Long before the causes of disease were known and long before the processes of recovery were understood, an interesting thing was observed:

if people recovered from a disease, rather than succumbing to it, they appeared to be immune from a second bout with the same illness

Smallpox: by exposing uninfected individuals to matter from smallpox lesions. (Chinese)

This process was known as "variolation" Edward Jenner : noticed a relationship between

the equine disease known as "grease" and a bovine disease known as "cow pox." He saw that farmers who treated horses with grease lesions often saw the development of cow pox in their cows, complete with blisters similar to those seen in smallpox infection. Unlike lethal smallpox, however, the cowpox blisters eventually disappeared, leaving only a small scar at the site of each blister.

Jenner got more interested when a milkmaid told him that she could not catch smallpox because she had had cowpox.

With this in mind, Jenner undertook a daring experiment in 1796: he infected a young boy with cowpox in hopes of preventing subsequent smallpox infection.

After allowing the boy to recover fully from cowpox, Jenner - in an experiment - intentionally infected the boy with smallpox by injecting pus from a smallpox lesion directly under his skin.

As Jenner had predicted, the boy did not contract smallpox.

Jenner went on to collect 23 case histories over the next months and published his own book detailing his observations. The book was called "An inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire, and known by the name of The Cow Pox."

Jenner's process came to be called "vaccination," after "vacca," the Latin word for cow, and the substance used to vaccinate was called a "vaccine."

First Generation of Vaccines (pre-1950s) 1798 Smallpox 1885 Rabies 1897 Plague 1917 Cholera 1917 Typhoid vaccine (parenteral) 1923 Diphtheria 1926 Pertussis 1927 Tuberculosis 1927 Tetanus 1935 Yellow Fever 1940s DTP 1945 The first influenza vaccines (flu) began

being used.

1950s-1960s 1955 Inactivated polio vaccine licensed (IPV). 1955 Tetanus and diphtheria toxoids adsorbed

(adult use) 1959 World Health Assembly passes initial

resolution calling for global smallpox eradication. 1961 Monovalent oral polio vaccine licensed. 1963 Trivalent oral polio vaccine licensed (OPV). 1963 The first measles vaccine licensed. 1964 Advisory Committee on Immunization

Practices (ACIP), designed to provide CDC with recommendations on vaccine use, holds its first meeting.

1964-1965 20,000 cases of Congenital Rubella Syndrome occurred during the largest rubella epidemic in the United States.

1966 U.S. Measles eradication goal enunciated. 1967 Mumps vaccine licensed. 1969 Rubella vaccine licensed - 57,600 rubella

cases reported this year.

1970s 1970 Anthrax vaccine manufactured by the

Michigan Department of Public Health. 1971 Routine smallpox vaccination ceases in

the United States. 1971 Measles, Mumps, Rubella vaccine

licensed (MMR). 1976 Swine Flu: largest public vaccination

program in the United States to date; halted by association with Guillain-Barré syndrome.

1977 Last indigenous case of smallpox (Somalia).

1978 Fluzone, the current flu vaccine that is made by Aventis pasteur, was licensed.

1979 Last case of polio, caused by wild virus, acquired in the United States.

1980s 1980 Smallpox declared eradicated from the

world. 1981 Meningococcal polysaccharide vaccine,

groups A, C, Y, W135 combined (Menomune) 1982 Hepatitis B vaccine becomes available. 1983 Pneumococcal vaccine, 23 valent 1986 The National Childhood Vaccine Injury Act

establishes a no-fault compensation system for those injured by vaccines and requires adverse health events following specific vaccinations be reported and those injured by vaccines be compensated.

1988 Worldwide Polio Eradication Initiative launched; supported by WHO, UNICEF, Rotary International, CDC and others.

1989-1991 Major resurgence of measles in the United States - 55,000 cases compared with a low of 1,497 cases in 1983. Two-dose measles vaccine (MMR) was recommended.

1990s 1990 The Vaccine Adverse Reporting System

(VAERS), a national program monitoring the safety of vaccines established.

1990 Haemophilus influenzae type B (Hib) polysaccharide conjugate vaccine licensed for infants.

1990 Typhoid vaccine (oral) 1991 Hepatitis B vaccine recommended for all

infants. 1991 Acellular pertussis vaccine (DTaP) licensed for

use in older children aged 15 months to six years old. 1993 Japanese encephalitis vaccine 1994 Polio elimination certified in the Americas. 1994 Vaccines for Children (VFC) program

established to provide access to free vaccines for eligible children at the site of their usual source of care.

1995 First harmonized childhood immunization schedule endorsed by ACIP, the American Academy of Family Physicians and the American Academy of Pediatrics is published.

1995 Varicella vaccine licensed; before the vaccine an estimated 4 million infected annually in the United States.

1995 Hepatitis A vaccine licensed. 1996 Acellular pertussis vaccine (DTaP)

licensed for use in young infants. 1998 First rotavirus vaccine licensed. 1999 Rotavirus vaccine withdrawn from the

market as a result of adverse events. 1999 Lyme disease vaccine approved by the

FDA. 1999 FDA recommends removing mercury from

all products, including vaccines. Efforts are begun to remove thimerosal, a mercury based additive, from vaccines.

2000s 2000 Worldwide measles initiative launched; 800,000

children still die from measles annually. Measles declared no longer endemic in the United States.

2000 Pneumococcal conjugate vaccine (Prevnar) recommended for all young children.

2001 September 11 results in increased concern of bioterrorism. The United States establishes a plan to re-introduce smallpox vaccine if necessary, a vaccine thought never to be needed again.

2002 Lyme disease vaccine withdrawn from the market by the manufacturer because of lawsuits and lack of demand for the vaccine.

2003 Measles declared no longer endemic in the Americas.

2003 First live attenuated influenza vaccine licensed (FluMist) for use in 5 to 49 year old persons.

2003 First Adult Immunization Schedule introduced. 2004 Inactivated influenza vaccine recommended for all

children 6 to 23 months of age. 2004 Pediarix,a vaccine that combines the DTaP, IPV,

and Hep B vaccines, into one shot, is approved.

2005 Rubella declared no longer endemic in the United States.

2005 Boostrix and Adacel, Tdap vaccines, are approved for teens.

2005 Menactra, a new meningococcal vaccine is approved for people between the ages of 11 to 55 years of age.

2006 RotaTeq is a new rotavirus vaccine from Merck. 2006 ProQuad is a new vaccine that combines the MMR and

Varivax vaccines for measles, mumps, rubella, and chicken pox into a single shot.

2006 Gardasil, the first HPV vaccine is approved. 2007 A booster dose of Varivax, the chickenpox vaccine, is

now recommended for all children. 2007 The recommended age for Flumist, the nasal spray flu

vaccine, was lowered to two years. 2008 Outbreaks of measles increasing across the U.S. as

vaccination rates drop among some communities over vaccine safety fears.

2008 Rotarix, a two dose rotavirus vaccine is approved. 2008 Pentacel, a combination of DTaP, IPV and Hib is

approved. 2008 Kinrix, a combination of DTaP and IPV that can be

used for children between the ages of 4 and 6 is approved.

Development of a vaccine is not an easy task

Even when the pharmaceutical companies recognize the market potential of a vaccine such as HIV, HCV, etc

There are many difficult steps to reach the desired goal

Pathogen must be characterized at the levels of

Biology, Molecular composition and Its genome Animal models that adequately mimic

the pathology of the human diseases and the human response to the infection should be developed.

There are numerous agents that are so highly adapted to humans that no animal model exists

Others, although utilize animal species but do not permit effective analysis of human immune response

Elucidation of mechanisms of protective immunity

Animal models that induce protective immunity without harmful side effects need to be developed.

During the past decade there has been an enormous influx of money by government funded research on vaccine production

This work can be broadly divided into 4 areas

1. Studies on mechanism of virulence of pathogens

2. Studies on host response to bacterial/viral pathogens

3. Studies to test and develop vaccine candidates

4. Studies to devise and evaluate new vaccine delivery platforms

Dr. Rino Rappuoli The basic idea behind Reverse

Vaccinology is that an entire pathogenic genome can be screened using bioinformatics approaches to find genes. Next, those genes are filtered for desirable attributes that would make good vaccine targets such as outer membrane proteins. Those proteins then undergo normal wet lab testing for immune responses.

The availability of the complete genome sequence of a free-living organism (Haemophilus influenzae) in 1995 marked the beginning of a "genomic era" that opened the eyes of vaccine biologists to a new approach to vaccine design for the treatment of bacterial infections.

This "reverse vaccinology" was not based on growing microorganisms but on running algorithms to mine the information contained in the blueprint of the bacterium .

Within 18 months of the beginning of the sequencing of meningococcus B, over 600 potential vaccine candidates had been predicted by computer analysis of the genome, and 350 of them were expressed in Escherichia coli, purified, and used to immunize mice .

Many novel antigens with properties that could overcome the limits of previous vaccine candidates were discovered and are now being tested in clinical trials.

Today, the genome-based approach is routine in vaccine development and is being applied to streptococci, Chlamydiae, staphylococci, Plasmodium falciparum, and bioterrorism-associated agents such as Yersinia pestis. In most cases, the new technology has identified treasure troves of novel vaccine candidates.

The recent emerging disease SARS is a perfect example of the speed with which genomic information can have an impact on public health.

In less than a month from the first suggestion that a coronavirus might have been implicated in the disease, the nucleotide sequence of the virus was available and provided instant answers to a number of pressing questions.

It was clear that the agent was a natural (and not a laboratory-fabricated) coronavirus, diagnostic tests were set up, and vaccine targets were identified.

Today, some of these vaccines are already being tested in animal models. None of this would have been possible without the public release of the genome sequence.

NEEDS The 140 sequenced bacterial genomes and 1600

sequenced viral genomes, comprising potentially over 400,000 encoded proteins, already exceed by 10-fold the complexity of the human genome, which less than 3 years ago was seen as a major challenge for biocomputing.

The analysis of single genomes is no longer satisfactory; comparisons of multiple genomes to provide insights into conserved or unique families of proteins or functional domains are needed to continuously improve the precision of annotation and to identify the basic building blocks of proteins, trace the evolution of virulence mechanisms, potentially reconstruct complex structures, and identify and design novel immunogens.

FUTURE These increasing needs are helping to drive the

beginning of the next phase of reverse vaccinology. It will take advantage of the new computing

infrastructure to solve problems of large-scale computation by connecting independent supercomputing centers, which is already being implemented by several institutions, including Argonne National Laboratory and CERN, and is spreading worldwide.

The system will be based on a grid of supercomputers connecting major scientific institutions, with decentralized databases containing a repository of nucleotide and protein sequences, three-dimensional structures, expression profiles, immunological properties, and functional data.

Today, a scientist working in an advanced research institution, with a cluster of Unix servers and workstations, needs 48 hours to compare one genome against all other available genomes and 2 weeks to compare all available genomes against all others. 

The time for the analysis could also be reduced

Finally, all these operations will be performed in real time, when the system will be available to any scientist able to formulate fundamental questions using delocalized databases and computing power.

The major advantage for Reverse Vaccinology is finding vaccine targets quickly and efficiently.

The downside is that only proteins can be targeted using this process.

Normal vaccinology approaches can find other biomolecular targets such as polysaccharides.

Our struggle with germs is endless and can be neither completely halted nor won by vaccines, no matter how great their immunological power.

Sadly, effective vaccines for two of the world’s leading killers, HIV and malaria, remain in the research stage. 

Furthermore, even the most knowledgeable scientist cannot precisely predict the strain of next year’s influenza, nor can an expert epidemiologist always explain why certain diseases rise and burn out at particular rates.

Molecular biology, genomics, and proteomics will certainly reveal a great deal about similar antigens and foster the development of vaccines through cellular manipulation rather than animal experimentation.

Nevertheless, this historical overview of vaccines and immunization since Jenner’s great cowpox discovery suggests that we can anticipate several of the key issues that could hinder and complicate the future of vaccinology.

Clearly, without adequate funding and fluid funding mechanisms, vaccine shortages will persist, and lives throughout the world will remain at risk.

Closely linked are the issues of vaccine safety and the strict maintenance of sterilization standards. Even as these have improved greatly over time, the fact that vaccines are biological agents often makes them much more difficult than drugs to produce.

Jenner and his peers faced this problem, and history has shown that the production of safe, efficacious vaccines will require persistent vigilance. Although antivaccinationists are still often portrayed as an annoying thorn in the side of medical progress, their concerns for safety and willingness to perform the duty of civic oversight has had some positive effects, especially in terms of popular health education.

There are important continuities in the history of vaccines and immunization.

There have been shifts as well; unfortunately, one of the most pronounced has been the divestment of public agencies in vaccine research and production. 

If we could match the enormous scientific strides of the twentieth century with the

political and economic investments of the nineteenth century, the world’s citizens

might be much healthier