1 Basic Concept of Vaccination

1.1 Definition of vaccines

What is a vaccine?
The word “vaccine” originates from the Latin Variolae vaccinae(cowpox), which Edward Jenner demonstrated in 1798 could
prevent smallpox in humans. Today the term ‘vaccine’ applies
to all biological preparations, produced from living organisms,
that enhance immunity against disease and either prevent(prophylactic vaccines) or, in some cases, treat disease(therapeutic vaccines). Vaccines are administered in liquid
form, either by injection, by oral, or by intranasal routes.
Vaccines are composed of either the entire disease-causing
microorganism or some of its components. They may beconstructed in several ways (See Figure 1):• From living organisms that have been weakened, usuallyfrom cultivation under sub-optimal conditions (also called
attenuation), or from genetic modification, which has theeffect of reducing their ability to cause disease;• From whole organisms that have been inactivated bychemical, thermal or other means;• From components of the disease-causing organism, suchas specific proteins and polysaccharides, or nucleic acids;• From inactivated toxins of toxin-producing bacteria;• From the linkage (conjugation) of polysaccharides
to proteins (this increases the effectiveness of 		polysaccharide vaccines in young children) (See Figure 2).
Examples of each type of vaccine are shown in Table 1.

4 | VACCINE FACT BOOK 2012

Type of vaccine

ExamplesLive-attenuatedMeasles, Mumps, Rubella,
Varicella zoster

InactivatedHepatitis A, Influenza, Pneumococcal
polysaccharide

Recombinant sub-unit

Hepatitis B

ToxoidTetanus, Diphtheria

Conjugate
Pneumococcal, meningococcal,
polysaccharide-protein Haemophlius influenzea type b (Hib)TABLE 1. EXAMPLES OF VACCINES BY TYPE

LIVE-ATTENUATED VACCINEFLUIDS AND
ADDITIVESSUB-OPTIMAL CONDITIONSPURIFICATIONFORMULATIONATTENUATIONDISEASE-CAUSING AGENTVACCINE

INACTIVATED VACCINEFLUIDS AND
ADDITIVESTHERMAL OR CHEMICAL TREATMENTPURIFICATIONDISEASE-CAUSING AGENT

INACTIVATIONFORMULATIONRECOMBINANT SUB-UNIT VACCINEVACCINE

FLUIDS AND
ADDITIVESPROTEIN SUB-UNIT

PURIFICATIONGENE
EXPRESSION CELLDISEASE-CAUSING AGENTPROTEIN EXPRESSIONTOXOID VACCINECHEMICALTREATMENTFORMULATIONVACCINE

FLUIDS AND
INACTIVATED ADDITIVES
TOXIN

TOXIN
PURIFICATIONDISEASE-CAUSING AGENTPRODUCING TOXIN

INACTIVATIONFORMULATIONVACCINE

FIGURE 1

F IGURE 1. T YPES OF VACCINE CONSTRUCTS

5

VACCINE FACT BOOK 2012 | 5

CONJUGATEVACCINEF IGURE2.

C ONJUGATIONHUMORAL RESPONSENO IMMUNE MEMORYIN INFANTS

HUMORAL RESPONSE
AND IMMUNEMEMORY IN INFANTS

HUMORAL RESPONSE
AND IMMUNEMEMORY IN ADULTS

HUMORAL RESPONSE
AND IMMUNEMEMORY IN ADULTS

unit vaccine, conjugated polysaccharide vaccine, recombinant protein vaccine, and

OF POLYSACCHARIDESTO PROTEINS
viral vaccine respectively(SEE Figure 3). INCREASESEFFECTIVENESS
OF
POLYSACCHARIDEVACCINESIN
YOUNG
CHILDREN
In addition to combining several serotypes of a disease-THE

causing organism in a single vaccine (e.g. 13-valent
BACTERIAL
VIRAL
pneumococcal conjugate vaccine), vaccines against
In addition
to combining
severalserotypes
different
disease-causingorganisms
can becombined of
to a disease-causing organism in a single vaccine
TOXOIDS
provideprotection
againstseveraldifferent
diseases.
These(e.g. 13-valent pneumococcal conjugate vaccine), vaccines against different disease-causing
TETANUSRECOMBINANT
combination vaccines may contain different types of vaccines.
organisms can be combined to provide protection against
These
PROTEIN several different diseases.
DIPHTHERIA
Combination vaccines against different diseases such as
HEPATITIS
B
combination
vaccines
containinfluenzae
different
diphtheria,
tetanus,
pertussis,may
Heamophilus
typetypes of vaccines. Combination vaccines against
VACCINESUBUNITb,
HepatitisB,andpolio,
arecommonlyusedinchildhooddifferent diseases such as diphtheria, tetanus, pertussis, Heamophilus influenzaePROTEIN
type b,
INACTIVATED
immunization schedules. These vaccines incorporate both
Hepatitis B, and polio, are commonly used in childhood
immunization schedules.
These
PERTUSSIS
POLIO
viral and bacterial vaccines and contain toxoids, purified
vaccines
incorporate
both
viral
and
bacterial
vaccinesandcontaintoxoids,
purified
proteinsubprotein sub-unit vaccine, conjugated polysaccharide vaccine,
PROTEINCONJUGATE
recombinant protein vaccine, and inactivated viral vaccine
respectively (See Figure 3).
HAEMOPHILUS
INFLUENZAE TYPE B

VACCINE FACT BOOK - 2011

POLYSACCHARIDEVACCINE

FIGURE 2

HUMORAL RESPONSE
AND IMMUNEMEMORY IN ADULTS

HUMORAL RESPONSE
AND IMMUNEMEMORY IN INFANTSPROTEIN
VACCINE

Vaccines
containagainst se(or seroty
same diseorganism,
protection
each typeinfluenzaeach prote
types ofsome
vaccines
pneumocoprotect ag
23 differenof Streptoc
pneumonia

6

A full list

F IGURE3.3.COMMONC OMMONCOMBINATIONCOMBINATIONPEDIATRICVACCINE
CONTAINING
FIGUREPEDIATRICVACCINE
CONTAINING
according
MULTIPLEANTIGENSANTIGENSOF
OFMULTIPLE
MULTIPLE
VACCINE
TYPES
MULTIPLE
VACCINE
TYPES

6 | VACCINE FACT BOOK 2012

can be se4, SECTION 1.2.

1 Basic Concept of Vaccination

Vaccines may also contain antigens against several types(or serotypes) of the same disease-causing organism,
providing protection against each type. Polio and influenza
vaccines each protect against 3 types of virus, and somebacterial vaccines like pneumococcal vaccine protect against
up to 23 different serotypes of Streptococcus pneumoniae.

In addition to preservatives, some vaccines contain adjuvants.
Adjuvants enhance the immune effect of the vaccine antigen,but do not themselves act as antigens. Aluminum salts are
the most commonly used adjuvant for vaccines. Adjuvanted
vaccines may have a slightly higher rate of adverse reactions,
including pain at the injection site, malaise and fever. A list ofcommonly adjuvanted childhood vaccines is shown in Table 3.

A full list of vaccines according to their type can be seen in
Table 4, Section 1.2.
What does a vaccine contain?
In addition to the bulk antigen that goes into a vaccine,
vaccines are formulated (mixed) with other fluids (such as
water or saline), additives or preservatives, and sometimes
adjuvants. Collectively, these ingredients are known as theexcipients. These ensure the quality and potency of thevaccine over its shelf-life. Vaccines are always formulated
so as to be both safe and immunogenic when injected into
humans. Vaccines are usually formulated as liquids, but may
be freeze-dried (lyophilized) for reconstitution immediately
prior to the time of injection.
Preservatives ensure the sterility of the vaccine over theperiod of its shelf-life. Preservatives may be used to prevent
contamination of multi-dose containers: when a first dose of
vaccine is extracted from a multi-dose container, a preservative
will protect the remaining product from any bacteria that
may be introduced into the container. Or, in some cases,
preservatives may be added during manufacture to prevent
microbial contamination. Preservatives used in vaccines
are non-toxic in the amounts used and do not diminish thepotency of vaccines. But not all preservatives can be usedin all vaccines. Some preservatives will alter the nature ofsome vaccine antigens. Preservatives commonly used in
vaccine formulation are shown in Table 2. Although there is noevidence of harm caused by any preservative, vaccines in the
US and Europe have, for the most part, been free of thimerosal(or contain only trace quantities) for several years now. And
some newer vaccines may not contain any preservative.

Preservative

Vaccines

PhenolTyphoid, pneumococcal polysaccharide

Benzethonium chloride

Anthrax2-phenoxyethanol

Inactivated polio

Thimerosal

Multi-dose influenza

Adjuvanted Vaccine

Type of Adjuvant

Hepatitis A

Aluminum salt

Hepatitis B

Aluminum salt

Diphtheria, Tetanus,acellular Pertussis
combinations (DTaP or
Tdap)

Aluminum salt

Haemophilus influenzae
type b (Hib)

Aluminum salt

Human Papilloma Virus(HPV)

Aluminum salt or AS04 (aluminum salt
and monophospholipid A)

Pneumococcal conjugate

Aluminum salt

Japanese encephalitis

Aluminum salt

H1N1 influenza

MF59 (oil in water emulsion) [onevaccine]

TABLE 3. EXAMPLES OF ADJUVANTED VACCINES2

TABLE 2. EXAMPLES OF VACCINES WITH PRESERVATIVES1US Department of Health and Human Services. US Food and Drug Administration. Thimerosal in vaccines.
http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/UCM096228#t2
2
US Centers for Disease Control and Prevention. Vaccine safety. Frequently asked questions about adjuvants.
http://www.cdc.gov/vaccinesafety/Concerns/adjuvants.html. [Accessed on June 7, 2011]
1

VACCINE FACT BOOK 2012 | 7

How do vaccines work?
When inactivated or weakened disease-causing microorganWhen inactivated or weakened disease-causing microorganisms enter the body, they initiate anisms enter the body, they initiate an immune response. Thisimmunemimics
response.
This
response
the body’s natural response to infection. But unlike
response
the body’s
naturalresponsemimics
to infection.
But
unlike disease-causingorganisms,
vaccines are
disease-causingorganisms,
vaccines
aremademade of components that have limited ability, or areofcomponentsunable,that havetolimited
ability,or are (SEEcompletely
completely
cause
diseaseFigure 4).
unable, to cause disease (See Figure 4).

DISEASE-CAUSINGORGANISMDISEASERECOVERY OR DEATH OR
DISABILITYRECOVERYIMMUNERESPONSE
INFECTION

DEATH

DISABILITYIMMUNEMEMORYVACCINE ANTIGENNO DISEASEIMMUNITYIMMUNERESPONSE
VACCINATIONIMMUNEMEMORYFIGURE 4. COMPARISON OF THE IMMUNE RESPONSE TO A DISEASES-CAUSING ORGANISM AND TO A VACCINEF IGURE 4. C OMPARISON OF THE IMMUNE RESPONSE TO A DISEASES - CAUSING ORGANISM
AND TO A VACCINE

The components of the disease-causing organisms or the vaccine components that trigger the
8immune| VACCINE response
FACT BOOK 2012
are known as “antigens”. These antigens trigger the production of“antibodies” by the immune system. Antibodies bind to corresponding antigens and induce their

1 Basic Concept of Vaccination

The components of the disease-causing organisms or thevaccine components that trigger the immune response are
known as “antigens”. These antigens trigger the productionof “antibodies” by the immune system. Antibodies bind tocorresponding antigens and induce their destruction by otherimmune cells (See Figure 5).

ANTIBODY PRODUCTION AND BINDING
ANTIGEN RECOGNITIONDISEASECAUSING AGENTIMMUNE SYSTEM ACTIVATIONANTIBODYANTIGEN DESTRUCTION BY
PHAGOCYTOSISANTIBODY PRODUCTION AND BINDING
ANTIGEN RECOGNITIONVACCINE ANTIGENIMMUNE SYSTEM ACTIVATIONANTIBODYANTIGEN DESTRUCTION BY
PHAGOCYTOSISFIGURE 5. ANTIBODY DESTRUCTION OF ANTIGEN

FIGURE 5. ANTIBODY DESTRUCTION OF ANTIGEN

The effectiveness and the duration of the protective effect of a vaccine depend both on thenature of the vaccine constituents and on the manner in which they are processed by the
immune system (SEE SECTION 1.3). Some disease-causing organisms, like influenza, change
from year to year, requiring annual immunization against new circulating strains.
VACCINE FACT BOOK 2012 | 9

In very young children, the immune system is immature and less capable of developing

OOK - 2011

The induced immune response to either a disease-causing organism or to a vaccine configures
the body’s immune cells to be capable of quickly recognizing, reacting to, and subduing therelevant disease-causing organism. When the body’s immune system is subsequently exposed
to a same disease-causing organism, the immune system will contain and eliminate theinfection before it can cause harm to the body (SEE Figure 6).

The induced immune response to either a disease-causingorganism or to a vaccine configures the body’s immune
cells to be capable of quickly recognizing, reacting to, andsubduing the relevant disease-causing organism. When the
body’s immune system is subsequently exposed to a samedisease-causing organism, the immune system will containand eliminate the infection before it can cause harm to thebody (See Figure 6).

and on the manner in which they are processed by the immune
system (See Section 1.3). Some disease-causing organisms,
such as influenza, change from year to year, requiring annual
immunization against new circulating strains.
In very young children, the immune system is immature andless capable of developing memory. In this age group, durationof protection can be very short-lived for polysaccharide
antigens.

The effectiveness and the duration of the protective effect of a
vaccine depend both on the nature of the vaccine constituents

FIRST EXPOSURE TODISEASE-CAUSINGORGANISMDISEASERECOVERY OR DEATH OR
DISABILITY

DEVELOPMENT OFIMMUNE MEMORYRECOVERY

DEATH
INFECTIONDISABILITY

NEXT EXPOSURE TO
SAME DISEASECAUSING ORGANISM

INFECTION

ACTIVATIONOF IMMUNEMEMORYNO DISEASEIMMUNEMEMORYFIGURE 4. COMPARISON OF THE IMMUNE RESPONSE TO A DISEASES-CAUSING ORGANISM AND TO A VACCINEF IGURE 6. I MMUNE RESPONSE TO A FIRST AND SECOND EXPOSURE TO A SAME DISEASE -10| VACCINEORGANISMFACT BOOK 2012
CAUSING

1 Basic Concept of Vaccination

BOX 1. THE HISTORY OF VACCINATION3

The first attempts to prevent disease by using thedisease–causing organism against itself are reported from
7th century India where Buddhist monks drank snake
venom in order to develop immunity against snake bites.
Variolation, the practice of inoculating the dried pustulesof smallpox (caused by the Variolae virus) from a sickindividual into a healthy individual, to prevent the healthy
individual from developing the disease, developed inCentral Asia in the second millennium. The practicethen spread east to China and West to Turkey, Africa,
and Europe.
In 1798, in England, Edward Jenner published theresults of his experiments on “vaccination”, the practiceof inoculating the cowpox virus (closely related to thehuman smallpox virus),
Variolae vaccinae,
to prevent smallpox
in humans. The term
vaccination was derived
from vaccinae virus.
The practice became
widely popularized.
At the end of the 19th
century, Louis Pasteurbegan to apply theconcept of vaccination
to other diseases. He
demonstrated thatthe harmful nature

Bust of Edward Jennerof disease-causingorganisms could be
weakened (or attenuated)in the laboratory. He
first demonstrated theeffectiveness of vaccines
against chicken cholera
and anthrax in animals,
before developing his
vaccine against rabies
for use in humansin 1885.
Painting of Louis Pasteur

In 1886, in the US,
Daniel Elmer Salmon and
Theobald Smith demonstrated that vaccines could be
produced not just from live organisms, but also from killed
disease-causing organisms. Their discovery would leadto the subsequent development of inactivated vaccines
against several human diseases.
In the early 20th century, it was discovered that somediseases were caused not by bacteria themselves, but by
the toxins that they produced. Inactivated toxins acted
like vaccines by providing protection against these toxininduced diseases. These vaccines are known as toxoids.
By the end of the 20th century, a spurt of innovation led
to the development of several new methods of producing
vaccines including by recombinant organisms, byconjugation of polysaccharides to carrier proteins, and by
the assembly of virus-like particles.

Photos: Source L Cranswick http://en.wikipedia.org/wiki/File:Jenner-statue-by-lachlan-mvc-006f.jpg;
and http://en.wikipedia.org/wiki/File:Tableau_Louis_Pasteur.jpg

3

Plotkin SL and Plotkin SA. A short history of vaccination. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.

VACCINE FACT BOOK 2012 | 11

1.2 Survey of vaccine preventable diseases

Which diseases are vaccine-preventable?
Smallpox was the first vaccine-preventable disease. After
Edward Jenner’s publication on the use of cowpox to protect
against smallpox, the practice of smallpox vaccination
became increasingly widespread. But about 100 years would
elapse until the development of a second human vaccine,Louis Pasteur’s rabies vaccine.

or relatively large size, may limit the ability of vaccines towork effectively.
Even when immune mechanisms for specific diseases areunderstood, there is no guarantee that a same vaccine design
can be successfully applied to other similar disease agents.
For many years, scientists have been unable to develop
safe and effective vaccines against diseases like respiratorysyncytial virus (RSV)—a very common childhood respiratory
infection—or dengue fever (a mosquito-borne disease thatabout 2.5 billion people are at risk of catching4).

The development of new vaccines then grew exponentially,
with several new human vaccines being introduced in the firsthalf of the 20th century, but even more becoming available
in the latter half and in the early 21st century. An intense
But very safe and effective vaccines have been developed
Photos:
L Cranswickat
http://en.wikipedia.org/wiki/File:Jenner-statue-by-lachlan-mvc-006f.jpg;
andperiodSourceof innovation
the end of the 20th century led to theagainst several
diseases over the past 120 years. These are
http://en.wikipedia.org/wiki/File:Tableau_Louis_Pasteur.jpg
development of several new methods of producing vaccines,
shown in Table 4 on page 15.
1including. 2 S u r vthe
e yexpressiono f v a c c iof
n proteinse p r e v einnrecombinantt a b l e d i s eorganisms,
ases
the conjugation of polysaccharides to carrier proteins, and the
Which diseases are routinely prevented in industrialized
construction of viral-like particles (See Figure 7). The rapid
countries?
Whichdiseases are vaccine-preventable?
growth in vaccine development is expected to result in more
new vaccines becoming available within the next decade.
Over 35 vaccines have been developed, many of which
Smallpox was the first vaccine-preventable disease. After Edward Jenner’s
publicationon theprotect
against fatalor permanently disabling diseases. Overuseof
cowpoxto
protect
againstsmallpox,thepracticeofsmallpox
vaccination
becameIn theory, any infectious disease might be preventablea dozen diseases are routinely targeted by industrialized
increasingly
widespread.
But about
100 years would
elapseuntil the development
second immunization schedules. Additionalwith a vaccine.
But a limited
understandingof theimmunecountries inof apediatric
human
vaccine,Louis
Pasteur’srabiesvaccine.
mechanisms involved, and the highly variable nature of thediseases are targeted in routine adolescent and adult
immuneresponse
each
specific
disease-causingorganism,
immunization
The
development
ofto
newvaccinesthengrew exponentially,
with several
new human schedules
vaccines or in schedules for high-risk groups
have meant
thatintheof vaccines
has but
so farbeen
such asavailable
the chronicallyevenmore becomingin the ill. Diseases commonly targeted bybeing
introduced
thedevelopment
first half of the20th century,
limiteda numberof viralbacterial
diseases.
For ofsome
immunization
latterhalftoandin the early
21standcentury.
An intense
periodinnovation
at the end ofprogramsthe 20th in industrialized countries are shown
century
led such
to theasdevelopmentof several
new methodsof producing invaccines,
including
the Other vaccines specific to travelers, ordiseases,
AIDS, vaccine
development
is particularly
Table 5 onpage 16.
expression
proteins inorganisms,
conjugation
to region,
carrier may also be recommended.
challengingofbecause
therecombinant
HIV virus escapes
the thebody’snatural of polysaccharides
to a geographic
proteins,
the constructionof viral-like(SEE
Error! Reference source not found.).
immune andresponse.
For parasitic
disease,particles
complexlife-cycles,
The rapid growth in vaccine development is expected to result in more Somenew vaccines
becoming
industrializedcountries are particularly eager to ensure
available within the next decade.
that life-saving vaccines are introduced quickly in national
programs when they become available. Other
In immunization
theory, any infectious
countries might
may take beseveral years to consider new vaccine
diseasepreventablewith a vaccine.
introductions.
Figure 8 shows the number of years that
But elapsed
a limited between
understanding
the granting of vaccine licenses in the USof theimmunemechanisms
and the grantingof licenses in Japan, for some vaccines.

involved, and the highlyvariable nature of theTable 6 on page 17 shows the difference between the
immune response to eachnumber of vaccines licensed in the USA and Japan over the
specific
disease-causing
last 40 years. Because of the societal and financial costs oforganism, have meant thattreating
and managing
vaccine-preventable diseases, thethedevelopment
of
delay
in
takingup
newvaccines
may have important social
NUMBEROF VACCINESDEVELOPED
vaccines has so far been
FFIGURE
IGURE 7.
7.CUMULATIVEC UMULATIVENUMBEROF VACCINESDEVELOPED
andeconomicconsequences.
SINCE THE FIRST VACCINE IN 1798, BY TYPE
limitedtoanumberofviral
SINCE THE FIRST VACCINE IN 1798, BY TYPE
and bacterial diseases.
For
somediseases,
like
AIDS,
vaccinedevelopment
isparticularly
challenging
because the HIV
4World Health Organization. Media center. Dengue and dengue haemorrhagic fever. Fact sheet n° 117. March 2009.
virus
escapes the body’s natural immune response. For parasitic disease, complex life-cycles,
http://www.who.int/mediacentre/factsheets/fs117/en/
or relatively large size, may limit the ability of vaccines to work effectively.
Even when immune mechanisms for specific diseases are understood, there is no guarantee
12 | aVACCINEFACT BOOK
thatsame vaccine
design2012
can be successfully applied to other similar disease agents. For
many years, scientists have been unable to develop safe and effective vaccines against1 Basic Concept of Vaccination	  FIGURE 8. NUMBER OF YEARS BETWEEN THE GRANTING OF VACCINE
LICENSES IN THE US AND THE GRANTING OF VACCINE LICENSES IN
JAPAN (FOR SOME VACCINES)“
For some
diseases, suchas AIDS, vaccine
development
is particularly
challenging
because the HIV
virus escapes
the body’s naturalimmune response.
VACCINE FACT BOOK 2012 | 13

Vaccine-preventablediseaseType of disease

Type of vaccine

Year vaccine developed

Most common severe
disease outcomes

Smallpox

viral

live attenuated1798

disfiguring, sometimes
fatal

Rabiesviral

inactivated1885

inactivated (cell culture)

1976

inactivated1886

live attenuated1983

polysaccharide

1994

protein conjugate

2008

inactivated (injectable)

1896

inactivated andrecombinant protein (oral)

1991

inactivated (oral)

1997

Typhoid

Cholerabacterial

bacterial

always fatal
intestinal hemorrhage andperforations, encephalitis,
psychosis, abscessesof internal organs,sometimes fatal
life-threatening
dehydration, electrolyte
imbalance, sometimes
fatal

Plaguebacterial

inactivated1897

seizures, coma, internal
bleeding, fatal within fourdays if not treatedDiphtheria

bacterial

toxoid1923

choking, heart andkidney failure, facial or
swallowing or respiratory
paralysis, sometimes fatal

toxoid1926

severe muscle spasms
and bone fractures, lockjaw, respiratory distress,
sometimes fatal

inactivated1914

purified protein*

1981

Tetanus

Pertussis

bacterial

bacterialchoking in young infants,
rib fractures, hernias,
incontinence, ruptured
blood vessels, sometimes
fatal

Tuberculosis

bacterial

live attenuated1921

coughing blood,
abscesses of internalorgans or bone,meningitis, sometimes
fatal

Yellow fever

viral

live attenuated1932

liver damage, internal
bleeding, sometimes fatal

inactivated

1936

live attenuated2003

inactivated1955

live attenuated1962

23-valent polysaccharide

1983

protein conjugate

2000

Influenza

Polio

Pneumococcal

viral

viral

bacterial

14 | VACCINE FACT BOOK 2012

life-threatening
pneumonia, worsening ofcoronary heart disease,
extreme muscular fatigue
or aches, high fever,sometimes fatal
respiratory paralysis,
life-long paralysis oflimb(s), skeletal deformity,
sometimes fatal
pneumonia, meningitis,
ear infections, infectionsof bone and heart muscle,
sometimes fatal

1 Basic Concept of Vaccination

Vaccine-preventablediseaseMeasles

Mumps

RubellaVaricella (chickenpox)

Type of diseaseviralYear vaccine developed

Most common severe
disease outcomes

live attenuated1963

diarrhea and severe
weight loss in infants,
convulsions, pneumonia,
ear and brain infections,
ulcerations of the eye,sometimes fatal

inactivated

1948

live attenuated**

1967

live attenuated***1969

incurable congenital
malformations, arthritis

1974

stroke in children, skininfections, pneumonia,
liver damage, kidney andheart diseases, brain
infections, incurable
congenital malformations

Type of vaccine

loss of male fertility, lossof pregnancy, meningitis,
pancreatitis, brain
infection, deafness

viral

viral

viral

live attenuated*

Herpes Zoster

viral

live attenuated2005

persistent pain, eyediseases and paralysis
and blindness, hearing
loss, vertigo, meningitis orbrain infections

Rotavirus

viral

live attenuated2006

severe dehydration,
sometimes fatal

Inactivated*

1935

Japanese encephalitis

viral
live attenuated1988

coma, deafness, lossof feeling, emotional
disturbances, sometimes
fatal

Tick-borne encephalitis

viral

inactivated1937

permanent
neuropsychiatric effects,
sometimes fatal

Hepatitis A

viral

inactivated1995

protracted illness andloss of productivity, liver
failure, sometimes fatal

polysaccharide

1971 (US Army) (1981
tetravalent US)

protein conjugate

1999 (conj C); 2005
(tetravalent)

polysaccharide

1985

protein conjugate

1987

plasma derived

1981

recombinant protein

1986

Meningococcal

bacterialpermanent brain damage,seizures, blood poisoning,deafness, respiratory
distress, organ failure,sometimes fatalmeningitis, pneumonia,
skin, bone and throat
infections, arthritis,
sometimes fatal

Heamophilus influenzae
type bbacterial

Hepatitis B

viral

Anthrax

bacterial

protein1954

blood poisoning, vomitingblood, sometimes fatal

Human Papillomavirus

viral

recombinant protein

2006

genital and cervical andoral cancers, genital
warts, sometimes fatalliver failure, cirrhosis, livercancer, sometimes fatal*Developed in Japan; **Urabe Am9 strain developed in Japan; ***Several Japanese vaccine strains.
TABLE 4. VACCINE-PREVENTABLE DISEASES, VACCINE TYPE, AND YEAR OF VACCINE DEVELOPMENTVACCINE FACT BOOK 2012 | 15

Bacterial diseases

Viral diseases

Diphtheria

Measles

Pertussis

Mumps

TetanusRubella

Pneumococcal diseases (pneumonia, meningitis, otitis media, andothers)Polio

Heamophilus influenzae type b diseases (pneumonia, meningitis andothers)Influenza A and B

Meningococcal diseases (meningitis and others)

Hepatitis B

Tuberculosis

Chickenpox
Herpes zoster
Rotavirus
Hepatitis A
Human Papilloma Virus diseases (genital/cervical/oral warts andcancers)
Japanese encephalitis (regional importance)
Rabies (in at-risk groups)

TABLE 5. DISEASES COMMONLY TARGETED BY ROUTINE IMMUNIZATION IN
INDUSTRIALIZED COUNTRIES EXCLUDING DISEASES TARGETED BY TRAVEL VACCINES

16 | VACCINE FACT BOOK 2012

1 Basic Concept of Vaccination

Year

Vaccines (all origins) licensed in the US

1971

Measles, Mumps, Rubella

1976
1977

Japanese encephalitis
Pneumococcal polysaccharide

1981
1982

Vacciness (all origins) licensed in Japan

acellular Pertussis
Hepatitis B

1985

Hepatitis B

1986

recombinant Hepatitis B

1987

conjugate Haemophilus influenzae type b;inactivated Polio

Varicella
recombinant Hepatitis B
Measles Mumps Rubella
Pneumococcal polysaccharide

1988
1991

acellular Pertussis

1992

Diphtheria, Tetanus, acellular Pertussis;
Japanese encephalitis

1993

Diphtheria, Tetanus, acellular Pertussis,
Haemophilus influenzae type b

1994

Plague1995

Varicella;
Hepatitis A

1996

Combination Haemophilus influenzae type b,
Hepatitis B (Hib-HepB)

2000

conjugate Pneumococcal (7 valent)

2001

Hepatitis A, Hepatitis B

2002

Diphtheria, Tetanus, Pertussis, Hepatitis B,
inactivated polio

2003

live attenuated Influenza;
adult formulation of diphtheria, tetanus,
pertussis

2005

Measles, Mumps, Rubella, Varicella (MMRV);
conjugate Meningococcal

2006

Rotavirus
Human Papilloma Virus

Hepatitis A

Measles, Rubella (MR)2007

conjugate Haemophilus influenzae type b

2010

conjugate pneumococcal
Human Papillomavirus

2011

Rotavirus (expected)

TOTAL

23

12

TABLE 6. VACCINES LICENSED IN THE US AND JAPAN 1971-2011

VACCINE FACT BOOK 2012 | 17

1.3 Vaccine efficacy and safety

What impact do vaccines have on diseases?
Vaccines have one of the greatest impacts on public health.
Their impact on reducing human mortality is second only tothe provision of safe drinking water5. Vaccines are provided toindividuals to protect them from disease, but they play an evengreater role in protecting entire populations from exposure
to infectious diseases. Vaccine-preventable diseases thatwere once prevalent in industrialized countries have virtuallydisappeared where vaccination has been implemented. In
the 20th century, vaccines have reduced the morbidity fromvaccine preventable diseases by as much as 89 – 100% (SeeFigure 9).

Two factors contribute to the ability of a vaccine to control or
eliminate a disease:• the effectiveness of the vaccine; and,• the level of vaccination coverage achieved in agiven population.
These vary slightly from one country to another, buteverywhere they are used licensed vaccines are consideredhighly effective at preventing disease (See Figure 10 and
Figure 11).

The prevention of disease has had an enormous impact on
economic development by limiting the costs of curative careand saving billions of dollars in countries where diseases havebeen well controlled or eliminated.

FIGURE 10. IMPACT OF IMMUNIZATION ON HIB DISEASE IN THE GAMBIA(ADAPTED – DATA ARE APPROXIMATE)8

FIGURE 9. IMPACT OF IMMUNIZATION ON THE NUMBER OF ANNUAL
CASES OF DISEASE IN THE USA6,7

FIGURE 11. MEASLES ELIMINATION IN THE AMERICAS FROM EFFORTS IN
IMMUNIZATION9,10

Plotkin SL and Plotkin SA. A short history of vaccination. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008
US Center for Disease Control and Prevention. Achievement in public health, 1900-1999 impact of vaccines universally recommended for children – United States
1990-1998. MMWR 48:243-248, 1999. http://www.cdc.gov/mmwr/preview/mmwrhtml/00056803.htm
7
US Center for Disease Control and Prevention. Summary of notifiable diseases – United States, 2009. MMWR 58 (53): 85-87, May 13, 2011.
http://www.cdc.gov/mmwr/pdf/wk/mm5853.pdf
5
6

18 | VACCINE FACT BOOK 2012

What is vaccine efficacy?

1 Basic Concept of Vaccination

Vaccine efficacy is the reduction in incidence of a disease amongst those who have been
vaccinated relative to the incidence in the unvaccinated. Because biologicals are inherently
variable, individuals do not respond identically to vaccines. Vaccines may fail to induce
immunity in a few individuals. But the most effective vaccines induce a protective immune
response in > 95% of individuals.

What is vaccine efficacy?

If a high level of vaccination coverage is achieved with aneffective vaccine,transmission
can be interrupted.
If a high level of vaccination coverage is achieved
with disease
an effective
vaccine,diseaseVaccine efficacy is the reduction in incidence of a disease
When disease transmission is interrupted, even thosetransmission can be interrupted. When disease transmission is interrupted, even thoseamongst those who have been vaccinated relative to theindividuals who were not vaccinated, or who were vaccinatedindividuals
whounvaccinated.
were not vaccinated,or whoare
were andvaccinatedandimmunity,
did notwill
developimmunity,will
incidencein theBecause biologicals
did not develop
be protectedfrom disease.
inherently
variable,
individuals
donotrespondidenticallyThiseffect
is
known
as
herd
immunity(See
Figure12).
be protected from disease. This effect is known as herd immunity (SEE Figure 12). Smallpox
to vaccines. Vaccines may fail to induce immunity in a
Smallpox was eradicated by achieving sufficient immunization
was eradicated by achieving sufficient immunization coverage to prevent transmission of
few individuals. But the most effective vaccines induce acoverage to prevent transmission of disease to unvaccinateddiseaseimmune
to unvaccinatedprotective
response in > non-immunes
95% of individuals.(susceptible).
non-immunes (susceptible).

DISEASE TRANSMISSION IN A NON-IMMUNE POPULATIONNON-IMMUNEDISEASE
TRANSMISSIONDISEASE
TRANSMITTERDISEASE TRANSMISSION IN A PARTIALLY IMMUNE POPULATIONDISEASE
TRANSMITTERNO DISEASE
TRANSMISSIONHERDIMMUNITYNON-IMMUNEFIGURE 12. HERD IMMUNITY

F IGURE 12. H ERD IMMUNITY
10

Pan American Health Organization. Number of measles confirmed cases in the Americas 1996-2008.
http://www.paho.org/English/ad/fch/im/Measles_NumberCases.pdf

Adegbola RA, Secka O, Lahai G, et al. Ellimination of Haemophilus influenzae type b (Hib) disease from The Gambia after the introduction of routine immunisation
with a Hib conjugate vaccine: a prospective study. Lancet. 2005;366:144-50.
9Andrus JK and Castillo-Solorzano C. Achieving and sustaining measles and rubella elimination. Partners for measles advocacy annual meeting. Washington DC,
July 27, 2010.
10
Pan American Health Organization. Number of measles confirmed cases in the Americas 1996-2008.
http://www.paho.org/English/ad/fch/im/Measles_NumberCases.pdf
8

VACCINE FACT BOOK 2012 | 19

VACCINE FACT BOOK - 2011

IMMUNE

22

The level of vaccination coverage required to interrupt diseasetransmission will depend on:• the ease with which a disease is transmitted; and,• the effectiveness of the vaccine at stimulating immunity.
The proportion of immune individuals in a population that will
prevent disease from spreading is known as the herd immunity
threshold. Each disease has its own herd immunity threshold.
The more easily transmitted the disease, the higher thethreshold (See Table 7). The higher the threshold, the greater
the vaccination coverage and vaccine effectiveness required
to interrupt disease transmission. Very easily transmissible
diseases, such as measles, can continue to transmit in acommunity even when vaccination coverage and vaccine
effectiveness are very high.

DiseaseHerd immunity threshold

Diphtheria

85%

Measles

83-94%

Mumps

75-86%

Pertussis

92-94%

Polio

80-86%

Rubella80-85%

Smallpox

83-85%TABLE 7. HERD IMMUNITY THRESHOLD FOR SOME DISEASES11.** When the proportion of immune individuals in a population reaches threshold, the spread of the disease to thenonimmune population can be interrupted.

Strategies to interrupt highly transmissible diseases, suchas measles, may require mass vaccination campaigns or reimmunization strategies to achieve disease elimination goals.
To monitor the impact of immunization programs and to
set realistic disease control targets, vaccine-policy makers
assess how effective vaccines are at preventing diseases intheir communities. The commonly used measure of impact
is vaccine efficacy (or vaccine effectiveness, when measured
under real operational conditions).
Vaccine Efficiency measures the decrease in incidence ofa disease in the vaccinated population compared to theincidence of the disease in the unvaccinated population. In
epidemiological terms, it is defined as the difference between
the Attack Rate of the disease in the Unvaccinated and the
Vaccinated relative to the Attack Rate in the Unvaccinated.
The Attack Rate is defined as the number of individuals who
become infected out of the total number who are exposed
to a disease. When categorized into Unvaccinated andVaccinated groups, vaccine efficacy is calculated as12:

Vaccine Efficiency =(Attack Rate in the Unvaccinated- Attack Rate in the Vaccinated)
Attack Rate in the Unvaccinated

x 100

and where Vaccine Efficacy (VE) is expressed as a percentage(See Figure 13).

The US Centers for Disease Control and Prevntion and the World Health Organization. History and Epidemiology of Global Smallpox Eradication.
http://www.bt.cdc.gov/agent/smallpox/training/overview/pdf/eradicationhistory.pdf
12
http://en.wikipedia.org/wiki/Vaccine_efficacy
11

20 | VACCINE FACT BOOK 2012

number who are exposed to a disease. When categorized into Unvaccinated and Vaccinatedgroups, vaccine efficacy is calculated as12:

1 Basic Concept of Vaccination

and, where Vaccine Efficacy (VE) is expressed as a percentage (SEE Figure 13).
PROPORTION INFECTED IN THE
UNVACCINATEDPROPORTION INFECTED IN
THEVACCINATEDPROPORTION INFECTED IIN THE
UNVACCINATED

X 100= INFECTEDVACCINE FACT BOOK - 2011

= NOT INFECTEDUNVACCINATED= NOT INFECTEDVACCINATED

FIGURE 13.

F IGURE 13. M ETHOD OF CALCULATION OF VACCINE EFFICACY

12

http://en.wikipedia.org/wiki/Vaccine_efficacy

24

VACCINE FACT BOOK 2012 | 21

Vaccine effectiveness is often distinguished from vaccine
efficacy. Vaccine effectiveness measures the performanceof a vaccine under field conditions (usually retrospectively),
whereas vaccine efficacy measures the performance ofa vaccine under study conditions (usually prospectively).
Therefore, vaccine effectiveness will depend not only on theperformance of the vaccine, but also on the performance ofthe vaccine delivery program. Furthermore, whereas vaccine
efficacy typically measures the prevention of a disease,vaccine effectiveness can assess the ability of a vaccine toprevent a specific outcome – for example: hospitalization ordeath from a specific disease.
How efficacious are vaccines?
Vaccine efficacy varies according to the type of vaccine andthe manner in which the vaccine antigen is processed by the
immune system. Vaccine efficacy may also vary between
different populations. However, in general, the efficacy oflicensed vaccines ranges from above 70% to almost 100%(See Figure 14). In other words, vaccines could be expected
to reduce the attack rates in the vaccinated population by
70-100% compared to the attack rates in the unvaccinatedpopulation.

How safe are vaccines?
The benefits of vaccination are indisputable. Immunization
has had one of the greatest impacts on health, second only
to clean drinking water14. Vaccines prevent death, illness and/ or disability. But because of the immune reactions that they
induce, vaccines can cause some discomfort.
The vast majority of adverse events associated with vaccines
are minor and transient. These are typically pain at the
injection site, or mild fever (See Table 8). More serious adverse
events occur rarely. Some serious adverse events may be sorare that they occur only once in millions of vaccine dosesdelivered15, and some serious adverse events may occur sorarely that their risk cannot be accurately assessed16. Some
individuals may be sensitive to some components or traceelements in some vaccines, such as eggs, antibiotics, orgelatin. Otherwise, the cause of rare or very rare adverse
events is usually unknown. It is believed that rare and veryrare adverse events are associated with individual differencesin immune responses.
Adverse events following immunization (AEFI) are often
categorized according to their frequency (See Table 9).

FIGURE 14. OBSERVED EFFICACIES OF SOME VACCINES (MAXIMUM VALUES ARE SHOWN FOR RANGES)13

US Centers for Disease Control and Prevention. Vaccines & Immunizations http://www.cdc.gov/vaccines/vpdvac/diphtheria/default.htm#clinical, and Immunization
Action Coalition. Vaccine information for the public and health professionals. http://www.vaccineinformation.org/. [Accessed on June 7, 2011]14
Plotkin SL and Plotkin SA. A short history of vaccination. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 200815
Australian government. The Australian immunization handbook 9th edition. 1.5. post-vaccination procedures.
http://www.health.gov.au/internet/immunise/publishing.nsf/Content/Handbook-adverse
16
Public Health Agency of Canada. Canadian Immunization Guide. Part 2 Vaccine safety and Adverse Events Following Immunization.
http://www.phac-aspc.gc.ca/publicat/cig-gci/p02-01-eng.php
13

22 | VACCINE FACT BOOK 2012

1 Basic Concept of Vaccination

VaccinePain, swelling, redness

Fever > 38˚C

Systemic symptoms

BCG (against tuberculosis)

90-95%

Haemophilus influenzae
type b

5-15%

2-10%

Hepatitis B

adults 15%
children 5%

1-6%

Measles / Measles, Mumps,
Rubella / Measles, Rubella

~10%

5-15%

5% rashOral polio

very rare< 1%<1% diarrhea, headache,muscle pains

Tetanus / Tetanus, diphtheria~10%50-85% booster doses~10%~25% irritability and malaise

Pertussis (whole cell)up to 50%

up to 50%

up to 55% irritability andmalaiseTABLE 8. COMMON REACTIONS TO VACCINES ROUTINELY USED IN SEVERAL INDUSTRIALIZED COUNTRIES17Classification

Frequency

very common> 1 / 10common> 1 / 100 and < 1 / 10

uncommon> 1 / 1 000 and < 1 / 100

rare> 1 / 10 000 and < 1 / 1 000very rare< 1 / 10 000

TABLE 9. CLASSIFICATION OF ADVERSE EVENTS FOLLOWINGIMMUNIZATION (AEFI)18“
The benefits ofvaccination are
indisputable.
World Health Organization. Immunization Safety Surveillance: guidlimes for managers of immunization programs on reporting and investigating adverse events
following immunization. Immunization Focus, World Health Organization Western Pacific Region, Manila, 1999.
http://www.who.int/immunization_safety/publications/aefi/en/AEFI_WPRO.pdf
18
Public Health Agency of Canada. Canadian Immunization Guide. Part 2 Vaccine safety and Adverse Events Following Immunization.
http://www.phac-aspc.gc.ca/publicat/cig-gci/p02-01-eng.php
17

VACCINE FACT BOOK 2012 | 23

All governments regulate the clinical development of vaccines.
A thorough evaluation of vaccine safety must be performed
before a government will grant a license to allow its use.
After a vaccine license has been granted, almost all national
immunization programs will continue to monitor the natureand frequency of adverse events following immunization. In
the US, for example, the Vaccine Adverse Event Reporting
System (VAERS) allows all stakeholders in immunizationfrom the public and private sectors to report on the safety oflicensed vaccines.
Vaccine policy-makers use the information from adverse
event reporting systems to guide vaccine policies, including
policies to assess the benefits and risks of immunization.

24 | VACCINE FACT BOOK 2012

1 Basic Concept of Vaccination

1.4 Vaccine safety surveillance and evaluation

How is vaccine safety surveillance conducted?
For severe illnesses, such as cancers, adverse events fromtherapeutic pharmaceuticals may be tolerated. But since
vaccines are typically administered to healthy individuals,
tolerance for adverse events is much lower. Most governments
mandate the investigation of possible adverse events following
immunization (AEFIs). Those investigations are conducted in
a comprehensive and systematic way.
Before a vaccine is licensed, it is carefully studied for all
possible harmful effects. Testing proceeds in a stepwise
approach. Safety is first evaluated in animals. If there is noevidence of harm in animals, testing can begin in a small
number of humans. If there is no evidence of harm in humans,
testing proceeds to increasing numbers of human subjects.
In humans, testing proceeds in three phases:• Phase I clinical trials involve a few dozen subjects;• Phase II  involve 50 – hundreds of subjects; and,• Phase III involve thousands or tens of thousands ofsubjects.
A safety concern that arises at one phase will stop the clinicalstudy from advancing to the next phase (See Figure 15).

FIGURE 15. SAFETY TESTING OF VACCINES IN THREE PHASES OF
CLINICAL TRIALSThe effects of the tested vaccine are compared to the effects
of a placebo to determine the cause of any adverse events.
Standardized case definitions of adverse events, set throughthe Brighton Collaboration, allow data from different clinical
trials to be compared19.
A license to allow use of the tested vaccine may be applied
for when clinical testing of the vaccine is completed. All safety
data from clinical testing must be submitted to a regulator for
review. The regulator will carefully consider the data from allphases of clinical testing to determine if the vaccine is safe
and meets the requirements for licensure. Only a vaccine
which meets all of the regulator’s safety requirements will beconsidered. The regulator may grant a conditional license if
there is a possibility that a rare adverse event is associatedwith the vaccine. The conditions of the license may include
conducting post-marketing (Phase IV) studies over a large
sample size and /or over a long period of time.
19

Offit PA, Davis RL, Gust D. Vaccine safety. pp 1630. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.

VACCINE FACT BOOK 2012 | 25

“Only a vaccine
which meets allof the regulator’ssafety requirements
will be considered.
The regulator may
grant a conditional
license if there isa possibility that arare adverse event
is associated withthe vaccine.

After a vaccine is licensed, many governments mandate thereporting of vaccine-related adverse events. In the US, thisis mandated by the National Childhood Vaccine Injury Act(NCVIA). The Vaccines Adverse Event Reporting System(VAERS) allows the US government to evaluate the incidenceof specific adverse events, or to detect variations in the rates
of vaccine-related adverse events.
Governments may use a variety of methods to monitor
vaccine safety. Most countries use spontaneous (or passive)
safety monitoring systems. These have a relatively low costof operation.
Some countries have a combined adverse event reporting
system for both vaccines and drugs. Other countries reportadverse events from vaccines and drugs through separate
reporting systems (See Table 10).

Countries that use the same
system for the reporting ofadverse events from drugs
and vaccines

Countries that have separate
systems for the reporting ofadverse events from drugs
and vaccines

SwedenJapan

New Zealand

CanadaFranceDenmark

United Kingdom

India

SwedenAustralia

New ZealandGermany

SwedenUSA

TABLE 10. SELECT COUNTRIES’ ADVERSE EVENT REPORTING SYSTEMSFOR DRUGS AND VACCINES20

Many countries also monitor immunization coverage rates.
In the US, the National Immunization Survey is conductedannually by telephone. The survey provides an estimate ofcoverage with a 95% confidence interval within 1% of theestimate.
How the US Vaccine Adverse Event Reporting System(VAERS) works
VAERS has been implemented jointly by the US Centers for
Disease Control and Prevention (CDC) and the Food and Drug
Administration (FDA) since 1990. VAERS collects reports ofvaccine adverse events from anyone: from the general public,
from patients or parents, from vaccine manufacturers, orfrom healthcare providers. These are collected without time
restrictions. Since 2002 reports of vaccine-related adverse

20

Offit PA, Davis RL, Gust D. Vaccine safety. pp 1631. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.

26 | VACCINE FACT BOOK 2012

1 Basic Concept of Vaccination

How the US Vaccine Adverse Event Reporting System (VAERS) works

How vaccine safety surveillance is conducted in countries
events can also be submitted on the VAERS website (http://
than the US
vaers.hhs.gov/index),
and24-hour
toll-freephone
assistance
VAERS has been implemented jointly by the US Centers for Disease Controlotherand Prevention
isavailable.
(CDC) and the Food and Drug Administration (FDA) since 1990. VAERS collects reports ofvaccine adverse events from anyone: from the general public, from patients Justor parents,
like infrom
the US, many countries mandate the reporting ofvaccinethey
manufacturers,
or allfromhealth adverse
care providers.
are collectedwithouttime
AEFIs.
Most
countries conduct spontaneous surveillance ofOnce
are received,
reported
eventsThese
are coded
restrictions. Since 2002 reports of vaccine-related adverse events can also be submitted on thevaccine safety. Commonwealth countries attach an adverse
andentered into the VAERS database. Reports of serious
VAERS website (http://vaers.hhs.gov/index), and 24-hour toll-free phone assistance is available.
event reporting form to officially issued prescription pads toadverse events initiate a follow-up of the events 60 days andOnceyearthey later
are received,
all reported
adverse eventsare coded
andas
entered facilitate
into the VAERS
the collection of AEFI reports.
one
to collectsupplemental
information,such
database. Reports of serious adverse events initiate a follow-up of the events 60 days and 1
information about patient recovery (See Figure 16). The data
year later to collect supplemental information, such as information about patient
recovery (SEE
Clinical centers for the study of adverse events may add to the surveillance capabilities of aIn
additionto spontaneous surveillance systems, many
on
AEFIs
VAERS
is madethe public
Figure16).from
The data
on AEFIs
fromavailable
VAERS isto
madeavailable(without
to the public (without
personalcountry. Phase
IV (post marketing) studies may also be used to evaluate specific events orrisks.
countries
have
supplemental active surveillance systems.
personal
identifiers).
identifiers).
Canada, for example, in addition to a spontaneous reporting
One
of
the
system,has
ansurveillance
active surveillancesystem:How vaccine
safetyis conducted incountriestheotherImmunization
than the US
US FDA and CDC
limitationsof
Monitoring (orProgram Active – IMPACT. This involves 12
spontaneous
VAERS database
Just likein the centers
US, many countries
mandate the more
reporting of
AEFIs.90%
Most countries
conduct
passive)surveillance
pediatric
representing
thanof tertiary
spontaneous surveillance of vaccine safety. Commonwealth countries attach an adverse eventis thatmore serious
21
pediatric
admissions
in the pads
country. the
A collection
nurse-monitor
andreporting form to
officially issued prescription
to facilitateof AEFI reports.
events are moreclinicalinvestigatorfrom eachperform
active caseIn addition tospontaneous surveillancesystems,center
many countries
have supplemental
activelikelyto be reported
surveillance systems. Canada, for example, in addition to a spontaneous reporting system, hasadverse eventof
AEFIs.
They investigate and report adverse eventscoding of events
thanfinding
less surveillance
seriousan active
system: the Immunization Monitoring Program Active – IMPACT. This
follow-up
involves immunization
12 pediatric centers to
representing
over 90% Safetyof tertiary Unit
pediatricin thefromthe Vaccine
ofadmissions
the Center
ones.
Therefore,
country21. A nurse-monitor and clinical investigator from each center perform active case-finding
some
less
seriousfor
Immunization
andRespiratory
Infectious
Diseases(Seeof AEFIs. They investigate and report adverse events from immunization to the Vaccine Safety
eventsmayreports of events
Unit of theCenterFigure17). forbeImmunization and Respiratory Infectious Diseases (SEE Figure 17).

Vaccineindustry

Healthcare
providers

F IGURE 16.
16.US
USVACCINE
V ACCINE
ADVERSEEVENTREPORTINGSYSTEM
FIGURE
ADVERSEEVENTREPORTINGSYSTEM( EXAMPLEOF
OFAASPONTANEOUS
SPONTANEOUSSURVEILLANCESURVEILLANCESYSTEM)SYSTEM )(EXAMPLE

increasereview
in reportingof admissions
recordsof events thatmay
be relatively minor.

VACCINE FACT BOOK - 2011

Publicunder-represented,
or not detected. Or,
reporting Canadianmay PediatricbeSociety
influenced by stories
centers
covered 12 pediatricbythemedia, leading to an

VACCINE FACT BOOK - 2011

Oneof the limitations of spontaneous (or passive) surveillance
active case-finding ofPassive surveillance systems, like VAERS, do not collect data on the total number of individuals
AEFI
is
that
more
serious
eventsaremorelikelytobereported
than
vaccinated, so the rate of AEFIs can not be calculated. However, by linking immunization
registries
with medical
files, an estimate
the frequency
eventsmay
can be made. The Vaccine
lessseriousones. Therefore,
someof lessserious of
eventsinvestigation and
SafetyDataLink Project (VSD),
the US, is Or
a databasecollects
vaccinationof AEFIsbeunder-represented
or notindetected.
reportingthatmay
be data on reporting
histories and health outcomes from Health Management Organizations (HMOs). The data are
influenced
by stories covered by the media, leading to an
used to study vaccine safety concerns.
increase in reporting of events that may be relatively minor.

Vaccine Safety Unit
Database

NURSE MONITOR
AND CLINICALINVESTIGATOR

obtain lot-specific anddistribution info frommanufacturer

calculate vaccine
adverse event rate

FIGURE
17. CCANADIANIMPACTSURVEILLANCESURVEILLANCESYSTEM(EXAMPLEANF IGURE 17.
ANADIAN IMPACTSYSTEM( EXAMPLE
OF AN OFACTIVESURVEILLANCESYSTEM )Passive surveillance systems, like VAERS, do not collect
ACTIVESURVEILLANCESYSTEM)
Public Health Agency of Canada. Vaccine safety. http://www.phac-aspc.gc.ca/im/vs-sv/caefiss-eng.php
data on the total number of individuals vaccinated, so the30
rate of AEFIs cannot be calculated. However, by linking 31 Australia also supplements passive surveillance with an active
immunization registries with medical files, an estimate ofsurveillance system of sentinel units to investigate severe
the frequency of events can be made. The Vaccine Safety
AEFIs22.
Datalink Project (VSD), in the US, is a database that collects
data on vaccination histories and health outcomes from
Most European countries have spontaneous surveillance
Health Management Organizations (HMOs). The data aresystems, supplemented by active surveillance activities. The
used to study vaccine safety concerns.
structure of each national AEFI surveillance system relates
to the organization of immunization in each country. In someClinical centers for the study of adverse events may add
countries, immunization and safety surveillance programs
to the surveillance capabilities of a country. Phase IV (postare the responsibility of the central government; in othermarketing) studies may also be used to evaluate specificcountries they are the responsibility of the states or provinces.
events or risks.
In Germany, individual physicians recommend vaccines to21

Public Health Agency of Canada. Vaccine safety. http://www.phac-aspc.gc.ca/im/vs-sv/caefiss-eng.php
Waldman EA, Luhm KR, Monteiro SAM, de Freitas FRM. 2011. Surveillance of adverse effects following vaccination and safety of immunization programs. Rev
Saude Publica. http://www.scielo.br/pdf/rsp/v45n1/en_1884.pdf
21
22

VACCINE FACT BOOK 2012 | 27

their patients, but reportable AEFIs are made to the local
health authority who then reports them to a national safetysurveillance center23. In some countries, reporting of AEFIs is
mandatory. In others it is voluntary.
In addition to national safety surveillance, some European
institutions conduct safety surveillance on a supra-national
level (See Figure 18).
The European Medicines Agency (EMA) has a database forthe reporting of adverse events from medicinal products(including vaccines) from the European Economic Area. And
the World Health Organization (WHO) Collaborating Centerin Uppsala, Sweden, collects data of reports of AEFIs fromabout 40 countries. The WHO also has a Global Advisory
Committee on Vaccine Safety (GACVS) that responds
promptly to potential issues of vaccine safety.

Supra-national
spontaneous safetysurveillance (from theEuropean Medicines
Agency database, theUppsala Center, and the
Global Advisory Committee
on Vaccine Safety)

National spontaneoussafety surveillace(from physicians, local
health authorities andnational institutions)

National active safetysurveillance (fromspecialized centers,
academia, and Phase IV
clinical trials)

Providing information on the benefits and risks ofimmunization
The public is increasingly demanding of information on thebenefits and risks of immunization. As such, healthcare
providers and vaccine policymakers need to provide
patients and parents with up to date information from theirown communities. In the US, the government provides the
public with written information on the risks and benefits ofimmunization, through the CDC, and a vaccine information
sheet (VIS) is required to be provided with each vaccination.
Many national immunization guides, and WHO guidelines,
provide advice to healthcare providers on how tocommunicate the risks and benefits of immunization. This
includes communications on AEFIs.

FIGURE 18. NATIONAL AND SUPRA-NATIONAL VACCINE SAFETYSURVEILLANCE IN EUROPE“
The public isincreasingly
demanding of
information on thebenefits and risksof immunization.

Waldman EA, Luhm KR, Monteiro SAM, de Freitas FRM. 2011. Surveillance of adverse effects following vaccination and safety of immunization programs. Rev
Saude Publica. http://www.scielo.br/pdf/rsp/v45n1/en_1884.pdf
23

28 | VACCINE FACT BOOK 2012

1 Basic Concept of Vaccination

1.5 Vaccine injury compensation systems

Origin of the US vaccine injury compensation system
Vaccines are produced under strict government regulations
and are thoroughly studied for safety before and after they
are licensed. Very rarely, severe vaccine adverse events may
occur following immunization with licensed vaccines. Thismay occur because the incidence of an AEFI was too low to be
detected during the registration process. When they do occur,
severe AEFIs are thoroughly investigated. The great majority
of severe AEFIs are found to be coincidental events that
occur over a large number of vaccines delivered (i.e., events
that occur around the time of vaccination, but are not caused
by vaccination).
If governments did not protect vaccine manufacturers
from liability for injury, vaccine manufacturers would becontinuously exposed to the risk of liability. This in turn could
reduce the willingness of manufacturers to produce and sellvaccines.
In the 1970s, precedent-setting legal actions caused several
vaccine manufacturers to stop producing several vaccines.
Gross sales of all vaccines, from all manufacturers in the US,amounted to $3 million in 1980. But damages awarded in a
lawsuit had the potential to be far greater.25 The negative impactof legal action on the willingness of vaccine manufacturers
to produce vaccines, and the observed increase in vaccine
prices to offset the increased risk of liability, compelled somegovernments to develop injury compensation systems. These
were designed to secure the supply of needed vaccines.

1986), the US National Childhood Vaccine Injury Act (NCVIA)
established the National Vaccine Injury Compensation
Program (VICP).
What is an injury compensation system?
Vaccine injury compensation systems are meant to rapidly
award those who inadvertently suffer injury from properly
produced and administered vaccines. They are designed
as no-fault systems that do not require proof of negligenceon the part of the manufacturer (e.g. from improper design)or healthcare provider (e.g. from inadequate warning ofrisk). As such, punitive damages cannot be sought unless amanufacturer can be shown to have been grossly negligent.
Instead, compensation is awarded based on the healthcare
needs of the allegedly injured.
In addition to providing protection from legal action against
vaccine manufacturers, vaccine injury compensation systems also provide protection for healthcare providers. In theabsence of protection, healthcare providers might be unwilling to provide immunization services.
The awards in an injury compensation program are generally
determined based on an established injury table which lists
mandatory reportable adverse events (See Table 11)25.

In the US ‘swine flu’ incident of 1976 (the emergence of a newstrain of H1N1 influenza in pigs that caused the death of amilitary recruit and was believed to be closely related to the
influenza pandemic strain of 1918), a swine flu vaccine was
highly demanded by the US government to prevent a humanepidemic of the disease from occurring. But because of prior,precedent-setting legal actions against vaccine companies,
no vaccine manufacturer was willing to produce and sell aswine flu vaccine. To get vaccine manufacturers to agree toproduce a swine flu vaccine, the US government had to enact
new legislation. The Swine Flu Act made the US government
the defendant in any legal actions brought against swine flu
vaccine manufacturers, for alleged injury. A decade later (in25

Health Resources and Services Administration. http://www.hrsa.gov/vaccinecompensation/table.htm

VACCINE FACT BOOK 2012 | 29

Vaccine

Adverse Event

Time interval

Anaphylaxis or anaphylactic shock

0-4 hours

Brachial neuritis

2-28 days

Any acute complication or sequela (including
death) of above events

Not applicableAnaphylaxis or anaphylactic shock

0-4 hours

Encephalopathy or encephalitis

0-72 hours

Any acute complication or sequela (including
death) of above events

Not applicableAnaphylaxis or anaphylactic shock

0-4 hours

Encephalopathy or encephalitis

5-15 days

Any acute complication or sequela (including
death) of above events

Not applicable

Chronic arthritis

7-42 days

Any acute complication or sequela (including
death) of above events

Not applicable

Thrombocytopenic purpura

7-30 days

Vaccine-Strain Measles Viral Infection in an
immunodeficient recipient

0-6 months

Any acute complication or sequela (including
death) of above events

Not applicable

Paralytic polio

0-30 days (non immunodeficient);
0-6 months (immunodeficient);
Not applicable (vaccine associated community case)

Vaccine-strain polio

0-30 days (non immunodeficient);
0-6 months (immunodeficient);
Not applicable (vaccine associated community case)

Any acute complication or sequela (including
death) of above events

Not applicableAnaphylaxis or anaphylactic shock

0-4 hours

Any acute complication or sequela (including
death) of above events

Not applicableAnaphylaxis or anaphylactic shock

0-4 hours

Any acute complication or sequela (including
death) of above events

Not applicable

Haemophilus influenzae
type b (Hib)

No condition specified

Not applicable

Varicella

No condition specified

Not applicable

Rotavirus

No condition specified

Not applicable

Pneumococcal conjugate

No condition specified

Not applicable

Any new vaccine
recommended by
the CDC for routine
administration to children(includes Hepatitis A,
influenza, meningococcal
conjugate, and Human
Papilloma Virus)

No condition specified

Not applicable

Tetanus containing

Pertussis containing

Measles, mumps, andrubella containing
vaccines

Rubella containing

Measles containing

Oral Polio

Inactivated Polio

Hepatitis B containing

TABLE 11. US VACCINE INJURY TABLE

The detailed Injury Table can be accessed at:
http://www.hrsa.gov/vaccinecompensation/table.htm

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1 Basic Concept of Vaccination

How the US National Vaccine Injury Compensation
Program (VICP) works
The US the National Childhood Vaccine Injury Act (NCVIA)
mandates that vaccine manufacturers and healthcare
providers report those adverse events listed in the Vaccine
Injury Table. In the US, reporting of adverse events is madethrough the Vaccine Adverse Event Reporting System(VAERS).

In addition, the VICP is monitored by the Advisory Committee
on Childhood Vaccines (ACCV). The ACCV is composedof physicians, parents and attorneys. The ACCV makes
recommendations on operations of the VICP, including forchanges to the Vaccine Injury Table, when appropriate. The
National Vaccine Advisory Committee (NVAC) has broadoversight of the VICP, and makes recommendations on abroad array of issues, including vaccine research, production,delivery, safety and efficacy (See Figure 20 on page 32).

Because childhood vaccination is mandatory in the US, thenational Vaccine Injury Compensation Program (VICP) covers
routine vaccines for children (against a total of 16 diseases).

Funding for the VICP is generated by the collection of anexcise tax of $0.75 on each dose of vaccine sold for eachdisease prevented (i.e. $0.75 X 3 = $ 2.25 for MMR).

The VICP is administered by the Department of Health andHuman Services (HHS), the Department of Justice (DOJ), andthe Office of Special Masters, US Court of Federal Claims.

The process for claiming compensation for injury from avaccine is shown in Figure 21 on page 3226.
The VICP Trust Fund was established in 1988. Since that time,
the annual number of vaccine injury compensation claims hasremained fairly constant. Spikes in claims occurred whenattention-getting allegations were made for the association of
encephalopathy with DTP and for the association of autism
with thimerosal. The annual numbers of petitions filed since
the start of the program are shown in Figure 1927.

“
The national Vaccine
Injury Compensation
Program covers
routine vaccines
for children(against a total of
16 diseases).

FIGURE 19.

US Department of Health and Human Services. Health Resources and Services Administration. National Vaccine Injury Compensation Program.
http://www.hrsa.gov/vaccinecompensation/
27
US Department of Health and Human Services. Health Resources and Services Administration. National Vaccine Injury Compensation Program. Statistics
reports. http://www.hrsa.gov/vaccinecompensation/statistics_report.htm
26

VACCINE FACT BOOK 2012 | 31

FIGURE 20. ORGANIZATION OF VACCINE INJURY COMPENSATION PROGRAM IN THE US

FIGURE 21. VACCINE INJURY COMPENSATION CLAIM PROCESS IN THE US

32 | VACCINE FACT BOOK 2012

1 Basic Concept of Vaccination

1.

Patients (or their attorneys) file petitions with the Courtof Claims;
2. Petitions are processed by eight dedicated special
masters for fact determination;
3. Valid claims are sent to the Department of Health andHuman Services (HSS) for evaluation by medical
reviewers - eligibility for compensation is determinedby proof of a condition listed in the Vaccine Injury Table(VIT), or by proof that an injury not listed in the VIT wascaused by a vaccine. Petitioners must also prove thatinjury required hospitalization or lasted for more thansix months;
4. Recommendations of the medical reviewers on
petitioners’ entitlement to compensation are forwarded
to the Court of Claims;
5. Recommendations for entitlement, are almost always
accepted by the Court of Claims and submitted to the
Department of Justice;
6. Recommendations against entitlement proceed to ahearing;
7. Hearings may, based on the testimony presented,
reject the recommendations of the medical reviewers
and recommend entitlement to compensation to thepetitioner;
8. Hearings that accept recommendations against
entitlement result in dismissal;
9. When entitlement has been awarded, the Department ofJustice will reach agreement with the petitioner on theamount to be awarded;
10. The award is evaluated based on the injured individual’s
future needs and paid in lump sum and an annuity. A lumpsum is limited to $250,000.00 for death. Compensation
ranges from $120 to $9.1 million. In addition, reasonable
attorney fees are paid for both successful andunsuccessful petitioners.
Note that the petitioner may, nevertheless, pursue a claim
against a vaccine manufacturer if a VICP award is deniedor rejected because it is deemed to be insufficient. Details
on the claims process for the VICP can be found at:
http://www.hrsa.gov/vaccinecompensation/
The number of awards granted, and the amount ofcompensation, has varied from year to year28. The highest
number of awards was granted in the late 1990s. The annual
amount of compensation has ranged from about $50 million
to $180 million (See Figure 22).The annual amounts paid out
by the VICP Trust Fund are slightly higher than the amounts of
the awards because payouts include attorney fees.

The number of petitions to the VICP by type of vaccine
varies considerably29. The greatest number of claims wasmade against DTP vaccine in the 1990s. DTP has since been
replaced with the less reactogenic DTaP vaccine in the US.
The cumulative number of claims against DTaP vaccine isnotably smaller. The numbers of claims for compensation filedwith the VICP, and the number of awards, for each type of
vaccine, from 1988 – 2010, are shown in Figure 23.

FIGURE 22. ANNUAL NUMBER OF VICP AWARDS AND ANNUAL AMOUNTSOF COMPENSATION AWARDED FROM THE VICP TRUST FUND“
The number ofawards granted,
and the amount ofcompensation, hasvaried from year
to year.

US Department of Health and Human Services. Health Resources and Services Administration. National Vaccine Injury Compensation Program. Statistics reports.
http://www.hrsa.gov/vaccinecompensation/statistics_report.htm
29
US Department of Health and Human Services. Health Resources and Services Administration. National Vaccine Injury Compensation Program. Statistics reports.
http://www.hrsa.gov/vaccinecompensation/statistics_report.htm
28

VACCINE FACT BOOK 2012 | 33

The number of petitions to the VICP by type of vaccine varies considerably29. The greatest
number of claims was made against DTP vaccine in the 1990s. DTP has since been replacedwith the less reactogenic DTaP vaccine in the US. The cumulative number of claims against
DTaP vaccine is notably smaller. The numbers of claims for compensation filed with the VICP,
and the number of awards, for each type of vaccine, from 1988 – 2010, are shown in Figure 23.

FIGURE 23. NUMBER OF PETITIONS TO THE VICP AND NUMBER OF AWARDS GRANTED BY VACCINE TYPE, FROM 1988 - 2010

F IGURE 23. N UMBER OF PETITIONS TO THE VICP AND NUMBER OF AWARDS GRANTED BY
VACCINE TYPE , FROM 1988 - 201029

US Department of Health and Human Services. Health Resources and Services Administration. National Vaccine
Injury Compensation Program. Statistics reports. http://www.hrsa.gov/vaccinecompensation/statistics_report.htm

34 | VACCINE FACT BOOK 2012

1 Basic Concept of Vaccination

National vaccine injury compensation programs, otherthan in the US
Nineteen countries have some form of vaccine injury compensation program (See Figure 24)30. Germany was thefirst country to introduce a program in 1961, and Hungary
adopted a program in 2005. All but two of these programs
are administered by the national or state governments. In
the other two countries (Sweden and Finland) the programs
are administered by the vaccine industry through voluntary
contributions to insurance. In all countries, except Taiwan,
compensation is awarded from the national treasury. Taiwan,
like the US, created a trust fund from an excise tax of Taiwan$1.00 / dose on the sale of vaccines. In all cases, these countries’ vaccine-injury compensation programs require causation
to be demonstrated by a standard of “more likely than not,”a standard that is lower than in tort law.

Some schemes cover only mandatory vaccines while others
cover any licensed vaccine. Eligibility criteria vary between
programs, but most require proof of disability of someduration to be compensable.
All programs, except in the UK, compensate for medical
expenses, disability pension, and death benefits. The UK
provides a lump sum payment of £120,000. Some programs
also compensate for pain and suffering, but none compensate
for legal costs.
Most programs aim to settle claims in a timely fashion andsome countries are mandated to resolve claims within six
months. Unlike the US program, which uses an Injury Table todetermine eligibility, most countries rely on the Bradford Hill
criteria to establish causality.

FIGURE 24. COUNTRIES WITH INJURY COMPENSATION PROGRAMS, YEAR INTRODUCED

Looker C & Kelly H. No-fault compensation following adverse events attributed to vaccination: a review of international programmes. Bull World Health Organ 2011;
89:371–378. http://www.who.int/bulletin/volumes/89/5/10-081901.pdf
30

VACCINE FACT BOOK 2012 | 35

1.6 Cost-effectiveness analyses and evaluation

Cost analyses are often used in healthcare. They enablerational decision-making, and enable policy-makers toevaluate cost-efficient program options. The costs andbenefits of several program options can be compared todetermine which provides the greatest value (either monetaryor effect) (See Figure 25).

Types of costs

ExamplesDirect medical

Medical personnel
Vaccines
Syringes

Direct non-medical

Several methods can be used to quantify the value of
immunization programs (See Figure 26). The most commonlyused analyses are:
COST: the additive costs, direct and indirect, of an intervention;
COST-BENEFIT: the ratio of the costs to the quantified
benefits in monetary value, i.e. costs of hospitalization
prevented because of immunization;
COST-EFFECTIVENESS: the relative costs and effects of
one intervention compared to another with a same objective
where the effect is typically a health gain, i.e., deaths averted,or life-years saved; and,
COST-UTILITY: the ratio of the costs to the quantified effectmeasured in years of full health, i.e., disability- or qualityadjusted life-years.
Costs (and benefits) can be both direct and indirect (seeTable 12)31:•

Direct costs are the costs of immunizing and the costs ofmedical treatment for the disease;
Indirect costs include loss of productivity, lost wages, etc,of the ill and their caregivers.

•

Administration
Clinic utilities

IndirectTime off from work due toillness (loss of wages, loss of
productivity)
Time off from work to care forthe ill (loss of wages, loss of
productivity)

TABLE 12. TYPES OF COSTS INCLUDED IN COST ANALYSES

Mathematical modeling is often used to estimate the costs
and benefits of vaccines in a given context and from a given
perspective.
Assessments of immunization programs may also take into
consideration the amount of time required to observe thedesired effect. Some diseases occur several years after
infection (e.g. liver cancer after infection with Hepatitis B
virus). Health economists typically discount future costs andbenefits at a rate of 3 – 10% / year. This favors short- term
effects over longer-term effects.
In the US, most of the economic burden from influenza($71.3–166 billion) is attributable to the indirect costs, theresult of loss of productivity32.

Assessments of immunization programs can be made fromseveral perspectives. They can benefit:•••

the individual;
the health system; and,society as a whole.

National Network for Immunization Information. Vaccine Economics. http://www.immunizationinfo.org/issues/immunization-policy/vaccine-economics
Lynd LD, Goeree R, O’Brien BJ. Antiviral agents for influenza: a comparison of cost-effectiveness data. Pharmacoeconomics 2005; 23(11): 1083-1106.

31
32

36 | VACCINE FACT BOOK 2012

1 Basic Concept of Vaccination

	
  OPTION	  A	
  BENEFITS	  COSTS	  

OPTION	  B	
  BENEFITS	  COSTS	  

OPTION	  C	
  COSTS	  

BENEFITS	  FIGURE 25. COST BENEFIT ANALYSES ASSIST IN DETERMINING WHICH
PROGRAM OPTIONS AND PROVIDE THE GREATEST VALUE

COST-BENEFITBENEFITCOSTS

COST-EFFECTIVENESSIntervention A
COSTS

GAIN IN
HEALTHIntervention B
COST-UTILITYCOSTSYEARS OF FULLHEALTH

FIGURE 26. TYPES OF ECONOMIC ANALYSES COMMONLY USED TO ASSESS IMMUNIZATION PROGRAMSVACCINE FACT BOOK 2012 | 37

The benefits: cost ratio of immunization(cost-benefit analyses)
The value of immunization is most commonly assessed interms of its ability to reduce the burden of a disease and its
consequences. Reducing disease has an economic impact
on the individual, on society, and on national health systems.
Some economic impacts can be quantified. Others, such as
the value of averted deaths, may be more difficult to quantify.
The quantified impacts of immunization are often reported interms of benefit : cost ratio. A ratio of > 1.0 is cost-saving.
Compared to other interventions in health, vaccines have oneof the highest cost : benefit ratios.
Because of their high value, vaccines are a core component of
all primary healthcare programs. Immunization can avert highexpenditures for curative care, particularly in very young andelderly populations. In fact, unlike many other interventions inhealth, because vaccines prevent diseases that are costly totreat vaccination often imparts an overall savings to the healthsystem. In the US, seven pediatric immunizations are costsaving, imparting a direct and societal benefit / cost ratio of
5.3 to 16.5, respectively (See Figure 27)33.

Benefit : cost ratios vary according to the healthcare costs ofeach country. The less a country expends to treat diseases, thelower the benefit : cost ratio. But immunization is universallyconsidered to be cost-effective.
The WHO recommends immunization as a fundamental
component of primary health care34.
The cost-effectiveness of immunization
A benefit : cost ratio assigns a monetary value to an effect.
“Cost-effectiveness” measures the costs and effects(measured as a gain in health), usually of two or moreinterventions with a same objective.
Cost-effectiveness analyses are used to inform program
choices by determining the relative value of one strategy
over another. For example, cost-effectiveness analyses in the
US showed that $90-150 million / year could be saved byadministering combined DTP and Hib vaccines or DTP, Hib,
and Hepatitis B vaccines, instead of administering separate
injections35.
Compared to other government interventions, including
other interventions in health, the cost-effectiveness of most
vaccines is exceptionally high (See Figure 28)36. Interventions
are generally considered highly cost-effective if they are≤ Gross National Income (GNI) / capita, and cost-effective ifthey are < 3 x GNI / capita37.

FIGURE 27. COST-SAVING BENEFIT: COST RATIOS FOR SOME VACCINESIN THE US

FIGURE 28. COST-EFFECTIVENESS OF IMMUNIZATION COMPARED TO
COMMONLY USED SCREENING TESTS IN THE US

Committee on the Evaluation of Vaccine Purchase Financing in the United States, Board on Health Care Services. Institute of Medicine. Financing Vaccines in the
21st Century: Assuring Access and Availability. National Academies Press, Washington DC, 2004.
34
World Health Organization. Immunization. http://www.who.int/topics/immunization/en/
35
Miller MA, and Hinman AR. Economic analyses of vaccine policies. pp 1597. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier,
China, 2008.
36
Zhou F, Santoli J, Messonnier ML et al. Economic evaluation of the 7-vaccine routine childhood immunization schedule in the United States, 2001. Arch Pediatr
Adolesc Med 159: 1136-1144, 2005
37
World Health Organization. Choosing interventions that are cost effective (WHO-CHOICE). Cost-effectiveness thresholds.
http://www.who.int/choice/costs/CER_thresholds/en/index.html
33

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1 Basic Concept of Vaccination

When cost effectiveness analyses are quantified in years offull health, they are termed “cost-utility” analyses (See Figure
26).
Disability-adjusted-life-years (DALY) or quality-adjusted-lifeyears (QALY) attribute different values to morbidity and mortality relative to full health.
DALY: number of healthy life years lost;
QALY: number of healthy life years lived.
DALY and QALY integrate a number of subjective assumptions.
But cost-utility analyses allow for the value of immunization
to be compared across diseases, since some diseases havemore immediate impacts than others.
Figure 29 shows the relative cost utility of some vaccines in
the US38,39,40.

FIGURE 29. COST-EFFECTIVENESS OF CHILDHOOD AND ADOLESCENT VACCINES IN THE US. VACCINES<$0 / QALY ARE COST SAVING. ALL VACCINES SHOWN EXCEED THE THRESHOLD FOR COST-EFFECTIVENESS.
(LOWEST COSTS WERE USED IF FROM A RANGE; COST FOR HUMAN PAPILLOMAVIRUS VACCINE IS FOR IMMUNIZATION OF
12 YEAR-OLD GIRLS)

Chesson H. HPV vaccine cost-effectiveness: update and review. Advisory Committee on Immunization Practices, Feb 24, 2011.
Shim E and Galvani AP. Impact of transmission dynamics on the cost-effectiveness of rotavirus vaccination. Vaccine 2009; 27:4025-4030.
40World Bank. World development indicators database, July 1, 2011. http://siteresources.worldbank.org/DATASTATISTICS/Resources/GNIPC.pdf
38
39

VACCINE FACT BOOK 2012 | 39

1.7 Vaccine implementation options

Vaccines are provided to the public upon the recommendationsof the medical profession. The recommendations for the useof certain vaccines are endorsed by national governments
who set policies with public health objectives for the control
and prevention of diseases.
The implementation of immunization programs varies fromcountry to country. All countries provide basic immunization
services through the public sector. The private sector plays
an important role in offering many of the same vaccines,
and several others, to segments of population that accesshealthcare outside of the public sector.
Implementation of immunization in the US
In the US, the Institute of Medicine has defined five key roles
for the government in immunization. To fulfill these roles,
adequate financing policies and practices for immunization
are necessary (Figure 30)41:
Vaccine purchase: the US CDC Vaccine for Children (VFC)
program purchases about 55% of childhood vaccines directlyfrom vaccine manufacturers. Funding for the program isprovided by Medicaid.

Vaccine delivery: VFC vaccines are provided to both public
and private sector healthcare providers. VFC vaccines are
made available, at no cost, to children eligible for Medicaid.
The remaining 45% of childhood vaccines (non-VFC vaccines)
are delivered through the private sector, in doctors’ offices
and health clinics.
Disease surveillance: in the US, most childhood vaccinepreventable diseases are notifiable. Notifiable vaccinepreventable disease data, including vaccination status, iscollected by the National Notifiable Disease Surveillance
System, at the US CDC, on a weekly basis.
Surveillance of vaccination coverage: there are several
systems used to monitor immunization performance:•

The annual National Immunization Survey provides anestimate of vaccine coverage by collecting information
over the telephone from a representative population
sample (a variety of methods are used to ensure that the
information is validated and is representative of ethnic
and income groups, e.g., by cross-checking records fromhealth providers);

FIGURE 30. KEY GOVERNMENT ROLES IN IMMUNIZATION SUPPORTED BY IMMUNIZATION FINANCE POLICIESAND PRACTICES

Committee on Immunization Financing Policies and Practices, Division of Health Care Services and Division of Health Promotion and Disease Prevention.
Calling the Shots. National Academy Press, Washington DC, 2000.
41

40 | VACCINE FACT BOOK 2012

1 Basic Concept of Vaccination•

The VFC providers and Health Management Organizations(HMOs) also assess immunization coverage using astandardized program through the Health Plan Employer
Data Information Set (HEDIS);•

Immunization Information Systems (previously
called immunization registries) are confidential 		
computerized databases that record vaccine doses
administered by participating healthcare providers.

Sustaining and improving immunization coverage
All 50 US states have laws requiring immunization before
school entry, but parents can file a request for their children
to opt out, and immunization is never coercive. Governments
link immunization reminders to other government services,like the supplemental food program for woman, infants, andchildren, to ensure that immunization coverage is maintained.
Standing orders in nursing homes and hospitals are also used
to improve coverage in adults and the elderly.

FIGURE 31.SUPPORT MECHANISMS IN EUROPE FOR NATIONALSURVEILLANCE OF VACCINE-PREVENTABLE DISEASES AND
VACCINATION COVERAGE	
  Immunization policies and implementation are determinedwithin each country. They are not subject to EU legislation.
But vaccines can be licensed in other European Union
countries through a centralized procedure. This procedure
grants marketing authorization in all EU member states.

Implementation of immunization in Europe
The European region is very diverse and immunization policies
vary considerably from country to country. Some countries,
such as Germany, have a decentralized public health system
where the states are responsible for the implementation of
immunization (as is the case in the US). In Germany, the costsof immunization are covered mostly by statutory insurance
provided by employers.
Other European countries, such as the UK, have a strong,
centralized, comprehensive health system that includes
responsibility for immunization. In the UK, the national
government provides for all recommended vaccines to the
public at no cost. The national government is also responsiblefor disease surveillance and monitoring and encouraging
vaccination coverage.
In all countries, disease surveillance and surveillance of
immunization coverage are a national responsibility. Supranational institutions, such as the European Center for Disease
Prevention and Control (ECDC), strengthen surveillance within
the European Union through a network of laboratories. And
the EU also funds other networks that support the surveillance
activities of member states. The WHO’s European Regional
Office (EURO), in coordination with the ECDC, also conducts
surveillance for vaccine-preventable diseases and monitors
the performances of countries’ immunization coverage (SeeFigure 31).

Implementation of immunization in the Asia-PacificRegionThe Asia-Pacific region is very heterogeneous. Countries in
the region span all classes of economic development. As aresult, approaches to immunization are widely varied. Unlike
Europe, the region does not have a centralized regulatory
body to license vaccines. But the Japan Pharmaceuticals
and Medical Devices Agency (PMDA) and the Ministry of
Health, Labor, and Welfare is a signatory to the International
Conference on Harmonization (ICH) with the US and Europe.
This is intended to encourage the standardization of therequirements for vaccine licensing between the three regions.
The Asia-Pacific region does not have a regional vaccination
support program, such as the one administered by the PanAmerican Health Organization (PAHO) in Latin America. Most
countries in the region rely on national expert immunizationcommittees to recommend vaccines. Most countries thenprovide recommended vaccines at no cost through public
sector health outlets. However recommendations for vaccines
vary considerably between countries in the region. Ironically,some of the lowest-income countries in the region recommend
the greatest number of vaccines (See Figure 32)42.

Tsai TFand Xu ZY. Immunization in the Asia-Pacific region. pp 1525-1539. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier,
China, 2008.
42

VACCINE FACT BOOK 2012 | 41

Gross National income (GNI) / capita
Number of diseases prevented in national immunization programs
FIGURE 32. DISPARITY IN THE NUMBER OF DISEASES PREVENTED IN NATIONAL IMMUNIZATION PROGRAMS IN COUNTRIES WITH DIFFERENTLEVELS OF GROSS NATIONAL INCOME / CAPITA IN THE ASIA-PACIFIC REGION

42 | VACCINE FACT BOOK 2012

1 Basic Concept of Vaccination

1.8 National immunization recommendation systems

How are immunizations recommended?
Many countries have national immunization technical advisorygroups (NITAGs) to help governments determine which
vaccines should be used to achieve public health objectives43.
The nature and composition of these committees vary bycountry, but the purpose and function of these committees
is similar.
How immunizations are recommended in the US
In the US, the Advisory Committee on Immunization Practices(ACIP) is the only federal government recommending bodyfor vaccines44. It issues recommendations for vaccines thatare used by healthcare providers in both public and private
systems. Other institutions, such as the American Academyof Pediatrics Committee on Infectious Disease (COID, the“Red Book” committee) and the American Academy of
Family Physicians, collaborate to issue a single immunization
schedule in the US. A separate committee, the National
Vaccine Advisory Committee (NVAC), advises the US
government primarily on program policies and strategies (SeeFigure 33).

World Health Organization. Immunizations, Vaccines and Biologicals. National advisory committees on immunization.
http://www.who.int/immunization/sage/national_advisory_committees/en/index.html
44
US Centers for Disease Control and Prevention. Vaccines & Immunizations. Recommendations and Guidelines: Advisory Committee on Immunization Practices(ACIP). About ACIP. http://www.cdc.gov/vaccines/recs/acip/#about
43

VACCINE FACT BOOK 2012 | 43

FIGURE 33. ORGANIZATION AND RECOMMENDATION PROCESS OF THE US ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP) AND ITS PARTNERS

44 | VACCINE FACT BOOK 2012

1 Basic Concept of Vaccination

The 15 ACIP members are appointed by the Secretary of
HHS for a term of two years, to provide advice to HHS andthe US CDC. They come from a broad array of institutions
across the country including academia, hospitals, publichealth and government institutions. In addition to committee
membership, the ACIP has a broad array of ex officio andliaison members representing a complete national spectrumof interests in immunization (See Figure 34 and Figure 35).

FIGURE 34. BROAD ARRAY OF REPRESENTATION IN THE ADVISORYCOMMITTEE ON IMMUNIZATION PRACTICES (ACIP)

Once ACIP’s recommendations have been accepted by HSS
and CDC, recommended vaccines are funded by the Vaccines
for Children Program (VFC). Children under 18 years of age
who qualify for Medicaid, or do not have health insurance, orwhose health insurance policies do not provide for vaccines,
or who are Native Americans receive vaccines at no costthrough the VFC.

“
Under the Affordable
Healthcare Act,
health insurers must
now provide ACIP
recommended
vaccines at no outof-pocket expense
to the policy holder,
and insurers cannot
charge premiums
for vaccines.
	  Likewise, under the Affordable Healthcare Act, health insurers
must now provide ACIP recommended vaccines at no outof-pocket expense to the policy holder, and insurers cannot
charge premiums for vaccines.

VACCINE FACT BOOK 2012 | 45

FIGURE 35. AFFILIATIONS OF MEMBERS OF THE US ACIP IN 2011 SHOWING REPRESENTATION FROM A WIDE DIVERSITY OF INSTITUTIONSAND ORGANIZATIONS

46 | VACCINE FACT BOOK 2012	  

1 Basic Concept of Vaccination

How Australia recommends immunizations
The Australian Technical Advisory Group on Immunization(ATAGI) is the national immunization technical advisory groupfor Australia45. ATAGI performs several functions:•provides technical advice to the Minister for Health andAgeing on the administration of vaccines in Australia;•

advises the Pharmaceutical Benefits Advisory Committee(PBAC) on the effectiveness and use of existing, new andemerging vaccines; and,•produces the Australian Immunisation Handbook(approved by the National Health and Medical ResearchCouncil)46 (See Figure 36).

In addition to providing the Minister of Health and Ageingwith recommendations for vaccines, ATAGI produces theAustralian Immunization Handbook. This provides clinicalguidelines for health professionals on the safest and mosteffective use of vaccines in their practice. It is produced inconsultation with the National Immunization Committee (NIC),
with the Communicable Diseases Network Australia (CDNA),
the Australian Drug Evaluation Committee (ADEC), and theAdverse Drug Reactions Advisory Committee (ADRAC).
Like the US ACIP, membership in ATAGI includes a broad arrayof stakeholders. In addition to the public health and infectious
diseases experts on the committee, the committee includes
membership from consumer groups, general practitioners,
and nursing representatives47. Member affiliations are shownin Figure 37.

FIGURE 36. FUNCTIONS OF THE AUSTRALIAN TECHNICAL ADVISORYGROUP ON IMMUNIZATION (ATAGI)As part of the process of providing advice to the Minister,
ATAGI submits evidence to the PBAC. The PBAC conducts aneconomic assessment of vaccines being considered. Oncethe assessment has been made, the recommendations of
ATAGI are then forwarded to the Minister for Health and Ageing. The final decision to adopt a new vaccine rests with the
Minister. If funding of more than AUS$ 10 million is required,the decision goes to the government’s cabinet.

Australian Government. Department of Health and Ageing. Immunisation Advisory Bodies. Australian Technical Advisory Group on Immunisation (ATAGI).
http://www.health.gov.au/internet/immunise/publishing.nsf/content/advisory-bodies
46
Australian Government. Department of Health and Ageing. The Australian Immunisation Handbook 9th Edition 2008.
http://www.health.gov.au/internet/immunise/publishing.nsf/Content/Handbook-home47
Australian Government. Department of Health and Ageing. Immunisation advisers appointed.
http://www.health.gov.au/internet/ministers/publishing.nsf/Content/health-mediarel-yr2005-ta-abb128.htm?OpenDocument&yr=2005&mth=10
45

VACCINE FACT BOOK 2012 | 47

FIGURE 37. AFFILIATIONS OF MEMBERS OF THE AUSTRALIAN TECHNICAL ADVISORY GROUP ON IMMUNISATION (ATAGI)

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1 Basic Concept of Vaccination

How countries, other than Australia and the US,
recommend immunizations
Most other countries have similar approaches to that of the
US for recommending immunization. In Germany and theUK, for instance, recommendations on vaccine use are madeby a national committee of experts (STIKO and the Joint
Committee on Vaccines and Immunization (JCVI), respectively)(See Table 13). These committees provide advice to theministry of health. In some countries, the recommendationsof the national advisory committee may be adapted at the
local level. In other countries, national advisory committees
recommend vaccines but local health authorities determine
which specific products they wish to utilize.

Country

National Immunization TechnicalAdvisory Group (NITAG)

AcronymAustralia

Australian Technical Advisory Groupon Immunization

ATAGI

Austria

Impfausschuss des OSR

CanadaNational Advisory Committee on
Immunization

NACI

FranceComite technique de vaccin

CTV

Germany

Ständige Impfkommission

STIKO

Hong Kong

Scientific Committee on
Vaccine Preventable Diseases

Indonesia

Immunization Committee of theIndonesian Pediatric Society

IrelandNational Immunization Advisory
Committee

Netherlands

Gezondheidsraad-Commissie RVPSingapore

Expert Committee on Immunization

ECI

Switzerland

Eidgenössischen Kommission fürImpffragen

EKIF

TaiwanAdvisory Committee on
Immunization Practices

ACIP

UK

Joint Committee on Vaccination
and Immunisation

JCVI

US

Advisory Committee on
Immunization Practices

ACIP

TABLE 13. SAMPLE LIST OF SOME NATIONAL IMMUNIZATION TECHNICALADVISORY GROUPS (NITAGS)In the Asia-Pacific region, many countries have expert
immunization committees: the Taiwan Advisory Committee
on Immunization Practices (ACIP), the Singapore Expert
Committee on Immunization (ECI), the Hong Kong ScientificCommittee on Vaccine Preventable Diseases. Other countries
may rely on Pediatric Societies or other academic-typebodies to act as the recommending body to governments.
These bodies may also recommend additional or optional
vaccines not included in a basic national schedule. Thai
recommendations include additional and optional vaccines in
addition to the basic pediatric schedule.
Countries that do not have a national advisory committeeof experts, or that are not advised by national medical
associations, typically follow WHO recommendations for an
Expanded Program on Immunization (EPI) schedule.
A sample list of national immunization technical advisorygroups (NITAGs) is shown in Table 1348.
How supra-national organizations recommend
immunizations
The WHO provides leadership on global health mattersfor the members of the United Nations. This includes
articulating evidence-based policies for health. In 1999,
the WHO established the Strategic Advisory Group ofExperts (SAGE) to provide guidance on immunization to thedepartment of Immunization, Vaccines and Biologicals (IVB).
The SAGE advises the IVB on policies and strategies for all
immunizations49.
For countries that do not have their own national immunization
technical advisory groups (NITAGs), the recommendations of
the SAGE often guide their policies and practices.
Like the US ACIP, the SAGE is composed of 15 members
who are experts in epidemiology, public health, vaccinology,
pediatrics, internal medicine, infectious diseases, immunology, drug regulation, programme management, immunization delivery, health-care administration, health economics,
and vaccine safety. And like the ACIP, the SAGE has affiliate
members who participate as observers (e.g. Unicef, GAVI,
WHO regional offices, vaccine companies). Affiliations ofmembers are shown in Figure 38.

World Health Organization. Immunizations, Vaccines and Biologicals.National Advisory Committees.
http://www.who.int/immunization/sage/national_advisory_committees/en/index1.html
49
World Health Organization. Strategic Advisory Group of Experts – Terms of Reference. March 29, 2011.
http://www.who.int/immunization/sage/SAGE_TOR_part_1_Annex_3_29_Mar_2011.pdf
48

VACCINE FACT BOOK 2012 | 49

The SAGE meets twice annually to review immunization
progress and policy issues and formulate recommendations
for the Director-General of the WHO, which are published in

the Weekly Epidemiological Record (WER, www.who.intwer).
For specific issues, the SAGE may constitute time-limited
working groups.

Areas of Expertise

Member Affiliations

Observers

Areas of Expertise

University of the
Witwatersrand

UNICEF

Public Health

Wake Forest University

GAVI Alliance

Vaccinology

International Clinical
Epidemiology Network

WHO Regional Offices

Pediatrics

Damascus University

WHO Regional TechnicalAdvisory Groups

Internal Medicine

Aga Khan University

NGOs

Infectious Diseases

University of Newcastle

International Professional
Organizations

Immunology

National Institute for Healthand Welfare, FinlandTechnical Agencies

Drug Relation

University of theWest Indies

Donor Organizations

Program Management

Chinese Center for Disease
Control and Prevention

Associations of manufacturersof vaccines andimmunzation technologies

Immunization Delivery

Center for Infections, UK

Vaccine companies

Healthcare Administration

University of Hong Kong

Other Experts

Health Economics

University of California,
Berkeley

Vaccine Safety

University Hospitalsof Geneva
Ministry of Public Health,ThailandRedeemer’s University
FIGURE 38. AFFILIATIONS OF CURRENT MEMBERS OF WORLD HEALTH ORGANIZATION’S STRATEGIC ADVISORY GROUP OF EXPERTS (SAGE)50

World Health Organization. Immunizations, Vaccines and Biologicals. Current SAGE members. http://www.who.int/immunization/sage/members/en/index.html

50

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1 Basic Concept of Vaccination

The WHO issues position papers on the use of vaccines on thebasis of the SAGE recommendations51. However, unlike ACIP,
the recommendations of the SAGE have no legal bearing on
the UN member states and do not result in appropriations offunding for vaccines. As such, in drafting its recommendations,
the SAGE often accounts for the difference in wealth between
nations and formulates its recommendations on the basisof greatest priority so that the lowest-income countries canapply their scarce resources to the areas of greatest publichealth need.
The WHO position papers on the use of vaccines can be found
at: http://www.who.int/immunization/position_papers/en/“
In drafting its
recommendations,
the SAGE often
accounts for thedifference in wealthbetween nations
and formulates its
recommendations
on the basis ofgreatest priority sothat the lowestincome countries
can apply theirscarce resources tothe areas of greatest
public health need.

World Health Organization. Immunization, Vaccines and Biologicals. WHO vaccine position papers. http://www.who.int/immunization/position_papers/en/

51

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