vaccine technology now

EMERGING INFECTIOUS DISEASES SINCE 1990 1993 (US) - Hantavirus pulmonary syndrome (Sin nombre virus) 1994 (US) – Human granulocyte ehrlichiosis 1995 (Worldwide) - Kaposi sarcoma (HHV-8) 1995 (US) – Cyclosporiasis from raspberries 1996 (England) – Variant Creutzfeld-Jakob disease (vCJD) 1997 (Japan) – Vancomycin-intermediate S. aureus 1998 (Malaysia) – Nipah virus 1999 (US) - West Nile encephalitis (West Nile virus) 2001 (US) - Anthrax attack via letters 2001 (Netherlands) – Human metapneumovirus 2002 (US) – Vancomycin-resistant S. aureus 2003 (China  worldwide) - Severe acute respiratory syndrome (coronavirus) 2003 (US) - Monkeypox What’s next?

1993 (US) - Hantavirus pulmonary syndrome (Sin nombre virus)

1994 (US) – Human granulocyte ehrlichiosis

1995 (Worldwide) - Kaposi sarcoma (HHV-8)

1995 (US) – Cyclosporiasis from raspberries

1996 (England) – Variant Creutzfeld-Jakob disease (vCJD)

1997 (Japan) – Vancomycin-intermediate S. aureus

1998 (Malaysia) – Nipah virus

1999 (US) - West Nile encephalitis (West Nile virus)

2001 (US) - Anthrax attack via letters

2001 (Netherlands) – Human metapneumovirus

2002 (US) – Vancomycin-resistant S. aureus

2003 (China  worldwide) - Severe acute respiratory syndrome (coronavirus)

2003 (US) - Monkeypox

What’s next?

Emerging Diseases Worst Case Scenario What are the critical elements Highly infectious pathogen Circumstances that permit transmission Crowding Travel Vectors Lack of preparedness Lack of treatment Lack of vaccine

Highly infectious pathogen

Circumstances that permit transmission

Crowding

Travel

Vectors

Lack of preparedness

Lack of treatment

Lack of vaccine

EMERGING INFECTIOUS DISEASES SINCE 1990 1993 (US) - Hantavirus pulmonary syndrome (Sin nombre virus) 1994 (US) – Human granulocyte ehrlichiosis 1995 (Worldwide) - Kaposi sarcoma (HHV-8) 1995 (US) – Cyclosporiasis from raspberries 1996 (England) – Variant Creutzfeld-Jakob disease (vCJD) 1997 (Japan) – Vancomycin-intermediate S. aureus 1998 (Malaysia) – Nipah virus 1999 (US) - West Nile encephalitis (West Nile virus) 2001 (US) - Anthrax attack via letters 2001 (Netherlands) – Human metapneumovirus 2002 (US) – Vancomycin-resistant S. aureus 2003 (China  worldwide) - Severe acute respiratory syndrome (coronavirus) 2003 (US) - Monkeypox 2004 (Asia) – Avian influenza (H5N1)

1993 (US) - Hantavirus pulmonary syndrome (Sin nombre virus)

1994 (US) – Human granulocyte ehrlichiosis

1995 (Worldwide) - Kaposi sarcoma (HHV-8)

1995 (US) – Cyclosporiasis from raspberries

1996 (England) – Variant Creutzfeld-Jakob disease (vCJD)

1997 (Japan) – Vancomycin-intermediate S. aureus

1998 (Malaysia) – Nipah virus

1999 (US) - West Nile encephalitis (West Nile virus)

2001 (US) - Anthrax attack via letters

2001 (Netherlands) – Human metapneumovirus

2002 (US) – Vancomycin-resistant S. aureus

2003 (China  worldwide) - Severe acute respiratory syndrome (coronavirus)

2003 (US) - Monkeypox

2004 (Asia) – Avian influenza (H5N1)

The FLU

Outline Vaccine Research and Development Immunology of Vaccines Some Case Studies: tetanus smallpox polio Emerging infectious diseases Vaccine technology now

The Old Way of Making Vaccines shake and bake

The New Way of Making Vaccines

The Even Newer Way In vitro screening epitope Bioinformatics

Less than the entire pathogen is required Hepatitis Virus or Vaccine Epitope Subset = Immunome Immune system ‘ filter’

T cell epitope At Intersection of Immune Response

EpiVax: Accelerating Vaccines and Biologics Research and Development Anne S. De Groot 1, 2,3, L.Moise 1, 3 , J.A. McMurry 1 , W. Yang 1 , William Martin 1 1 EpiVax, Inc. 2 Brown Medical School and 3 University of Rhode Island [email_address] http://www.EpiVax.com

We think about what a vaccine does. . . . . . Trains the immune system to recognize and fight infection . . . Without requiring exposure to the pathogen using “epitopes” = chains of amino acids

Current Vaccine–Related NIH Funding 1R43AI058376 "A novel Smallpox Vaccine Derived from the VV/VAR Immunome“ 1R43AI065036 "A Genome-Derived, Epitope-Driven H pylori Vaccine“ 1R43AI058326 "A Genome-Derived, Epitope-Driven Tularemia Vaccine" 1R43AI075830-01 “ Optimization of a Multivalent Tuberculosis Vaccine” 7R01AI050528 (new R21: Optimization of HIV Vaccine Delivery) Epitope Driven HIV Vaccine Development Unfunded : Influenza, HPV, EBV

EpiVax Genome-derived, epitope-driven vaccine approach : In Silico EpiMatrix / ClustiMer / OptiMatrix [class I and class II alleles] Conservatrix / BlastiMer/. EpiAssembler/ VaccineCAD In Vitro HLA binding assay ELISpot - ELISA - Multiplex ELISA - FACS - T regulatory T cell profiling In Vector DNA prime/peptide (pseudoprotein boost) vaccines Vaccine delivery / formulation optimization / detolerizing delivery agents In Vivo HLA DR3, DR4 transgenic mice HLA class I transgenic mice Vaccination, Comparative studies

Prime-boost Smallpox Vaccine Immunization Sacrifice Birth 1. epitope DNA vaccine prime 2. epitope peptide boost 1. control DNA prime 2. control peptide boost Week 0 Week 8-14 IFN-gamma and multiplex ELISA Challenge Lethal Intratranasal Challenge 3 mice week 16 Week 18

Results: 100% survival of Vaccinated mice vs. 17% of placebo 100% 100% 0 20 40 60 80 100

No significant weight loss in vaccinated mice – surviving mice in placebo arm are regaining weight

HIV Vaccine Development The GAIA HIV Vaccine •  In Development since 1998 - More than 300 epitopes mapped • Highly Variable Pathogen – Conserved epitopes • HLA Diversity -- 6 HLA supertypes • T cell help -- Immunogenic consensus sequence epitopes • Validation in HLA transgenic mice -- Good progress.

Better Vaccines and Health for All Our Hope for the Future

Fearless Science

QUESTIONS EpiVax: Science without Fear/ Fearless Science

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