INTRODUCTION

A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine

typically contains an agent that resembles a disease-causing microorganism, and is often made
from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent
stimulates the body's immune system to recognize the agent as foreign, destroy it, and
"remember" it, so that the immune system can more easily recognize and destroy any of these
microorganisms that it later encounters.
Vaccines may be prophylactic (example: to prevent or ameliorate the effects of a future infection
by any natural or "wild" pathogen), or therapeutic (e.g. vaccines against cancer are also being
investigated; see cancer vaccine).
The term vaccine derives from Edward Jenner's 1796 use of cow pox (Latin variola vaccinia,
adapted from the Latin vaccn-us, from vacca, cow), to inoculate humans, providing them
protection against smallpox.
[1]

History


Edward Jenner
Prior to vaccination, inoculation was practised, and brought to the West in 1721 by Lady Mary
Wortley Montagu, who showed it to Hans Sloane, the King's physician.
[23]

Sometime during the 1770s Edward Jenner heard a milkmaid boast that she would never have the
often-fatal or disfiguring disease smallpox, because she had already had cowpox, which has a
very mild effect in humans. In 1796, Jenner took pus from the hand of a milkmaid with cowpox,
inoculated an 8-year-old boy with it, and six weeks later variolated the boy's arm with smallpox,
afterwards observing that the boy did not catch smallpox.
[24][25]
Further experimentation
demonstrated the efficacy of the procedure on an infant.
[25]
Since vaccination with cowpox was
much safer than smallpox inoculation,
[26]
the latter, though still widely practised in England, was
banned in 1840.
[27]
Louis Pasteur generalized Jenner's idea by developing what he called a rabies
vaccine, and in the nineteenth century vaccines were considered a matter of national prestige, and
compulsory vaccination laws were passed.
[24]

The twentieth century saw the introduction of several successful vaccines, including those against
diphtheria, measles, mumps, and rubella. Major achievements included the development of the
polio vaccine in the 1950s and the eradication of smallpox during the 1960s and 1970s. Maurice
Hilleman was the most prolific of the developers of the vaccines in the twentieth century. As
vaccines became more common, many people began taking them for granted. However, vaccines
remain elusive for many important diseases, including malaria and HIV.
The Immune Response
The purpose of vaccination is quite simple: to acquaint the immune system with the
biochemical profile / molecular signature of the infectious agent. Any foreign molecule
which can initiate an immune response in a host is termed an antigen. The body's
response is to produce antigens which will retain a biochemical memory and remain
sensitive to future infections by the same (or similar) agents.
The normal immune response involves a series of cellular and biochemical agents,
some of which directly attack invading molecules and cells, others which summon other,
more specific cells and molecules to assist in the process. A very simplified overview is
provided below:
1. Recognition - T Cells recognize the antigen (likely specific proteins on the
surface of the invading molecule). The T Cells also begins to reproduce
creating many more cells capable of recognizing and responding to the
antigen / virus.
2. Attack - some T Cells attack the virus / antigen directly, as well as
attacking and destroying host cells which are already infected.
3. Reinforcements - some T Cells send chemical signals to stimulate B
Cells. The B Cells produce antibodies which locate, bind and hold the
antigen with absolute molecular specificity.
4. Agglutination - the antibody-antigen complex begins to form, locating
and immobilizing the invading pathogen. This permits other cells and
systems (Killer Cells, Complement System) to respond and eliminate the
antigenic molecule / pathogen.
In addition to recognizing and eliminating the foreign / invading pathogen, the immune
system deploys memory cells to ensure a rapid immunological response against future
infections by the same (or closely related) pathogens. It is the goal of vaccination to
create the memory (and effective immune response) without the clinical consequences
of the pathological condition.
Developing immunity
The immune system recognizes vaccine agents as foreign, destroys them, and "remembers" them.
When the virulent version of an agent is encountered, the body recognizes the protein coat on the
virus, and thus is prepared to respond, by (1) neutralizing the target agent before it can enter cells,
and (2) by recognizing and destroying infected cells before that agent can multiply to vast
numbers.
Route of administration

The route of administration is the path by which a vaccine (or drug) is brought into contact with
the body. This is a critical factor for success of the immunization. A substance must be
transported from the site of entry to the part of the body where its action is desired to take place.
Using the body's transport mechanisms for this purpose, however, is not trivial.
Intramuscular (IM) injection administers the vaccine into the muscle mass. Vaccines
containing adjuvants should be injected IM to reduce adverse local effects. Subcutaneous (SC)
injection administers the vaccine into the subcutaneous layer above the muscle and below the
skin.

Intradermal (ID) injection administers the vaccine in the topmost layer of the skin. BCG is the
only vaccine with this route of administration. Intradermal injection of BCG vaccine reduces the
risk of neurovascular injury. Health workers say that BCG is the most difficult vaccine to
administer due to the small size of newborns' arms. A short narrow needle (15 mm, 26 gauge) is
needed for BCG vaccine. All other vaccines are given with a longer, wider needle (commonly 25
mm, 23 gauge), either SC or IM.
Oral administration of vaccine makes immunization easier by eliminating the need for a needle
and syringe.
Intranasal flu vaccine example
Intranasal spray application of a vaccine offers a needle free approach through the nasal
mucosa of the vaccinee. Click on the More About link for an example of an intranasal flu
vaccine.
Routes of administration vary to maximize effectiveness of vaccine
.
[42]

In 2010, India produced 60 percent of the world's vaccine worth about $900 million.
[43]

Excipients
Beside the active vaccine itself, the following excipients are commonly present in vaccine
preparations:
[44]

Aluminum salts or gels are added as adjuvants. Adjuvants are added to promote an earlier, more
potent response, and more persistent immune response to the vaccine; they allow for a lower
vaccine dosage.
Antibiotics are added to some vaccines to prevent the growth of bacteria during production and
storage of the vaccine.
Egg protein is present in influenza and yellow fever vaccines as they are prepared using chicken
eggs. Other proteins may be present.
Formaldehyde is used to inactivate bacterial products for toxoid vaccines. Formaldehyde is also
used to kill unwanted viruses and bacteria that might contaminate the vaccine during
production.
Monosodium glutamate (MSG) and 2-phenoxyethanol are used as stabilizers in a few vaccines to
help the vaccine remain unchanged when the vaccine is exposed to heat, light, acidity, or
humidity.
Thimerosal is a mercury-containing preservative that is added to vials of vaccine that contain
more than one dose to prevent contamination and growth of potentially harmful bacteria.
Role of preservatives
Many vaccines need preservatives to prevent serious adverse effects such as Staphylococcus
infection, which in one 1928 incident killed 12 of 21 children inoculated with a diphtheria
vaccine that lacked a preservative.
[45]
Several preservatives are available, including thiomersal,
phenoxyethanol, and formaldehyde. Thiomersal is more effective against bacteria, has a better
shelf life, and improves vaccine stability, potency, and safety, but in the U.S., the European
Union, and a few other affluent countries, it is no longer used as a preservative in childhood
vaccines, as a precautionary measure due to its mercury content.
[46]
Although controversial
claims have been made that thiomersal contributes to autism, no convincing scientific evidence
supports these claims
VACCINES
Properties of ideal vaccine:
Provide long lasting immunity.
Should induce both humoral and cellular immunity.
Should not induce autoimmunity or hypersensitivity.
Should be inexpensive to produce, easy to store and administer.
Vaccines must also be perceived to be safe.
The vaccine vial may contain relevant antigen, adjuvant (usually alum), preservatives and/or traces of
protein
derived from the cells in which the vaccine agent was cultured e.g. egg protein
Types of vaccines:
A. KILLED VACCINES:
When it is unsafe to use live microorganisms to prepare vaccines, they are killed or inactivated. These
are
preparations of the normal (wild type) infectious, pathogenic microorganisms that have been rendered
nonpathogenic, usually by treatment with using heat, formaldehyde or gamma irradiation so that they
cannot replicate
at all. Such killed vaccines vary greatly in their efficacy.
Microorganism Vaccine Method Route
Salmonella typhi TAB Heat, Phenol, Acetone SC
Vibrio cholerae Phenol SC or ID
Yersinia pestis Haffkine Formalin SC
Bordetella pertussis - Merthiolate IM
Poliomyelitis Salk Formalin IM
JE virus Nakayama Strain Formalin IM
Rabies virus Semple Phenol SC
BPL BPL SC
HDCV BPL IM or SC
DEV BPL IM or SC
Influenza virus - Formalin IM
Hepatitis A HM175 Formalin IM

Advantages:
Safe to use and can be given to immunodeficient and pregnant individuals.
Cheaper than live attenuated vaccine
Storage not as critical as live vaccine
Disadvantages:
Since the microorganisms cannot multiply, a large number are required to stimulate immunity.
Periodic boosters must be given to maintain immunity.
Only humoral immunity can be induced.
Most killed vaccines have to be injected.
Some vaccines such as Bordetella pertussis induce ill effects like postvaccinial encephalomyelitis.
Anaphylactic reaction to neomycin or streptomycin may occur in (Inactivated Polio Vaccine) recipients.
Anaphylactic hypersensitivity to eggs may occur in recipients of influenza vaccine.
Inactivation, such as by formaldehyde in the case of the Salk vaccine, may alter antigenicity.
Presence of some un-inactivated microbes can lead to vaccine-associated disease.


B. LIVE ATTENUATED VACCINE:
These vaccines are composed of live, attenuated microorganisms that cause a limited infection in their
hosts
sufficient to induce an immune response, but insufficient to cause disease. To make an attenuated
vaccine, the
pathogen is grown in foreign host such as animals, embryonated eggs or tissue culture, under conditions
that make
it less virulent. The strains are altered to a non-pathogenic form; for example, its tropism has been
altered so that it
no longer grows at a site that can cause disease. Some mutants will be selected that have a better ability
to grow in
the foreign host. These tend to be less virulent for the original host. These vaccines may be given by
injection or by
the oral route. A major advantage of live virus vaccines is that because they cause infection, the vaccine
very
closely reproduces the natural stimulus to the immune system.
Bacteria/virus Vaccine Method Route
Vibrio CVD103Hgr Genetically modified Oral
Salmonella Ty21a Genetically modified Oral
Mycobacterium BCG Prolonged subculture ID
Polio Sabin Passage in MK cells Oral
JE SA 14-14-2 Passage in weanling mice IM
Yellow Fever 17D Passage in chick embryo cells SC
Influenza - Temperature sensitive mutant IN
Mesales, Mumps,
Rubella
MMR
Rubella (Wistar RA 27/3)
Passage in fibroblasts cells SC
Chicken pox Oka/Merck Human diploid cell cultures SC
Small pox Vaccinia virus Naturally avirulent ID
The influenza vaccine contains cold-adapted vaccine strains of the influenza virus that have been grown
in tissue
culture at progressively lower temperatures. After a dozen or more of these passages, the virus grows
well only at
around 25 C and in vivo growth is restricted to the upper respiratory tract.
Advantages:
Infectious microbes can stimulate generation of memory cellular as well as humoral immune
responses.
Since these can multiply in the host, fewer quantities must be injected to induce protection.
A single administration of vaccine often has a high efficacy in producing long-lived immunity. Multiple
booster doses may not be required.
Whole microbes stimulate response to antigens in their natural conformation. They raise immune
response
to all protective antigens.
Some live vaccines can be given orally; such vaccines induce mucosal immunity and IgA synthesis,
which
gives more protection at the normal site of entry.
Oral preparations are less expensive than giving injections.
They can lead to elimination of wild type virus from the community

Disadvantages:
May very rarely revert to its virulent form and cause disease.
Live vaccines cannot be given safely to immunosuppressed individuals. Administration of live
attenuated
vaccines to people with impaired immune function can cause serious illness or death in the vaccine
recipient.
Since they are live and because their activity depends on their viability, proper storage is critical.
Spread to contacts of vaccinee who have not consented to be vaccinated. In some cases, it turns out be
an
advantage.
C. SUBUNIT VACCINES:
Subunit vaccines contain purified antigens instead of whole organisms. Such a preparation consists of
only those
antigens that elicit protective immunity. Subunit vaccines are composed of toxoids, subcellular
fragments, or surface
antigens. Administration of whole organism, as in case of pertussis was found unfavorable immune
reactions
resulting in severe side effects. The effectiveness of subunit vaccines in increased by giving them in
adjuvants.
Adjuvants slow antigen release for a more sustained immune stimulation.
Antigen Vaccine Microorganism Route
Cell wall polysaccharide Hib Hemophilus influenzae b IM
ACW-135 Y Nesseria meningitides IM
23 Valent Streptococcus pneumoniae IM
- Group B Streptococcus IM
Vi (Typhim) Salmonella typhi IM
Toxoid Tetanus Clostridium tetani IM
Diphtheria Corynebacterium diphtheriae IM
Membrane proteins - Influenza virus IM
HbsAg Hepatitis B IM
Microbial proteins Acellular DTP Bordetella pertussis IM
Advantages:
They can safely be given to immunosuppressed people
They are less likely to induce side effects.
Disadvantages:
Antigens may not retain their native conformation, so that antibodies produced against the subunit
may not
recognize the same protein on the pathogen surface.
Isolated protein does not stimulate the immune system as well as a whole organism vaccine.

Peptide vaccines: Peptide vaccine consists of those peptides from the microbial antigen that stimulates
protective
immunity. Synthetic peptides are produced by automated machines rather than by microorganisms.
Peptide
immunogenicity can be increased by giving them in ISCOMS, lipid micelles that transport the peptides
directly into
the cytoplasm of dendritic cells for presentation on Class I MHC. Injected peptides, which are much
smaller than the
original virus protein, induce an IgG response. Example: spf66 anti-malarial vaccine
Advantages:
If the peptide that induces protective immunity is identified, it can be synthesized easily on a large
scale.
It is safe and can be administered to immunodeficient and pregnant individuals.
Disadvantage:
Poor antigenicity. Peptide fragments do not stimulate the immune system as well as a whole organism
vaccine.
Since peptides are closely associated with HLA alleles, some peptides may not be universally effective
at
inducing protective immunity.
D. CONJUGATE VACCINES:
Conjugate vaccines are primarily developed against capsulated bacteria. While the purified capsular
antigen can act
as subunit vaccine, they stimulate only humoral immunity. Polysaccharide antigens are T independent,
they Sridhar Rao P.N (www.microrao.com)
generate short-lived immunity. Immunity to these organisms requires opsonizing antibodies. Infants
cannot mount
good T-independent responses to polysaccharide antigens. By covalently linking the polysaccharides to
protein
carriers, they are converted into T-dependent antigens and protective immunity is induced.
Examples: Haemophilus influenzae HiB polysaccharide is complexed with diphtheria toxoid. Tetramune
vaccine,
which combines the tetanus and diphtheria toxoids, whole-cell pertussis vaccine, and H. influenzae type
b
conjugate vaccine.
E. RECOMBINANT VACCINES:
The vaccines are produced using recombinant DNA technology or genetic engineering. Recombinant
vaccines are
those in which genes for desired antigens of a microbe are inserted into a vector. Different strategies
are:
Using the engineered vector (e.g., Vaccinia virus) that is expressing desired antigen as a vaccine
The engineered vector (e.g., yeast) is made to express the antigen, such is vector is grown and the
antigen
is purified and injected as a subunit vaccine. Other expression vectors include the bacteria Escherichia
coli,
mutant Salmonella spp., and BCG.
Introduction of a mutation by deleting a portion of DNA such that they are unlikely to revert can create
an
attenuated live vaccine.
Live attenuated vaccines can also be produced by reassortment of genomes of virulent and avirulent
strains.
Genes coding for significant antigens are introduced into plants, such that the fruits produced bear
foreign
antigens. This is edible vaccine and is still in experimental stage.
Examples:
Hepatitis B Virus (HBV) vaccine is a recombinant subunit vaccine. Hepatitis B surface antigen is
produced
from a gene transfected into yeast (Saccharomyces cerevisiae) cells and purified for injection.
Vaccinia virus may be engineered to express protein antigens of HIV, rabies etc. Foreign genes cloned
into
the viral genome are expressed on the surface of infected cells in association with class I MHC molecules.
The antigen-MHC complex induces a Tc cell response.
B subunit of cholera toxin, the B subunit of heat-labile E. coli enterotoxin (LT), and one of the
glycoprotein
membrane antigens of the malarial parasite are being developed using this technique.
Salmonella typhimurium engineered to express antigens of Vibrio cholerae.
Bacille Calmette-Gurin vaccine strain engineered to express genes of HIV-1.
Reassortment of genomes between human and avian strains to create Influenza vaccine. Human and
swine
strains to create Rotavirus vaccine.
Advantages:
Those vectors that are not only safe but also easy to grow and store can be chosen.
Antigens which do not elicit protective immunity or which elicit damaging responses can be eliminated
from
the vaccine. Example Cholera toxin A can be safely removed from cholera toxin.
Disadvantages:
Since the genes for the desired antigens must be located, cloned, and expressed efficiently in the new
vector, the cost of production is high.
When engineered vaccinia virus is used to vaccinate, care must be taken to spare immunodeficient
individuals.

F. DNA VACCINES:
These vaccines are still in experimental stage. Like recombinant vaccines, genes for the desired antigens
are
located and cloned. The DNA is injected into the muscle of the animal being vaccinated, usually with a
"gene gun"
that uses compressed gas to blow the DNA into the muscle cells. DNA can be introduced into tissues by
bombarding the skin with DNA-coated gold particles. It is also possible to introduce DNA into nasal tissue
in nose
drops. Some muscle cells express the pathogen DNA to stimulate the immune system. DNA vaccines
have induced
both humoral and cellular immunity.
Advantages:
DNA is very stable, it resists extreme temperature and hence storage and transport are easy.
A DNA sequence can be changed easily in the laboratory.
The inserted DNA does not replicate and encodes only the proteins of interest. Sridhar Rao P.N
(www.microrao.com)
There is no protein component and so there will be no immune response against the vector itself.
Because of the way the antigen is presented, there is a cell-mediated response that may be directed
against any antigen in the pathogen.
Disadvantages:
Potential integration of DNA into host genome leading to insertional mutagenesis.
Induction of autoimmune responses: anti-DNA antibodies may be produced against introduced DNA.
Induction of immunologic tolerance: The expression of the antigen in the host may lead to specific
nonresponsiveness to that antigen.
G. ANTI-IDIOTYPIC VACCINE:
An antigen binding site in an antibody (paratope) is a reflection of the three-dimensional structure of
part of the
antigen (epitope). This unique amino acid structure in the antibody is known as the idiotype, which can
be
considered as a mirror of the epitope in the antigen. Antibodies can be raised against the idiotype by
injecting the
antibody into another animal. This anti-idiotype antibody mimics part of the three dimensional structure
of the
antigen. This can be used as a vaccine. When the anti-idiotype antibody is injected into a vaccinee,
antibodies (antianti-idiotype antiobodies) are formed that recognize a structure similar to part of the
virus and might potentially
neutralize the virus.
Advantage:
Antibodies against potentially significant antigen can be produced.
Disadvantage:
Only humoral immunity is produced. There is no cellular immunity and poor memory. Identification and
preparation
of idiotypes is labor intensive and difficult.



How Are Vaccines Made?
Vaccines are made in several ways. However, all vaccines have the same general goal: weaken
the virus or bacteria in a way that allows the recipient to develop an immune response without
developing any symptoms of infection. Vaccines are made using the same components that are
found in the natural virus or bacteria.
Several basic strategies are used to make vaccines. The strengths and limitations of each
approach are described below.
Weaken the virus
Using this strategy, viruses are weakened so they reproduce very poorly once inside the body.
The measles, mumps, German measles (rubella), rotavirus, oral polio (not used in the U.S.),
intranasal influenza, chickenpox (varicella), and shingles vaccines are made this way. Viruses
usually cause disease by reproducing themselves many times in the body. Whereas natural
viruses reproduce thousands of times during an infection, vaccine viruses usually reproduce
fewer than 20 times. Because vaccine viruses don't reproduce very much, they don't cause
disease, but vaccine viruses replicate well enough to induce "memory B cells" that protect against
infection in the future.

The advantage of live, "weakened" vaccines is that one or two doses provide immunity that is
life-long. The limitation of this approach is that these vaccines usually cannot be given to people
with weakened immune systems (like people with cancer or AIDS).
Inactivate the virus
Using this strategy, viruses are completely inactivated (or killed) with a chemical. By killing the
virus, it cannot possibly reproduce itself or cause disease. The inactivated polio, hepatitis A,
influenza (shot), and rabies vaccines are made this way. Because the virus is still "seen" by the
body, cells of the immune system that protect against disease are generated.
There are two benefits to this approach:
The vaccine cannot cause even a mild form of the disease that it prevents
The vaccine can be given to people with weakened immune systems
However, the limitation of this approach is that it typically requires several doses to achieve
immunity.
Use part of the virus
Using this strategy, just one part of the virus is removed and used as a vaccine. The hepatitis
B and HPV vaccines are made this way. The vaccine is composed of a protein that resides on the
surface of the virus. This strategy can be used when an immune response to one part of the virus
(or bacteria) is responsible for protection against disease.

These vaccines can be given to people with weakened immunity and appear to induce long-lived
immunity after three doses.
Use part of the bacteria
Some bacteria cause disease by making a harmful protein called a toxin. Several vaccines are
made by taking toxins and inactivating them with a chemical (the toxin, once inactivated, is
called a toxoid). By inactivating the toxin, it no longer causes harm. The diphtheria, tetanus and
pertussis vaccines are made this way.

Another strategy to make a bacterial vaccine is to use part of the sugar coating (or
polysaccharide) of the bacteria. Protection against infection by certain bacteria is based on
immunity to this sugar coating (and not the whole bacteria). However, because young children
don't make a very good immune response to the sugar coating alone, the coating is linked to a
harmless protein (this is called a "conjugated polysaccharide" vaccine). The Haemophilus
influenzae B (or Hib), pneumococcal, and recently licensed meningococcal vaccines are made
this way.

Just like for inactivated viral vaccines, bacterial vaccines can be given to people with weakened
immune systems, but often require several doses to induce adequate immunity.
Making a vaccine
Before a vaccine can be made, researchers must spend time isolating and studying the virus or
bacteria in question and learning how it causes disease. Researchers then begin studying how to
protect someone from the disease. Sometimes researchers ask questions like: What is the best
quantity of virus to give? Does one dose of the vaccine work? Do additional doses help even
more? How long does protection last?
There are three phases of studies that need to be done in people before the vaccine can be used
by the general population:
Phase I
Phase I studies are designed to answer two questions: Is the vaccine safe and does it induce an
immune response? If the answer to either of these questions is "No", the vaccine cannot be
developed further. People enrolled in these studies are usually healthy adults with a low risk for
the infection. These studies usually include fewer than 100 participants.
Phase II
If a vaccine passes the Phase I studies, larger Phase II studies are designed. They are based on
information gained from the Phase I study. Phase II studies are usually done in the type of people
who will ultimately use the vaccine. Typically, these studies enroll a few hundred participants. If
the vaccine is determined to be unsafe or doesn't consistently induce an immune response, it will
not be further developed.
Phase III
Phase III studies determine whether vaccines work and include thousands to tens of thousands of
people studied for many years. In many cases, more than one Phase III trial will be performed.
Often, these trials are done across a large geographic area to ensure that the vaccine is working in
people with different backgrounds and lifestyles. Phase III studies typically include more than
5,000 people.
If a vaccine appears to be safe and to work, all of the data will be submitted to scientists and
regulatory personnel at the U.S. Food and Drug Administration (FDA). They will check the data
to be sure the studies were done correctly and the results were consistent.
While much of the early research is done in academic research laboratories using grants obtained
from foundations or the government (e.g., the National Institutes of Health), Phase I, II and III
studies are performed by pharmaceutical companies. These studies typically cost hundreds of
millions of dollars.
Once a vaccine has been reviewed by the FDA and considered to be safe, it is still not ready to be
given to people. All of the information generated about how the vaccine works in people is then
provided to members of a recommending group of scientists and doctors that advise the Centers
for Disease Control and Prevention (CDC). This group, called the Advisory Committee on
Immunization Practices or ACIP, then recommends how the vaccine should be used and by
whom. The CDC, as well as the American Academy of Pediatrics (AAP) and the American
Academy of Family Physicians (AAFP), then make a final recommendation that doctors and
healthcare professionals can follow in deciding who should receive the new vaccine.
Phase IV (After licensure)
Once the vaccine begins to be distributed, additional studies occur. These studies are called Phase
IV studies. Because some rare side effects may not have been detected in the phase III trials,
vaccine safety is continually monitored by the CDC. These studies take at least four forms:
First, the CDC will have certain health departments (usually in areas where there is a high
occurrence of disease and hence, high vaccine distribution) monitor every person who receives
the vaccine and report to it regularly.
Second, the CDC monitors disease that is reported to every health department in the country, so
they will see if there are any abnormal occurrences of disease after the vaccine is introduced and
consider whether the two events may be related.
Third, there is a Vaccine Adverse Event Reporting System (or VAERS). If a doctor, nurse or
consumer believes that a person who received a vaccine had a significant negative side effect, he
or she can file a report in this system, which is continuously monitored for trends in the data.
Fourth, the Vaccine Safety Datalink (VSD) includes about 6 million people in six large HMOs on
the West Coast to look at who did and did not receive the vaccine and answer safety questions.
The VSD is one of the most effective post-licensure measures we have.
These systems proved their utility in 1999 when a newly licensed rotavirus vaccine was found to
be a rare cause of intussusception, a folding of the intestine into itself that may require emergency
surgery and can result in death if untreated. Once the relationship was confirmed, use of that
rotavirus vaccine was discontinued. A few years later, safer rotavirus vaccines were developed,
and phase III studies were of sufficient size to make sure these newer versions were not also
causing intussusception.