“Life or death for a young child too often depends on whether he is born in a country where vaccines are available or not”

Vaccines: All the things considered

The Spanish FLU

1918-1919 more than 50million people

GO

OD

ARI

HIV

Diarrhoeal diseases

Tuberculosis

Malaria

Measles, Hepatitis B virus

The infectious diseases

The World Health Organisation

Vaccination is probably the most beneficial therapy that a physician can provide a patient

Vaccines are an excellent, technically feasible defense against these threats with the potential to limit disease spread

Prevention is better than cure

Success stories of vaccines

Small pox

Polio, by 99.9% from 3,50,000 cases in 1998 to 800 in 2002 39% decrease in mortality because of Measles

End of 2003 78% of world population got immunized with DTP

Biological basis for immune response to a vaccine ?

Late 20th Century T cell

21st Century Dendritic Cell

Controller of immune response

Dendritic cell

T cell

“Unfortunately the DC biology is still very confusing”“Unfortunately the DC biology is still very confusing”

Immature DC Pathogens

DCCytokines

APC

APC T-Cell Cytokines Activated Cells

Conserved microbial molecules shared by many pathogens Bacterial lipopolysaccharides – TLR4

Peptidoglycan – TLR2

Flagellin – TLR5

Nucleic acids

Pathogen-associated molecular patterns (PAMPS)

Pattern Recognition Receptors (PRR) Toll like receptors

Toll-like receptors & Host-Pathogen Interaction

What decides Th1 or Th2 response ?

IL-12, IFN-Controll Intra cellular pathogens

Combination of both antibody and CMI

Th1

Th2 Predominantly antibody response

Th1 Th2 Antagonistic

Need to look for new adjuvants

What is the role of adjuvants ?

Alum based adjuvants are only approved and Problem with Alum ?

IL-12 cytokines and antigen loaded dendritic cells as adjuvants are in pipeline

MPL (monophosphoryl lipid A) Montanide ISA51 (seppic) MF59

Mix of different adjuvants (Alum+MPL) also used in few vaccines ex. Human papillomavirus , Herplex simplex virus (GlaxoSmithkline)

LEAPS (Ligand epitope antigen presentation system)

ICBL (Immune cell binding ligands)

Newer adjuvants

Problems with small peptide vaccines

Reason for these Studies

Increased understanding of the immune response

Technology advances in Proteomics Genomics Structural biology Instrumentation

New developments in vaccine designNew developments in vaccine design

Hurdles to the development and licensing of new vaccines

Difficulty in preparing 100% safe and effective

Almost unavoidable minor adverse event

The high cost of testing

Long time to get through phase III trials

Profit margin is 1/10 or less than that of a successful drug that must be taken daily

Target for lawsuits

Hurdles…Contd.

Beyond that

Vaccine program's are expensive

Vaccines are perishable

Administration by professionals

People may not accept without a defined urgent microbial threat

Produce an immune response ?Protect after challenge?

Safe ?Immune response ?

Best dose?Safe ?How much of an immune response ?

Does it work ?

Preclinical Phase I Phase II Phase III

Animals30-50 people

200-400 people3000-5000 people

Goals of vaccine Trial process

Fails if it is effective only in a subgroup of patients or if a subgroup experiences extreme side effects

Failure on the way to success

Variable outcomes caused by the particular genetic makeup of the individuals

ex. Worlds first AIDS vaccine AIDSVAX

ex. In 2000 Rotashield® vaccine was withdrawn from the US market due to safety concerns

Risk benefit ratio must be reasonable

Vaccines also have some undesired side effects

A safety evaluation must ask not only “what are the bad things that can happen if this vaccine is used?”

It must also ask, “what bad things can happen if this vaccine is NOT used?”

Bitter truth

Clinically not proven in preventing disease

Simple reason that no researcher has directly exposed test subjects to diseases

Go to doctor and you get a toxic additive than the viral component

ex. Thimerosal - Autism BSA - Prion diseases

Drive for Vaccine development

Benefit to mankind

Profit

The big Three vs neglected diseases

HIV

Malaria

TB

Hookworm disease

Schistosomiasis

MoneyTime

SuccessProfit

Worries with vaccines

231million $ in 1987 to 802 million$ in 2000

Vaccine is expensive to develop, licensure, and marketing

As a result funds are always from Government

Drive for vaccine funding by Government

Fear : Fear of Bioterrorism Fear of being blamed for inaction Concern over lost revenue due to illness

“Fear of bioterrorism elevates infectious diseases to the status of a military weapon and changes the definition of vaccine program in to military deterrent”

“Fear of bioterrorism elevates infectious diseases to the status of a military weapon and changes the definition of vaccine program in to military deterrent”

Bioterrorism

Boom in the Vaccine development

Project Bioshield

Goals of Project Bioshield

Accelerate the R & D on vaccines Purchase Availability of priority medical countermeasures to protect the US population

Change in Vaccine industry after Bioshield

Contracts since 2001 to pileup

80 million doses of Anthrax vaccine Botulin antitoxin Smallpox vaccine Plague Ebola fever

“Change the future of vaccine development”“Change the future of vaccine development”

To improve child health in poorest countries

GAVI ALLIANCE

Innovative partnership for benefit of mankind

Bill and Melinda Gates foundation

The largest transparently operated charitable foundationin the world

Malaria Vac I

Childrens Vac I

HIV

WARREN BUFFET

Global vaccine industry

US$ 11.42 Billion in 2006

US$ 21.05 Billion by 2010

After decades of malaise vaccine industry is getting injection

But remains small piece 3% of drug industry

24.3

22.6

21.3

17.8

8.15.9

•Novartis/•Chiron*

•GSK

•Wyeth

•Merck**

•Sanofi-Aventis**

•Oth

er

Growing market with a restricted number of mostly US-prone vaccine players

Vaccine industry in India

Shanta is first to indigenously produce a rec Hep B vaccine

Shantha and Serum institute are working on pentavalent vaccine ( DPT, HepB, influ B)

Bharath biotech working on malaria & rotavirus (Bill & melinda)

Contd…

Indian immunologicals Biological E Panacea biotech Serum Institute of India

Shanta supplies 40% of UNICEF global requirement for Hep B Serum institute highest exporter-138 countries

Surprising facts

Summary More R&D on immunology and host pathogen interaction is required

Government can enrich the funding for vaccine R&D

NIH remains primary funding source for most vaccine projects

Database of NIH for past 10 years indicate more funding for pharmacy

3%

17.5%

NIH

Vaccine research shouldn’t stop there

Thank you

“ We cannot be a strong nation unless we are a healthy nation“