VACCINEFACT BOOK

2012

Preface“Prevention is better than cure” is a proverb in many other languages as well. This idea iscentral to the development of vaccines, which have transformed human health since the time of
Edward Jenner in the late 18th Century. Smallpox has been eradicated, polio largely controlled
and measles and rubella have been targeted for elimination. Bacterial meningitis is becomingrare in countries that vaccinate their children. Acquisition of hepatitis B at birth can now be
prevented. All of this and more has been accomplished by the development and deploymentof vaccines. Most of these advances occurred in the last 50 years.
More and more vaccines are being developed and brought into use. Japanese scientists
have contributed to the recent creation of powerful vaccines, notably against pertussis andchickenpox. These two vaccines are used throughout the world. It is, therefore, fitting thatJapan also takes advantage of other new vaccines such as rotavirus, pneumococcal conjugatesand human papillomavirus, which can, respectively, prevent infantile diarrhea and dehydration,
invasive infections and pneumonia, and various forms of cancer, particularly cancer of the cervix
in women. Japanese children and adults should share in the benefits of vaccination. Moreover,
governments have a reason to promote vaccination: better health of a general population
lowers medical costs and is associated with broad economic benefits. Therefore, the vaccine
industry has been growing in importance and in many countries, including Japan, governments
consider vaccine production as a precious resource, for example, to control epidemics of new
types of influenza and other emerging infections.
New techniques and strategies of vaccine development are being constantly discovered and
it is likely there will be more diseases that can be prevented. It will be challenging to educate
physicians and the public about vaccines and to find the best ways to implement vaccination.
Nevertheless, industrialized and poor countries will want their populations to have access topreventive measures that make life better and safer.
This book seeks to explain to non-specialists what vaccines do, how they are developed,
how they are given, and what results have been obtained when they are routinely used. It isa dramatic and impressive story, but unfortunately not well understood by the general public.
However, once people understand it is likely that they will demand that vaccines be madeavailable to them in sufficient quantity and at an affordable price.
I know that my dear student and friend, the late Hitoshi Kamiya, would have agreed with me.
Hitoshi studied in my laboratory at Philadelphia Children’s Hospital in 1981. After his returnto Japan, we kept in touch and I had the opportunity to visit him many times. I watched him
become the chief exponent of vaccines in Japan through his knowledge and the force of his
personality. Hitoshi Kamiya’s untimely death was a tragedy and I miss him very much. I would
like to dedicate this book to his memory because he was a remarkable person and did muchgood for his country.

Stanley A Plotkin, MD
Emeritus Professor of Pediatrics
University of Pennsylvania

VACCINE FACT BOOK 2012 | 1

Contents

1
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8

Basic Concept of Vaccination
Definition of Vaccines....................................................................................................... 4
Survey of Vaccine Preventable Diseases ....................................................................... 12
Vaccine Efficacy and Safety........................................................................................... 18
Vaccine Safety Surveillance and Evaluation .................................................................. 25
Vaccine Injury Compensation Systems ......................................................................... 29
Cost-Effectiveness Analyses and Evaluation................................................................. 36
Vaccine Implementation Options ................................................................................... 40
National Immunization Recommendation Systems ....................................................... 43

2
2.1
2.2
2.2.1
2.3
2.3.1
2.4
2.5
2.5.1
2.5.2
2.5.3

Vaccine Development and Implementation
The Global Vaccine Market ............................................................................................ 53
Vaccine Development .................................................................................................... 54
Clinical Development ..................................................................................................... 55
Vaccine Manufacturing .................................................................................................. 57
Cost Trends in Vaccine Development and Manufacturing ............................................. 59
Vaccine Registration and Approval ................................................................................ 60
Vaccine Funding ............................................................................................................ 65
US Advisory Committee on Immunization Practices (ACIP) .......................................... 65
Australia ......................................................................................................................... 67
Other .............................................................................................................................. 68

3
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9

Public Health Effectiveness of Vaccine Implementation
Polio Eradication, Global ............................................................................................... 70
Haemophilus Influenzae Type B (Hib) ............................................................................ 73
Mumps ........................................................................................................................... 75
Measles Eradication, Global .......................................................................................... 76
Rotavirus ........................................................................................................................ 78
Human Papillomavirus (HPV) ......................................................................................... 82
Pneumococcal Disease ................................................................................................. 88
Varicella Zoster Virus (VZV) ............................................................................................ 92
Hepatitis B ..................................................................................................................... 94

4
4.1
4.2
4.3
4.4
4.5
4.5.1

Vaccines in Use
Globally .......................................................................................................................... 96
US .................................................................................................................................. 97
European Union ........................................................................................................... 100
Australia ....................................................................................................................... 101
Japan ........................................................................................................................... 102
Current Situation in Japan ........................................................................................... 103

5

Vaccines in Development .......................................................................................... 104

2 | VACCINE FACT BOOK 2012

VACCINE FACT BOOK 2012 | 3

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

30 | VACCINE FACT BOOK 2012

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

38 | VACCINE FACT BOOK 2012

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)

48 | VACCINE FACT BOOK 2012	  

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

50 | VACCINE FACT BOOK 2012

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

VACCINE FACT BOOK 2012 | 51

2 Vaccine development and implementation

Vaccine implementation varies between countries, but,
generally, those with similar levels of income have comparable
immunization systems. One exception is Japan. Japan has
a level of wealth similar to countries in Western Europe,
Australia and the US, but has an immunization program thatis considerably less progressive. Most industrialized countries
strongly value immunization as a cost-effective means toprevent disease and save on treatment costs, and as a means
to preserve economic development. Immunization is also
valued by some industrialized countries as an asset against
bioterrorism.
Like many other complex and capital-intensive industries, thevaccine industry in highly consolidated. The vaccine market
is dominated by a few large vaccine suppliers in industrializedcountries. The costs associated with developing new vaccinesrequire that vaccines be sold on the global market in order
to be able to recoup R&D investments. Furthermore, almost
all countries import at least some vaccines because not all
national suppliers produce every antigen available.
Vaccine research and development has largely been restricted
to the few vaccine-producing countries. More than two thirdsof new vaccines developed in the past 25 years have beendeveloped in the US52.

52 | VACCINE FACT BOOK 2012

2.1 The global vaccine market

The vaccine market represented about 3% of the pharmaceutical market, at about $28 billion in 201053. Five manufacturers (Merck & Co, GlaxoSmithKline, Sanofi Pasteur, Pfizer,
and Novartis) account for the majority of the market (79.4% in2010) (See Figure 39)54.

sales (See Figure 41)57 and the Global Alliance for Vaccines
and Immunization (GAVI Alliance) is expected to expend morethan $1 billion per year on vaccines.
New vaccines under development are projected to add to thegrowth of the current market.

Vaccine Market Share 2010	
  Other, 20.6 %GSK, 23.0 %Sanofi Pasteur
MSD, 4.2 %Merck, 12.0 %Sanofi Pasteur,
17.5%
Pfizer, 12.7 %	  FIGURE 39. THE DOMINANT SUPPLIERS INF THE GLOBAL VACCINE
MARKET 2010

FIGURE 40. PROJECTED GROWTH OF THE VACCINE MARKET BY ADULTAND PEDIATRIC SEGMENTS

The pediatric vaccine market accounted for about 52% of
the total vaccine market in 2009. Sales of influenza vaccines,
including H1N1 vaccine, were approximately $5 billion in
2010, accounting for about 18% of the vaccine market.
Growth in the market is expected to continue at around 10%compound annual growth rate (CAR) over the next five years.
The pediatric market is expected to grow slightly faster than
the adult vaccine market, at 11% versus 8.2% (See Figure40)55. By comparison, the pharmaceutical market grew by 4 –6% in 2010 and is expected to grow at 4 – 7% through 201356.
The growth in the vaccine market is driven by the sales ofrecently developed vaccines and by new vaccine markets.
Several vaccines now generate more than $1 billion in global

FIGURE 41. BRAND NAME VACCINES THAT GENERATED MORE THAN
$1 BILLION IN SALES IN 2010.

Douglas RG, Sadoff J, Samant V. The vaccine industry. pp 37. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
Knol. Global Vaccine market 2010. Top vaccine companies and blockbuster vaccines.
http://knol.google.com/k/krishan-maggon/global-vaccine-market-2010/3fy5eowy8suq3/152#
54
Hiller A. Vaccines continue to bolster pharma market. PharmPro. December 2, 2010.
http://www.pharmpro.com/articles/2010/12/busines-Vaccines-Continue-to-Bolster-Pharma-Market/
55
Hiller A. Vaccines continue to bolster pharma market. PharmPro. December 2, 2010.
http://www.pharmpro.com/articles/2010/12/busines-Vaccines-Continue-to-Bolster-Pharma-Market/
56
Pharmaceutical Drug Manufacturers. Pharmaceutical market trends 2010.
http://www.pharmaceutical-drug-manufacturers.com/articles/pharmaceutical-market-trends-2010.html
57Knol. Global Vaccine market 2010. Top vaccine companies and blockbuster vaccines.
http://knol.google.com/k/krishan-maggon/global-vaccine-market-2010/3fy5eowy8suq3/152#
52
53

VACCINE FACT BOOK 2012 | 53

2.2 Vaccine development

The development process for vaccines is unique. Vaccine
development is highly capital intensive and risky. Given theimportance of safety with biologics, the vaccine industry ishighly regulated. Vaccine development proceeds in an iterative
fashion. Less than one-tenth of vaccine candidates achievelicensure. The high failure rate is due to the unpredictability ofthe biological organisms needed to produce vaccines, and to
the uncertainty of how the human immune system will process
and react to the vaccine antigen. Some vaccine candidates
may produce appropriate levels of immune response, but
induce important adverse reactions. Other vaccine candidates
may be safe, but ineffective at preventing diseases. With thecurrent tendency to combine several antigens into a single
vaccine, the challenges associated with developing safe andeffective vaccines are even greater.

Process development is further divided into bulk manufacturing
and product finishing. Bulk manufacturing involves the cultureof live organisms, followed by separation and purification of
the desired antigen. Finishing involves the formulation witheither adjuvant and / or stabilizer and the filling of vials orsyringes.

Research to discover new vaccine antigens and novel
approaches to immunization usually takes several years, andcosts tens of millions of dollars. Once a discovery is made,several developments must be undertaken to reach thelicensing stage. Those developments include (See Figure 42):

The development of each of these processes is very lengthy,requiring on average 10–15 years. The total development
costs can reach close to $US1 billion (See Figure 43)58.

Clinical development, as described earlier, involves theiterative process of testing a vaccine candidate in a
progressively larger number of human subjects.
Assay development is required because the vaccine candidate
will be novel and will, therefore, require specific tests to
identify it and characterize the product to the satisfaction of
the regulators.

process development, to produce an economically viablevaccine, consistently, in a manner that satisfies regulators;
and,clinical development, to demonstrate the safety and measure
the protective effect of the vaccine in humans;
assay development, to develop the appropriate tests toascertain the purity, potency and stability of the vaccine underdevelopment.

FIGURE 42. DIFFERENT TYPES OF DEVELOPMENT NECESSARY TO REACH THE VACCINE LICENSING STAGE

54 | VACCINE FACT BOOK 2012	  

2 Vaccine development and implementation

Discovery
several years

Phase I Safety≤ 100
subjects< 1 yearPhase II
Safety / Dose
Ranging
severalhundredsubjects
1 - 3 years

Phase III
Large Scale
Safety /Efficacy
thousands ofsubjects
3 - 5 years

LicenseSubmission
Preparation< 1 year

Licensure

FIGURE 43. VACCINE DEVELOPMENT PROCESS OVER A PERIOD OF UP TO 15 YEARS AT A COST OF UP TO$1 BILLION

2.2.1 Clinical development

After being thoroughly tested in an animal model, vaccine
candidates that are found to be safe and induce immunity
can advance to testing in humans. To license a vaccine,
three phases of clinical testing must be completed in healthy
subjects (See Figure 44)59:

Phase III – large-scale safety and efficacy trials involving thousands of subjects
and requiring 3–5 years
to complete.

Phase I – early safety and immunogenicity trials that involve≤100 subjects and can be completed in under one year;
Phase II – safety, dose ranging, and immunogenicity trials
that involve several hundred subjects and that take 1–3 years
to complete ; and,Image 3. Vaccine manufacturing
in an aseptic environment	
  FIGURE 44. THE FOUR PHASES OF CLINICAL DEVELOPMENT OF VACCINES

Bentley W. Research and the University of Maryland. Center for Bioprocess Innovation.
http://www.umresearch.umd.edu/VPRPubfiles/Center%20for%20Bioprocess%20Innovation%201.29.08.pdf
59
Douglas RG, Sadoff J, Samant V. The vaccine industry. pp 37. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
58

VACCINE FACT BOOK 2012 | 55

“Clinical testing
costs hundreds ofmillions of dollars
to complete. In thefirst three phasesof clinical testing
regulators may
require data from90,000 subjects ormore to affirm safety
and efficacy.

These phases proceed in a stepwise fashion. Only vaccine
candidates that are determined to be safe and capable ofinducing an immune response advance to the next phase(See Figure 15 - Section 1.4). Vaccines under development
are compared to a placebo control group to ensure that theirobserved effectiveness and safety are not random.
A regulator may also require further clinical testing after
a vaccine license has been granted. Clinical studies after
licensure are Phase IV post-marketing studies. These typicallyassess safety and or efficacy in very large populations.
Because of their size, these studies may detect very rare
vaccine-associated events that may have gone undetectedin Phase III testing.
Clinical testing costs hundreds of millions of dollars tocomplete. In the first three phases of clinical testing, regulators
may require data from 90,000 subjects or more to affirm safety
and efficacy60. These subjects may be recruited from multiple
trial centers on all continents.
All clinical data collected from clinical testing must be
thoroughly analyzed and submitted to regulators for theirreview.

GlaxoSmithKline. European Medicines Agency maintains position on the continued use of Rotarix™ (rotavirus vaccine). Media Center, May 21, 2010.
http://www.gsk.com/media/pressreleases/2010/2010_pressrelease_10048.htm
60

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2 Vaccine development and implementation

2.3 Vaccine manufacturing

The manufacture of vaccines is achieved from the
propagation of living organisms. Some of these may be
dangerous human pathogens. Therefore, the manufacture of
vaccines is conducted in a highly regulated and controlledenvironment. All vaccine manufacturers are subject tonational and international regulatory control and mustcomply with specifications for Good Manufacturing Practices(GMP). These requirements vary between countries, but thefundamentals are common:

Propagation entails the multiplication (or amplification) of theliving organism used in the vaccine;•ensure that products are safe for use in humans; and,•ensure that the identity, strength, quality and purity of
products consistently meet regulatory specifications.

Formulation involves the mixing of the purified productin solutions to obtain a desired concentration. It may also
include the addition of preservatives to some vaccines, toensure the sterility of the product over a longer period of time,or to prevent cross-contamination during dose extraction
from vials.

Manufacturing is conducted in an aseptic environment andclosely monitored by quality control measures. Vaccines also
require a strict cold chain to maintain their stability. Under
most circumstances vaccines are shipped and stored underrefrigeration.

Isolation entails the separation of the living organism from thecells or growth media used in the propagation step;
Purification removes all materials that may be adhering to
the isolated organisms, or selectively separates the portion of
the living organism to be used in the vaccine;At the end of the manufacturing process, vaccines are
typically filled in vials or syringes and packaged for shipping
to healthcare providers. (See Figure 46).

The actual production processes vary somewhat for different
types of vaccines. Some components of the manufacturing
process are specific to either viral or bacterial vaccine
production. In all cases, biologicals are inherently variable.
Manufacturers must, therefore, carefully characterize andstore the master seed viruses or bacteria used to start eachproduction run. This helps to ensure the consistency of theend product.
In general, the production of vaccines entails four basic steps(See Figure 45):

FIGURE 45. THE FOUR STEPS IN THE PRODUCTION OF VACCINES	  VACCINE FACT BOOK 2012 | 57

	
  
	
  

2	
  

ISOLATION	  SOLUTIONS	
  

1	
  

FORMULATION	
  PROPAGATION	
  

4	
  

3	
  
FILLING	  

PURIFICATION	
  FIGURE 46. PROCESSES INVOLVED AT EACH OF THE FOUR STEPS OF VACCINE MANUFACTURING

VIRAL VACCINES – Because viruses only grow within living
cells, viruses for vaccines are propagated in cells (e.g. inchicken eggs) or in continuous cell lines (e.g. Vero cells). Oncethe virus has been propagated, it must then be isolated fromthe cells and the cell-culture medium. This may be achievedby several techniques including chemical lyses of the cell,
centrifugation and filtration, or homogenization.
The next step, purifying the virus, may likewise involve multiple
techniques of centrifugation, ultra-filtration, chromatography,
or chemical purification. At this stage, viruses may also bechemically inactivated for killed vaccine preparations.
Then the viral preparation is formulated by mixing it with theconstituents that allow each dose to be safely delivered in theright concentration. This is the point where the product may
also be combined with other antigens (e.g. measles–mumpsrubella vaccine). The formulated product is filled in vials orsyringes. Some vaccines are freeze-dried (lyophilized) at thisstage, to prolong their shelf-life.

58 | VACCINE FACT BOOK 2012

BACTERIAL VACCINES – Bacteria do not require living cells
to propagate and are instead grown in bioreactors containing
specific culture media. After propagation, isolation may
be conducted by centrifugation or specific polysaccharide
extraction techniques. Purification is specific to the antigen,but may include chemical precipitation or fractionation, or
ultra-filtration and chromatography steps. At this stage,
carrier proteins may be conjugated to some polysaccharide
vaccines and the conjugate vaccine is then purified by various
filtration or chromatography techniques. The purified products
are then formulated and at this stage may be combinedwith several other antigens. Some polysaccharide vaccines
contain several types of polysaccharide (e.g. pneumococcal
polysaccharide vaccine contains 23 different types ofpolysaccharide), and some bacterial vaccines are combinedwith other bacterial and / or viral antigens (e.g. diphtheriatetanus-pertussis-Haemophilus influenzae type b-Hepatitis B
or DTP-Hib-HepB).

2 Vaccine development and implementation

2.3.1 Cost trends in vaccine development and manufacturing

Vaccine manufacturing has	
  evolved dramatically overthe last half century (SeeImage 4, Image 5, Image
6)61. New techniques forthe manufacture and testing of vaccines have transformed the manufacturing
environment. New vaccines,
like multivalent conjugate
vaccines, are considerably
more complex to manufacImage 4. Vaccine manufacturing in
the 1950s
ture than traditional inactivated whole-cell ones. The
increased sophistication of
the manufacturing process means that the cost of manufacturing has significantly increased in the last few decades.
In addition, the regulatory environment has evolved to a point
where as many as 500 quality control tests may be conductedin the manufacture of a single vaccine62.

Vaccine manufacture ishighly capital intensive.
A manufacturing facility
alone will cost up to €500
million (about ¥52.6 billion at September 2011)63.
As manufacturing costs arelargely fixed, large manufacturers may produce vaccines in massive amounts(e.g. hundreds of millions ofdoses every year) to achieve
economies of scale in production.

	  Image 5. Vaccine manufacturing in
the 1970s

But scaling vaccine production requires a significant
investment in time. Even for relatively simple processes, suchas vaccine packaging, up to two years may be required to
install and validate new packaging machinery. Building a new
manufacturing facility takes on average five years to complete
and validate with regulatory authorities (See Figure 47).

	  Image 6. Vaccine manufacturing in the 2000s

Rutty CJ, Barreto L, Van Exan R, Gilchrist S. Conquering the Crippler, Canada and the Eradication of Polio. Can J Pub Health 2005; 96 (2) : 12-24.
GlaxoSmithKline. Global Vaccines Public Policy Issues. Addressing developing world production – technology transfer. December 2009.
http://www.gsk.com/policies/Technology-Transfer-Vaccines.pdf
63
Pharmaceutical Networking. GlaxoSmithKline – New vaccine manufacturing plant – St-Amand-les-Eaux, France. 2010.
http://www.pharmaceutical-networking.com/glaxosmithkline-new-vaccine-manufacturing-plant-st-amand-les-eaux-france/
61
62

VACCINE FACT BOOK 2012 | 59

FIGURE 47. TYPICAL TIMELINES TO INSTALL AND VALIDATE NEW INDUSTRIAL CAPACITY FOR DECISIONS MADE IN 2011	  2.4 Vaccine registration and approval

Because of their biological nature and that they are largely
administered to healthy individuals, the entire vaccine
development and manufacturing process is regulated. Before
vaccines are licensed, the three successive phases of clinicaldevelopment must be approved by a national regulatory
authority and may only proceed from one phase to the next
upon approval of the national regulator. When a Phase III
trial has been completed, the manufacturer must apply fora license to sell the vaccine. The license application review
is so thorough and complete that it takes between one andtwo years to complete (See Figure 48). The regulator has
the authority to refuse or withdraw a product license if the
manufacturer is not compliant with current regulations.
After vaccines are licensed, manufacturing is strictly controlled
by regulators who test and have authority over the release ofeach production batch of vaccine. Regulators test for:••safety;identity;

60 | VACCINE FACT BOOK 2012•••

purity;potency; and,sterility.

Regulators also monitor the consistency of product from one
production batch to the next (See Figure 49). Inactivation
and attenuation are also checked to ensure that the productdoes not expose to risk. Regulators will subject the productto multiple tests, with redundant checks, to ensure that thetesting itself is yielding correct results.
General safety testing is performed by injection of the finalcontainer product in the abdomen (intraperitoneal) of mice orguinea pigs.
Identity testing is specific to the nature of the vaccine, but
can include neutralization of a live-attenuated viral vaccinewith an antiserum.
Purity testing must demonstrate that the vaccine is free of2 Vaccine development and implementation	  FIGURE 48. REGULATORY PROCESS FOR VACCINES UNDER DEVELOPMENT

Sterility
Testing

FIGURE 49. REGULATORY TESTING OF LICENSED VACCINES

extraneous materials, including moisture and pyrogenic
substances. The products used in the manufacture of thevaccine must also meet standards of purity.
Potency testing involves demonstrating that the vaccine
confers protective immunity. The tests are specific to thevaccines being tested, but often involve virulent challenge inan animal model, or virus titration, or other quantification of anantigen. It is also necessary to demonstrate that the potencyof the individual components of a combination vaccine arepreserved when combined (because some antigens can
reduce the immune response to others).

	
  Sterility is tested on both bulk and finished vaccines.
Regulators require viral seeds and cell substrates used in
vaccine production to be tested to ensure that they do not
introduce contaminants. Cell substrates are well characterized
to ensure that they are as safe as possible.
Regulators also regularly inspect manufacturing facilities
to ensure compliance with current Good Manufacturing
Processes (GMPs). GMPs are a set of guidelines that ensure
consistency in quality of production.

VACCINE FACT BOOK 2012 | 61

Regulators control the labels on final containers andaccompanying product inserts. Labeling and package inserts
must be supported by scientific data and the regulator reviews
the language to ensure that it is not misleading, or false. Anychanges will usually require the regulator’s approval first.
Regulators may also regulate the advertising of products andmonitor advertising for misleading claims. Claims for products
must be balanced with information about their safety.

Prior to licensure, vaccines are regulated by the Investigational
New Drug (IND) Regulations. The vaccine developer (sponsor)
must apply for permission to conduct a clinical study. The
application must include information about:In order to produce safe and efficacious vaccines and tocomply with regulations, vaccine manufacturers carry out
extensive quality assurance and quality testing during the
manufacture of vaccines. Up to 500 quality control tests
may be conducted in the manufacture of a single vaccine64.
Quality testing may account for as much as 70% of the time
to manufacture65.

•

How vaccines are regulated in the US•••

the composition of the investigational new product;
the source of the investigational new product;
the method of manufacture of the investigational new
product; and,the methods used to determine the safety, purity, andpotency of the investigational new product.

The sponsor must also provide a summary of all laboratory
and animal pre-clinical testing. A description of the proposed
clinical trial and the qualifications of the investigators are also
required (See Figure 51). The endpoints for vaccine licensure
include vaccine safety and efficacy, but safety must be
demonstrated at each phase of the study.

The US Biologics Control Act, enacted in 1902, noted that
testing the purity of a final product was insufficient to ensure
quality. It required that manufacturing facilities be inspected.
In 1944, the Public Health Services Act empowered the
US government to license both biologicals and biologicalmanufacturing facilities. It became illegal for biologicals to be
sold without a license.
Vaccines are regulated by the Food and Drug Administration’sCenter for Biologics Evaluation and Research (CBER).
Vaccine developers must apply to CBER for permission toboth develop and sell vaccines (See Figure 50).

FIGURE 50. PERMISSIONS THAT MUST BE SOUGHT FROM THE FDA’S CENTER FOR BIOLOGICS EVALUATION AND RESEARCH (CBER) FOR
THE DEVELOPMENT AND SALES OF VACCINES	
  GlaxoSmithKline. Global Vaccines Public Policy Issues. Addressing developing world production – technology transfer. December 2009.
http://www.gsk.com/policies/Technology-Transfer-Vaccines.pdf
65
Cutliffe N. 2010. Pathway to access: Manufacturing, supply, and procurement systems. In: Building on the legacy of vaccines in Canada: value, opportunities, andchallenges. BIOTECH Canada. http://www.biotech.ca/uploads/vic/vaccines_7_2010.pdf
64

62 | VACCINE FACT BOOK 2012

2 Vaccine development and implementation	  FIGURE 51. REQUIREMENTS FOR AN INVESTIGATIONAL NEW DRUG APPLICATION

When studies are near completion and show promise of safety
and efficacy, the sponsor may submit a Biologics License
Application (BLA) to the CBER Office of Vaccines Researchand Review (OVRR). The application must submit evidenceof compliance with standards for all of the requirements
shown in Table 14. In addition, the application must include
a description of:
•
•
•
•
•
•

the manufacturing process;data on stability;
product samples and lot test results;
samples labels, enclosures and containers;
address of locations of manufacture; and,an environmental assessment.

Evidence of Compliance

Required submissions

Organization and personnel

Manufacturing process

Buildings and facilities

Stability data

Equipment

Lot testing results

Control of components,
containers and closures

Product samples

Production and processcontrols

Sample labels

Packaging and labeling controls

Enclosures and containers

Holding and distribution

Environmental assessment of
manufacture

Laboratory controls
Records to be maintained
TABLE 14. REQUIREMENTS FOR A BIOLOGICS LICENSE APPLICATION(BLA) SUBMISSIONVACCINE FACT BOOK 2012 | 63

The BLA also includes a site inspection. This involves an indepth review of:
•
•
•
•
•
•

facilities;
records;
production processes;
equipment;
quality control methods; and,personnel.

Once a vaccine has been licensed, post-marketing regulation
requires manufacturers to submit test samples and test
results from each production lot. CBER must “release” orreject the lot based on the results submitted and/or its own
testing. Manufacturers are inspected at least every two years(every year for influenza vaccine producers, since there is a
new influenza formulation every year) for:•••process related issue (documentation of processes);quality related issues (reporting of out-of-specs, productrelease, training of personnel); and,facility and production related issues (heating, ventilation,
air conditioning).

See Figure 52.

Committee for Medicinal Products for Human Use (CHMP)
at the European Medicines Agency (EMA), may also regulate
vaccines.
In Europe, manufacturers can license vaccines either througha centralized procedure of the EMA, which allows for a single
market authorization within EU member states, or they canalternatively license through their national regulatory authority.
If they license through their national regulatory agency,
licenses will be limited to the country where the license wasissued.
Regulatory harmonization
Europe, the US and Japan, have sought to increase regulatory
harmonization between countries through the International
Conference on Harmonization (ICH) of drugs. Increasingly,
national regulatory agencies are exchanging information.
The EMA and US FDA, for instance, have confidentiality
agreements that allow for the exchange of information on legal
and regulatory issues, inspection reports, and post-marketingsurveillance. The US FDA also has similar confidentiality
agreements with the NRAs of Australia, Canada, France,
Germany, Israel, Japan, Mexico, New Zealand, Ireland,
Singapore, South Africa, Switzerland and the UK.

How vaccines are regulated in countries other thanthe US
Industrialized countries have similar regulatory agencies
to the US FDA’s CBER. But each country’s requirementsof vaccine manufacturers are slightly different. In addition,
supra-national regulators, such as the European Union’s
Processes

Quality

Facilities andProduction

Documentation ofprocesses

Reporting ofout-of-specs

Heating

Product release

Ventilation

Personnel training

Air-conditioning

FIGURE 52. AREAS INSPECTED BY THE CENTER FOR BIOLOGICS EVALUATION AND RESEARCH (CBER) AT VACCINE MANUFACTURING SITES

64 | VACCINE FACT BOOK 2012

2 Vaccine development and implementation

2.5 Vaccine funding

Routine immunization of children is considered one of themost cost-effective interventions in health. Governments
have a vested interest in immunization because, in addition
to protecting the individual, immunizations also protect
the community from disease. Therefore, all governments
recommend vaccines for public use as a cost-effective means
to reduce the occurrence of diseases and their associatedtreatment or management costs.

How governments select which vaccines to use is alsovariable from country to country. Usually, governments rely on
their National Technical Advisory Groups (NITAGs) to review
the balance of benefits and risks associated with available(or soon to be available) vaccines. Their recommendations
may be periodically reviewed and modified, if epidemiology
changes (e.g., the eradication of smallpox) or safety issues
arise.

Which vaccines a government recommends depend on
several factors. For example:

Many countries are also mandated by their national laws
to fund recommended vaccines, to ensure that the target
population has sufficient access to recommended vaccines.

•••

the epidemiology of a vaccine-preventable disease(i.e., how frequently it occurs, how many people it affects
when it does occur);the severity of a disease (i.e., whether it can be fatal); and,the public’s concern for the disease (e.g. meningitis).

2.5.1 US Advisory Committee on Immunization Practices (ACIP)

The goals of the Advisory Committee on Immunization
Practices (ACIP) are to provide advice that will reduce theincidence of disease and increase safe use of vaccines. The
committee members are appointed by the Secretary of Healthand Human Services (HHS) to provide guidance to HHS andthe CDC on the control of vaccine-preventable diseases. The
committee develops written recommendations on age ofvaccination, number of doses, and contraindications. HHS
and the CDC must endorse ACIP’s recommendations forthem to be enacted.
ACIP’s recommendations are the basis for the annual CDC“childhood and adolescent” and “adult” immunization
schedules. Vaccines recommended for routine administrationin children are covered by the Vaccines for Children program(VFC). The VFC covers children up to 18 years of age whoare eligible for Medicaid, uninsured, Native American, or
underinsured. These vaccines are provided to private sector
providers for vaccination of eligible children (about 45% ofbirth cohort) (See Figure 53). Historically, HHS and the CDC
have endorsed all ACIP recommendations.
In addition, the section 317 Federal Grant Program,appropriated annually by Congress, can be used to ensure
coverage of both children and adults who would otherwise
not have access to ACIP recommended vaccines, through the
public or private sectors.
In the US, most private insurers cover ACIP recommended
vaccines and about 55% of children have insurance coveragefor immunization. Under the Affordable Healthcare Act, healthinsurers must now provide ACIP recommended vaccines at
no out-of-pocket expense to the policyholder, and insurers
cannot charge premiums for vaccines.

VACCINE FACT BOOK 2012 | 65

US Congressappropriates
funds
HHS Endorses
ACIP
Recommendations
ACIP
Recommends
vaccines

FIGURE 53. FUNDING FOR THE VACCINES FOR CHILDREN (VFC) PROGRAM IN THE US“
The goals of theAdvisory Committee
on Immunization
Practices (ACIP) are
to provide advice
that will reduce theincidence of disease
and increase safeuse of vaccines.
66 | VACCINE FACT BOOK 2012

VFC purchases
vaccines for children
up to 18 eligible for
Medicaid, under- or
uninsured, or Native
American2 Vaccine development and implementation

2.5.2 Australia

The decision to adopt a vaccine into the national immunization
schedule includes advice from the Australian TechnicalAdvisory Group on Immunisation (ATAGI) and an economic
assessment of the candidate vaccine by the Pharmaceuticals
Benefits Advisory Committee (PBAC). A decision to adopt
a vaccine incurs an obligation to fund the new vaccine. The
decision is made by the Minister for Health and Ageing, or thegovernment’s cabinet, if funding of more than AUS$10 million
is required (See Figure 54).

adviseThe National Immunisation Committee, in turn, is responsible
for the implementation of the Immunise Australia Program.
The Immunise Australia Program provides vaccines at nocharge through the National Immunisation Program (NIP)
Schedule, which currently includes 16 vaccines66.
Funding is provided by the Australian government througha number of channels, including governments of States andTerritories for the NIP, Medicare (the universal health insurancein Australia), the subsidy of immunization provided throughprivate care, and to the Victorian Cytology Service for theadministration of HPV (See Figure 55).

Australian TechnicalAdvisory Group on
Immunisation (ATAGI)

Pharmaceutical Benefits
Advisory Committee(PBAC)

review submissions fromvaccine companies

implement

adviseconduct economic
assessments

recommend

National Immunisation
Programdecide andfund
Australian Minister for
Health and Ageing or
cabinet of government

FIGURE 54. DECISION-MAKING PROCESS FOR VACCINE FUNDING IN AUSTRALIA

Australian Government. Department of Health and Ageing. Immunise Australia Program. About the Program.
http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/about-the-program
66

VACCINE FACT BOOK 2012 | 67

MedicareState andTerritorial
Governments
for NIP

Victorian
Cytology
Service(HPV)

Australian
Gov’t
Funding

Subsidizationof Private Sector
Delivery

FIGURE 55. CHANNELS OF GOVERNMENT FUNDING FOR IMMUNIZATION IN AUSTRALIA	
  2.5.3 Other

Most industrialized countries have similar advisory groups(see Table 13, section 1.8) and formal funding processes for
immunization. In Europe, the source of funding varies between
countries. In Germany, the costs of immunization are covered
mostly by statutory insurance provided by employers. In other
European countries, such as the UK, the national government
provides for all recommended vaccines to the public at
no cost.
Most countries in the Asia-Pacific region rely on national
expert immunization committees to recommend vaccinesand most countries then provide recommended vaccines at
no cost through public sector health outlets.

68 | VACCINE FACT BOOK 2012

Many developing countries do not have functioning NITAGs
and may rely heavily on the WHO for immunization policy andon donor funding for immunization. A full review of NITAGs
is available in Vaccine at: http://www.sivacinitiative.org/
download/Vaccine_Supplement_NITAGs_19042010.pdf.

VACCINE FACT BOOK 2012 | 69

3.1 Polio eradication, global

The Cause67
Poliomyelitis is a paralyzing, sometimes fatal, viraldisease that dates backmore than 3000 years (SeeImage 7 and Image 8).
But the disease was notdescribed in medical literature until 1789. It remained
relatively uncommon until
the 19th century when small
outbreaks began occurring in Europe. By the endof the 19th century, polio
was occurring in epidemics in Europe and North
America. Karl Landsteinerand Eric Popper identified
the causative virus in 1908.
Their discovery paved theway for the development ofa vaccine.

Image 7. Egyptian stele portraying
priest with polio

HTTP://UPLOAD.WIKIMEDIA.ORG/WIKIPEDIA/	  SOURCE:COMMONS/5/5C/POLIO_EGYPTIAN_STELE.JPG	  tive vaccines were alreadyavailable and being widelyused, the World Health
Assembly (WHA), the decision-making body of theWHO, resolved to eradicate
polio from the planet by theyear 2000. At that time, polio had already been virtually eliminated from North
America, Western Europe
and Japan. The goal has
not been achieved, but the
number of cases of polio
is at an all-time low and intense efforts are underway
to achieve the goal as soon
as possible.

Image 9. Bust of Jonas Salk	  The Vaccine

In 1931, Jean Mcnamara
and Frank Burnet discovered that polio was causedby more than one strain of
Image 8. Bilateral polio of the legs
the virus and by 1951 it was
SOURCE: HTTP://WWW.POLIOERADICATION.ORG/
POLIOANDPREVENTION.ASPX
understood that there were
3 types of polio virus: types
1, 2, and 3. This was critical for the development of a protective vaccine. In 1949, John Enders, Thomas Weller andFrederick Robbins won a Nobel Prize for demonstrating how
a virus could be cultured in order to produce a vaccine.

The first polio vaccine wasdeveloped by Jonas Salk
(See Image 9), in 1955.
His vaccine was produced
from inactivated virus. A
live-attenuated oral polio
vaccine was later developed
Image 10. Albert Sabin
by Albert Sabin (See Image
SOURCE: HTTP://UPLOAD.WIKIMEDIA.ORG/WIKIPEDIA/COMMONS/B/B9/ALBERT_SABIN.JPG
10) in 1963. Both vaccines	  were trivalent vaccines
incorporating all three types. The development of safe andeffective vaccines allowed for mass immunization on anational scale. Vaccines made the goal of polio eradication
possible, given that polio is strictly a disease of humans,transmitted directly from one person to another.

The disease is spread by the oral-fecal route (See Figure 56).
The Impact of the Disease
Prior to a vaccine, the US
experienced an average of
20,000 cases of polio annually. By 1988, an estimated 350,000 cases were
occurring annually in 127
countries. Because effec-

70 | VACCINE FACT BOOK 2012	
   FIGURE 56. POLIOVIRUS
REPLICATES IN THE GUT
AND IS TRANSMITTED BY
THE ORAL-FECAL ROUTE

Both vaccines are still in use today. The inactivated vaccine
is widely used in industrialized countries. The live-attenuatedvaccine is primarily used in developing countries.
The impact of the Vaccine
The introduction of a vaccine in 1955 had an almost immediate
effect. Cases of indigenous polio began disappearing
altogether within a few years. Sweden introduced a vaccine
in 1957 and by 1962 had stopped wild polio transmission.

3 Public health effectiveness of vaccine implementation

Iceland introduced a vaccine in 1956 and by 1960 had no
more wild polio. Likewise, in the US, the incidence of polio
fell by 95% between the introduction of a vaccine in 1955
and 1961, in spite of incomplete vaccination coverage (SeeFigure 57)69.

inactivated vaccine

total

1992

1990

1988

1986

1982

1984

1980

1978

1976

1972

1974

1970

1968

1966

1962

1964

1960

1958

1956

1952

1950

1954

1948

oral vaccine

1946

70,00060,00050,00040,00030,00020,00010,0000

1944

Number of Cases

Reported Cases of Polio in the
United States Before and After
Vaccine Introduction

paralytic	
  FIGURE 57. IMPACT OF IMMUNIZATION ON CASES OF POLIO IN THE US

By 1994, 2000, and 2002 wild polio transmission was certified
eliminated in all of the Americas, the Western Pacific, andEurope, respectively70. In 2010 polio was endemic in only four
countries: Afghanistan, India, Nigeria and Pakistan71. Wild
polio type 2 virus has been eradicated, but vaccine-derived
type 2 virus has recently spread in Nigeria. Wild type 1 and3 polioviruses continue to be transmitted in endemic andneighboring countries. By mid-2011, the number of cases
reported globally was approximately 30072 (See Figure 58,
Figure 59, Figure 60). Countries reporting cases in 2011 areshown in Figure 60 and Figure 6173.
Stopping immunization after the spread of polio has beeninterrupted exposes countries to risk. Live-attenuatedvaccine viruses can survive in the environment for a periodof time, and they can spread from human to human. Under
these conditions, live-attenuated vaccine viruses can revert
to their wild form. After immunization ceases, a reverted liveattenuated poliovirus could accidentally be reintroduced into
a population. As a consequence, even after polio has been
globally eradicated, many countries will opt to continue toimmunize indefinitely with an inactivated vaccine.

The economic impact of polio immunization - In theabsence of polio control, the cost of treating polio cases,in the US alone, has been estimated to approach $1
billion annually74. Globally, polio eradication is estimatedto have incremental net benefits of $40–50 billion between
1988 and 203575.

“
Prior to a vaccine,the US experienced
an average of
20,000 cases ofpolio annually. By
1988, an estimated350,000 cases
were occurring
annually in
127 countries.

Sutter RW, Kew OM, Cochi SL. Polio vaccine-live. pp 632. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
Plotkin SA, Vidor E. Polio vaccine-inactivated. pp 620-623. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
69
US Centers for Disease Control and Prevention. MMWR Summary of notifiable diseases, United States, 1993.
http://www.cdc.gov/mmwr/preview/mmwrhtml/00035381.htm
70
Global Polio Eradication. History of Polio. http://www.polioeradication.org/Polioandprevention/Historyofpolio.aspx
71
Global Polio Eradication. Infected countries. http://www.polioeradication.org/Infectedcountries.aspx
72
Global Polio Eradication. Data and monitoring. http://www.polioeradication.org/Dataandmonitoring.aspx
73
Global Polio Eradication. Data and monitoring. Polio this week. http://www.polioeradication.org/Dataandmonitoring/Poliothisweek.aspx
74
Sutter RW, Kew OM, Cochi SL. Polio vaccine-live. pp 643. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
75
Duintjer Debbens RJ, Pallansch MA, Cochi SL, et al. Economic analysis of the global polio eradication initiative. Vaccine 2010; 29: 334-343.
67
68

VACCINE FACT BOOK 2012 | 71

Polio-endemic country
Country in polio-endemic region
No data

Data is projected to 2008 WHO legal template

58. IN 1988, 125 COUNTRIES HAD RECURRING (ENDEMIC) POLIO DISEASE (COUNTRIES IN RED),	  	
  FIGURE
BEFORE AN ACCELERATED IMMUNIZATION ERADICATION PROGRAM BEGAN
Polio-endemic country
Country in polio-endemic region
No data

Data is projected to 2008 WHO legal template

FIGURE 59. IN 2010, ONLY FOUR COUNTRIES CONTINUED TO BE CLASSIFIED AS HAVING RECURRENT (ENDEMIC)POLIO DISEASE (COUNTRIES IN RED)

Wild polio virus type 1
Wild polio virus type 3
Importation countries
Endemic countries

Data at HQ as of 19 July 2011

60. TOTAL NUMBER OF CASES OF POLIO DISEASE IN 2011 (RED DOTS ARE POLIO TYPE 1;
	
  FIGURE
BLUE DOTS ARE POLIO TYPE 3) (COLORED COUNTRIES ARE THE SAME FOUR ENDEMIC COUNTRIES AS IN 2006 AND COUNTRIES WHERE
CASES HAVE BEEN IMPORTED)

72 | VACCINE FACT BOOK 2012

3 Public health effectiveness of vaccine implementation

The Impact of the Disease76, 77, 78

3.2 Haemophilus influenzae type b (Hib)

Prior to immunization, about 3 million cases and 400,000
annual deaths were attributable to Hib globally. Incidence inthe US was 20-88/100,000 children under 5 years of age, orabout 20,000 cases annually, over half of which were casesof meningitis. Incidence was much higher in some Native
American populations, reaching 491/100,000 in children
under 5 years.
In Europe, rates comparable to those of the US were observed.
In Africa, the Pacific Islands, and the Middle East incidenceswere very high. Incidence in the < 1 year age group is thehighest at as many as 200 cases of meningitis/100,000 in
Africa. Case fatality rates from meningitis can be as high as
40%, depending on the setting.
In Asia, incidence has been found to be lower than elsewhere
but some experts believe that this is likely due to masking of
the disease from widespread use of antibiotics.

FIGURE 61. COUNTRIES REPORTING CASES OF POLIO IN 2011
(AS OF JULY 2011)

The Cause
Figure 63 shows reported incidences of Hib disease inchildren under 5 years of age, prior to the introduction of a
vaccine.

Haemophilus influenzae type b (Hib) is a bacteria responsible
for meningitis, pneumonia, and other invasive diseases
particularly in infants and children under 5 years of age (SeeImage 11).
There are six serotypes of the polysaccharide encapsulated
Haemophilus influenza. Type b accounts for 95% of all serious
diseases caused by this organism. Non encapsulated, nontypable forms of the bacteria also exist.
The organism is carried in the pharynx and spread byrespiratory droplets (Figure 62).

FIGURE 62. NASOPHARYNGEAL CARRIAGE AND AEROSOL SPREADOF HAEMOPHILUS INFLUENZAE TYPE B.
SOURCE: CDC PUBLIC HEALTH IMAGE LIBRARY	  Image 11. Purulent meningitis from Haemophilus influenzae type B.
Source CDC Public Health image library

FIGURE 63. INCIDENCE OF HEAM

Chandran A, Watt JP, Santosham M. Haemophilus influenzae vaccines. pp 162. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier,
China, 2008.
77
Hib Initiative. Research and Surveillance. http://www.hibaction.org/research.php#disease_burden
78
Broker M. Burden of invasive disease caused by Haemophilus influenzae type b in Asia. Jpn J Infect Dis 2009; 62: 87-92.
76

VACCINE FACT BOOK 2012 | 73

The Vaccine
The first vaccine developed in the early 1980s was apolysaccharide vaccine. Polysaccharide vaccines do notstimulate lasting immunity in children less than 2 years of age.
In 1987, the first protein conjugate polysaccharide vaccine waslicensed for use in infants. Unlike polysaccharide vaccines,
protein conjugate vaccines stimulate lasting immunity inyoung children. Today there are several licensed protein
conjugate Hib vaccines. One of three different carrier proteins
are used to conjugate (link) with the Hib polyribosylribitol
phosphate (PRP) polysaccharide:•••

tetanus toxoid;
outermembrane protein complex of Neisseria
meningitidis strain B11; ornontoxic variant of diphtheria toxin from
Corynebacterium diphtheria C7 (CRM197).

Conjugate Hib vaccine is now usually provided in combination
with DTP or DTaP containing vaccines.

In the UK, the incidence of disease declined immediately after
the introduction of a vaccine in a 3 dose primary series (SeeFigure 64)81. The incidence rose slightly in the late 1990s, but
has since fallen again since the introduction of a 4th booster
dose at 12 months of age. Most countries deliver three doses
in a primary series. Most industrialized countries also deliver
a booster dose after 12 months of age.

The vaccine has also been found to have an important herd effect (See Figure 12). This is because thevaccine prevents the bacteria from being carried in
the nasopharynx of those individuals vaccinated.
Vaccinated individuals, in addition to
not getting infected, do not spreadthe disease in thecommunity. For thisreason, in settings
where immunization
Image 11. Purulent meningitis from Haemophilus
coverage has been influenzae type B. Source CDC Public Healthless than optimal,
image library: HTTP://PHIL.CDC.GOV/PHIL/DETAILS.ASP?PID=130
declines in incidence of the disease have nevertheless been observed.
Countries that have introduced conjugate
Hib vaccine have eliminated Hib disease as apublic health problem.

FIGURE 64. ALMOST IMMEDIATE IMPACT OF CONJUGATE HIB VACCINEON THE INCIDENCE OF HIB IN < 5 YEARSS-OLDS IN THE UK

The impact of the vaccine
Everywhere the vaccine has been introduced, very rapid
declines of over 90% in the rate of disease have been
observed. In the US, since the introduction of a conjugate Hib
vaccine, the incidence of the disease has declined by 99%79.
African countries where the vaccine has been introduced haveexperienced marked declines in the incidence. The Gambia
has reduced the incidence to 0 from a high of > 200 cases /100,000 in < 1 year-olds (See Figure 10)80.

Wikipedia. Hib vaccine. http://en.wikipedia.org/wiki/Hib_vaccine#Impact
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(9480):144-50.
81
McVernon J, Trotter CL, Slack MPE et al. Trends in Haemophilus influenzae type b infections in adults in England and Wales: surveillance study.
BMJ 2004; 329: 655-658.
79
80

74 | VACCINE FACT BOOK 2012

3 Public health effectiveness of vaccine implementation

3.3 Mumps

Complication

Frequency

inflammation of thetesticles (orchitis)

37% post-pubertal men

inflammation of thebreasts (mastitis)

31% post-pubertal women

deafness

0.5-5.0 / 100,000 mumps cases;
1 / 1000 mumps cases in JapanTABLE 15. COMPLICATIONS AND FREQUENCIES OFMUMPS COMPLICATIONS

thought. Deafness was thought to occur in about 0.5 – 5.0 /100,000 cases of mumps. Hashimoto, et al., found the incidence
of deafness from mumps to be approximately 1 / 1000 in Japan83.
In 2005, Kawashima, et al, found that the number of casesof deafness from mumps was steadily increasing in Japan84.
The number of cases in 1987 was estimated at 300, but had
jumped to 650 by 2001. The increase in number of casesof deafness correlated with an increase in the incidence ofmumps.
Complications of mumps are summarized in Table 15.

The Cause82
The Vaccine85
Mumps is a viral disease first described by Hippocrates
in the 5th century BC. The virus was identified by Johnson
and Goodpasture in 1934. The virus most commonly
invades the salivary glands, causing swelling and pain
(See Image 12). It is transmitted by respiratory droplets(See Figure 65).
The Impact of the Disease

The first vaccines from the 1950s were formalin-inactivatedand did not impart lasting immunity. Instead, live-attenuatedvaccines replaced inactivated vaccines in the 1960s. Thirteen
different vaccine strains are produced today in several
different types of cells.
Mumps vaccine is available as a monovalent or in combination
with measles (MM), or measles and rubella (MMR), or measles,
rubella and varicella vaccines (MMRV).

cases / 100 000

Although children are often affected, outbreaks of the disease
are noted to occur commonly in military personnel. In children, in addition to infection of the salivary glands (parotitis),
The impact of the vaccine
the virus can cause lower respiratory disease. In adults, thevirus causes inflammation of thePrior to the use of mumps vaccines,
testicles (orchitis) in 37% of post- 	
  the incidence of the disease was
Incidence of Mumps Before and After the
pubertal men and inflammation
several hundred cases / 100,000
Introduction of a Vaccineof the breasts (mastitis) in 31% of
population with most cases oc800
post-pubertal women.
curring in children from 5–9 years
700
600
of age in industrialized countries.
Denmark
500
In the pre-vaccine era, mumps wasCountries that introduced mumps
Finland400
the leading cause of viral encephavaccine have virtually eliminatedNorway300
litis in the US. Neurological comthe disease. In the US, cases have
Slovenia
200
plications can occur from mumps
declined by more than 98% since100
Swedenencephalitis, including deafness.
the introduction of a vaccine. Other01977 - 1979
1993 - 1995
countries that have used mumps
In Japan, deafness from mumps
vaccine have experienced similar
FIGURE 66. DECLINE IN INCIDENCE OF MUMPS
has recently been found to occur at
declines in cases (See Figure 66)86.
FOLLOWING THE INTRODUCTION OF A VACCINE IN A
a higher incidence than previously
TWO-DOSE SCHEDULE

Plotkin SA, Rubin SA. Mumps vaccines. pp 435-465. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
Hashimoto H, Fujioka M, Kinumaki H et al. An office-based prospective study of deafness in mumps. Pediatr Infect Dis J 2009; 28: 173-5.
84
Kawashima Y, Ihara K, Nakamura M et al. Epidemiological study of mumps deafness in Japan. Auris Nasus Larynx 2005; 32: 125-128.
85
Plotkin SA, Rubin SA. Mumps vaccines. pp 435-465. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
86
Plotkin SA, Rubin SA. Mumps vaccines. pp 440-442. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
82
83

VACCINE FACT BOOK 2012 | 75

The efficacy of mumps vaccines varies by stain, the numberof doses used, and by outbreak settings. In initial clinical trials
with the Jeryl Lynn strain efficacy ranged from 92–96%. Whenstudied in outbreaks (in the US), efficacy has ranged from
78–91%. Efficacy with other strains of vaccine in othercountries has generally been within these ranges.
Mumps vaccines are associated with a very small risk of
aseptic meningitis, which varies by strain and by manufacturer.
But the long-term effects of post-vaccine meningitis are either
very rare or absent. Furthermore, the risk of meningitis fromnatural mumps infection is much higher (1–10%). In Japan,
mumps immunization was found to lower the risk of aseptic
meningitis by 25-fold compared to natural mumps infection87.

3.4 Measles eradication, global

The Cause88
Measles is one of the most contagious viral diseases. It causes
a rash, acute upper respiratory illness, and can lead to complications that can be fatal, especially in children (See Image14). In ancient times, the disease was confused with otherrash-causing diseases, including smallpox. It was recognized
as a separate disease by the end of the 17th century. It wasunderstood to be caused by an infectious agent by the beginning of the 20th century. The disease is spread by aerosol (SeeFigure 67).
The measles virus was first isolated in 1954 by Enders andPeebles and developed into a live-attenuated vaccine by
1963.
The Impact of the Disease89

	
  

	
  

Image 14.
Measles rash. Source:
CDC

FIGURE 67. TRANSMISSION OF MEASLES
VIRUS IS BY AEROSOL ROUTE.
SOURCE: CDC PUBLIC HEALTH IMAGE LIBRARY
HTTP://PHIL.CDC.GOV/PHIL/DETAILS.ASP?PID=8429

In 2000, measles remained the leading cause of death inchildren from a vaccine-preventable disease and the fifth
most frequent cause of all deaths in children under 5 years ofage, killing about 777,000 children every year.
The Vaccine

The case-fatality rate in industrialized countries is about 1–3
deaths / 1000 cases, but is several times higher in developing countries and can reach 15%. In the pre-vaccine era,because of the highly contagious nature of the disease, virtually everyone in industrialized countries was infected withthe measles virus by adolescence. In developing countries, allchildren could be infected by as early as 4 years of age. It wasa leading cause of infant deaths, blindness, and disability.

Measles vaccines are live-attenuated, produced on chickembryo fibroblasts. Unlike polio and some other viruses, there
is a single serotype of measles virus.
Measles vaccines are highly effective (90–95%) against wild
virus. Initially, a single dose in infancy or early childhood wasrecommended in most immunization schedules.

Plotkin SA, Rubin SA. Mumps vaccines. pp 451-452. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
Strebel P, Papania MJ, Dayan GH et al. Measles vaccines. pp 353-398. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China,
2008.
89
Strebel P, Papania MJ, Dayan GH et al. Measles vaccines. pp 358-359. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China,
2008.
mmwrhtml/mm5453a1.htm
87
88

76 | VACCINE FACT BOOK 2012

3 Public health effectiveness of vaccine implementation

600,000
500,000
400,000
300,000
200,000
100,000
0

vaccine licensed

1960
1963
1966
1969
1972
1975
1978
1981
1984
1987
1990
1993
1996
1999
2002
2005

cases

Reduction in Cases of Measles in the US
after Introduction of a Vaccine	
  FIGURE 68. DECLINE IN CASES OF MEASLES IN THE US
AFTER INTRODUCTION OF A VACCINEWith increasing measles control, a second dose of measles
vaccine is now recommended in most immunization schedules, at varying intervals after the first dose. In the US, a firstdose is recommended at 12–15 months and a second doseat 4-6 years of age.
Some countries (Canada, UK, Australia, New Zealand) havealso conducted a one-time nationwide campaign among
school children to reduce the number of persons at risk. Most
industrialized countries also now deliver measles vaccine in
combination with mumps and rubella vaccines MMR (alsolive-attenuated viral vaccines). Most recently, some industrialized countries have introduced a combination vaccine
containing measles, mumps, rubella, and varicella (MMRV)in childhood immunization schedules. Developing countries
often use measles vaccine alone.
Adverse events are mild and commonly include fever and/or rash in 5–15% of recipients (or higher rates with MMR or
MMRV). Evidence does not support any causal relation toirritable bowel syndrome or childhood autism.
The impact of the vaccine
Prior to the introduction of the vaccine, virtually every
child became infected with measles. In the US alone, thisamounted to almost half a million infections every year. Today,
it is estimated that 2.7 million deaths would occur worldwide,
every year, in the absence of measles immunization90. Most

industrialized countries introduced measles vaccines in the
1960s and have since experienced remarkable declines indisease incidence (See Figure 68.)91, 92.
However, because the virus is so highly transmissible, theelimination of wild measles virus requires a 2-dose vaccination strategy. In the Americas, intense efforts in the 1980s and1990s to eliminate measles included mass immunization campaigns to increase immunization coverage and to immunize
the un-immunized or re-immunize the previously immunized.
The economic impact of measles immunization—In theUS, in 2001 dollars, the benefit / cost ratio was estimated at
14.2 for direct costs and 26.0 for indirect costs93. Likewise, inAustralia, economic analyses suggest that measles immunization results in a net benefit to the community of $9.1 billion,
or $8.5 billion to the government94.
The goal of eradication
Because of the high morbidity and mortality associated withmeasles in the absence of immunization, and because of
the excellent benefit / cost ratio for measles immunization,
5 out of 6 regions of the world have set elimination targets
for measles: the Americas by 2000; Europe and Middle Eastby 2010; western Pacific by 2012, and Africa by 2020. The
Americas has achieved a 99% reduction in disease since1990 and the transmission of virus is considered interrupted.
The remaining cases that occur in the Americas are primar-

American Academy of Pediatrics. Why Immunize? http://www.aap.org/advocacy/releases/whyimmunize.htm
Centers for Disease Control and Prevention. Summary of notifiable diseases, United States, 1994. MMWR 1995; 43:1. http://www.cdc.gov/mmwr/preview/
mmwrhtml/00039679.htm
92
Centers for Disease Control and Prevention. Summary of notifiable diseases, United States, 2005. MMWR 2007; 54: 2-92. http://www.cdc.gov/mmwr/preview/
93
Strebel P, Papania MJ, Dayan GH et al. Measles vaccines. pp 359. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
94
Applied economics. Immunisation programs: measles and Hib disease. http://www.appliedeconomics.com.au/pubs/reports/health/ph05.htm
90
91

VACCINE FACT BOOK 2012 | 77

ily from persons who have travelled to the US and spreadtheir infection.
The WHO, in 2003, resolved to halve the deaths from measles
by 2005, by increasing routine immunization coverage anddelivering supplemental immunizations. Now a 2-dose strategy is endorsed for all countries, regardless of economic status or vaccine coverage. The eradication (global elimination)is technically feasible, but will require very high vaccination
coverage to achieve.
Enormous progress toward a goal of eradication has been
made in all regions of the world. Deaths from measles havedeclined by more than 50% (See Figure 69)95.

FIGURE 69. DECLINE IN THE NUMBER OF DEATHS FROM MEASLES
DUE TO INCREASED IMMUNIZATION COVERAGE	  

3.5 Rotavirus

The Cause
Rotavirus is a highly contagious common viral disease spreadby oral-fecal route (See Figure 70).
It is the most common cause of severe diarrhea in infants andyoung children (See Image 15). There are five groups of rotaviruses: A, B, C, D and E. Group A contains animal and human
serotypes (strains). Fourteen G serotypes and several P types
are known to exist but only 6 G serotypes are commonly associated with human disease: G1, G2, G3, G4, G9, and G12.
Each of these G types is further characterized by a P typewhich is numbered. Common types of virus circulating in the
US are P[8]G1, P[4]G2, P[8]G3, P[8]G4, P[8]G9, and P[6]G996.
These viruses multiply in the gut, and transmission of the

Image 15. Child dehydrated from rotavirus diarrhea.
Source: WHO, D Mahalanabis
HTTP://WWW.VACCINEINFORMATION.ORG/ROTAVIRUS/
PHOTOS.ASP	
  disease is from person to person contact—not from contaminated water and food(See Figure 70).

	  The Impact of
the Disease
Rotavirus is the mostcommon cause of severe FIGURE 70. TRANSMISSION OFROTAVIRUS BY FECALE-ORAL ROUTE.
diarrhea
ininfants. SOURCE: CDC PUBLIC HEALTH IMAGE
It is responsible for LIBRARY
2.7 million episodes of HTTP://PHIL.CDC.GOV/PHIL/DETAILS.
ASP?PID=197
illness per year in theUS, and for about $1 billion in direct and indirect costs97.
Globally, rotaviruses kill over 500,000 children every year andaccount for about 25% of deaths from all diarrheal diseases(SEE Figure 71)98. Rotavirus accounts for about 40% of
hospitalization for diarrhea in children under 5 years of age,
and approximately 100 million episodes of diarrhea every
year.
By 2–3 years of age, all children have been exposed torotavirus. In Asia, without rotavirus vaccination, an estimated171,000 children will die of rotavirus by the age of 5 years,

Centers for Disease Control and Prevention. Progress in global measles control and mortality reduction, 2000-2007. MMWR 2008; 57: 1303-1306. http://www.cdc.
gov/mmwr/preview/mmwrhtml/mm5748a3.htm?s_cid=mm5748a3_e
96Centers for Disease Control and Prevention. Prevention of rotavirus gastroenteritis among infants and children recommendations of the Advisory Committee on
Immunization Practices (ACIP)/ MMWR 2009; 58: 1- 25. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5802a1.htm
97
Clark HF, Offit PA, Parashar UD et al. Rotavirus vaccines. pp 715-734. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China,
2008.
98
Tate JE, Patel MM, Steele AD, et al. Global impact of rotavirus vaccines. Expert Rev Vaccines 2010; 9: 395-407
95

78 | VACCINE FACT BOOK 2012

3 Public health effectiveness of vaccine implementation

1.9 million will be hospitalized, and 13.5 million will require an
outpatient visit (See Figure 72)99.
Because rotavirus is equally prevalent in industrializedcountries, vaccines are also important for prevention insettings with good sanitation.
The Vaccine
Rotavirus vaccines are made from either a single strain(monovalent) of live-attenuated human rotavirus (GSK,
Rotarix™) or from five (pentavalent) live-reassortant humanbovine viruses (Merck, RotaTeq™). Both are administeredorally, in two and three doses, given before 24 and 32 weeks,
respectively.

	
  FIGURE 71. GLOBAL BURDEN OF ROTAVIRUS DISEASE	  The first rotavirus vaccine licensed for use in humans wasmade from simian-human reassortant rotaviruses. Carefull
study of adverse events following immunization showed that
this vaccine was associated with a higher risk of the extremelyrare event of intestinal folding (intussusception) (15 cases /1 million children vaccinated). The risk was highest after afirst dose of vaccine. Even though the public health benefits
far exceeded the risks associated with intussusceptions, thesimian-human reassortant vaccine was discontinued becauseof the concerns for liability.

FIGURE 72. IMPACT OF ROTAVIRUS ASIA IN THE ABSENCE
OF IMMUNIZATION

Because of the history of the simian-human reassortantvaccine, the two currently licensed vaccines have been
extensively evaluated for the risk of intestinal intussusception.
Neither vaccine is associated with a higher risk ofintussusceptions (See Table 16).

1 year after
dose 1

Live Reassortant Human-Bovine
Rotavirus

Placebo(n = 34,788)

Live-Attenuated
Human Rotavirus(n = 10,159)

Placebo(n = 10,010)

Intussusception

13

15

4

14

TABLE 16. RISK OF INTUSSUSCEPTION IS NOT ELEVATED FOLLOWING ROTAVIRUS VACCINATION WITH LICENSED LIVEHUMAN-BOVINE REASSORTANT AND HUMAN LIVE-ATTENUATED VACCINES

Podewils LJ, Antil L, Hummelman E, et al. Projected cost-effectiveness of rotavirus vaccination for children in Asia. J Infect Dis 2005; 192: s133-145.

99

VACCINE FACT BOOK 2012 | 79

Adverse events reported from both vaccines are mild andtemporal and include vomiting, diarrhea, and fever. In clinical
trials, these adverse events were reported at similar rates tothose from the placebo groups (See Table 17).

Adverse Event

Live Reassortant Human-Bovine
Rotavirus

PlaceboLive-Attenuated Human
Rotavirus

PlaceboVomiting

4%

3%

8%

8%

Diarrhea

6%

5%

3%

3%

Fever

18%

18%

28%

34%

TABLE 17. COMMON ADVERSE EVENTS FROM ROTAVIRUS VACCINES (SOLICITED WITHIN SEVEN DAYS AFTER THREE DOSES OF
LIVE-REASSORTANT HUMAN-BOVINE ROTAVIRUS; WITHIN EIGHT DAYS AFTER TWO DOSES OF LIVE-ATTENUATED HUMAN ROTAVIRUS) 100, 101

The Impact of the Vaccine
The two currently licensed rotavirus vaccines have excellent
efficacy, ranging from 85 - 98% against rotavirus disease. In
some settings, the vaccines have reduced hospitalizations fordiarrhea of any cause by 42% to 63% in children < 1 year ofage (See Figure 73)103.
The impact of rotavirus vaccines has been almost
immediate in countries where they have been introduced(See Figure 74)104.
Reduction in Diarrhea-Associated Hospitalizations in Panama
Following Introduction of Rotavirus Vaccine
100
75

%

FIGURE 74. REDUCTION IN HOSPITALIZATION RATES FOR
GASTROENTERITIS BY AGE GROUP DURING ROTAVIRUS SEASON IN THE
US, FOLLOWING INTRODUCTION OF ROTAVIRUS VACCINE

	
  

50
25
0
2007
full year

January to June

2008

	
  
FIGURE 73. REDUCTION IN HOSPITALIZATION FOR ANY-CAUSE DIARRHEAIN CHILDREN < 5 YEARS IN PANAMA, FOLLOWING INTRODUCTION OF AROTAVIRUS VACCINE IN 2006

Merck. RotaTeq prescribing information. July 2011. http://www.merck.com/product/usa/pi_circulars/r/rotateq/rotateq_pi.pdf
GSK Source. Rotarix prescribing information. February 2011. https://www.gsksource.com/gskprm/en/US/adirect/gskprm?cmd=ProductDetailPage&product_id=1
244173585205&featureKey=600594#nlmhighlights
102
Sirica C and Wuethrich B. Roatvirus: interesting facts about a virus on the rise. Micobiowiki. Jan 9, 2009. http://microbiowiki.wetpaint.com/page/Rotavirus%3A+Interesting+facts+about+a+virus+on+the+rise
103
Molto Y, Cortes JE, de Oliveira LH et al. Reduction of diarrhea-associated hospitalizations among children aged < 5 years in Panama following the introduction ofrotavirus vaccine. Pediatr Infect Dis J 2011; 30: s16-s20.
104
Curns AT, Steiner CA, Barrett M et al. Reduction in acute gastroenteritis hsopitalizations amond US children after introduction of rotavirus vaccine: analysis of
hospital discharge data from 18 US states. JID 2010; 201(11):1617-1624.
100
101

80 | VACCINE FACT BOOK 2012

3 Public health effectiveness of vaccine implementation

Marked declines in the incidence of rotavirus disease havebeen observed in the seasons following rotavirus vaccine
introduction in both Latin America105 and Europe106 andAustralia107 and the US108 (See Table 18).

Country

ImpactVaccine Effectiveness

Australia• 45% reduction in proportion of positive rotavirus tests in 2007;• 43%reduction in proportion of positive rotavirus tests in 2008;• 75% reduction in rotavirus hospitalizations in New South Wales in 2008-2009• 85% against rotavirus infections;• 89.3% efficacy against rotavirus
infections in Queensland

Austria• 74% reduction in rotavirus-associated hospitalizations• 61–98%

Belgium• 65% reduction in mean hospitalization days from rotavirus gastroenteritis in
2007-2008;• 83% reduction in mean hospitalization days from rotavirus gastroenteritis in
2008-2009;• 50% reduction of rotavirus infections in 2008–2009;• 75% reduction in rotavirus positive gastroenteritis

Mexico• 42% reduction in any-cause diarrhea mortality;• 11% reduction in diarrhea-associated hospitalizations in 2007;• 40% reduction in diarrhea-associated hospitalizations in 2009

El Salvador• 79% reduction of rotavirus diarrhea;• 81% reduction in rotavirus-associated hospitalization in < 5 years in 2008;• 48% reduction in diarrhea-associated health visits during rotavirus season in 2008;• 35% reduction in diarrhea-associated health visits during rotavirus season in 2009;• 69% reduction in rotavirus-associated hospitalization

Nicaragua• 23% reduction for any-cause diarrhea

Panama

• 22% reduction in diarrhea-associated hospitalizations in < 5 years in 2007
(37% for Jan–Jun);• 37% reduction in diarrhea-associated hospitalizations in < 5 years in 2008(58% for Jan–Jun)

US• 60% reduction in peak proportion of positive rotavirus tests in 2007–2008;• 42% reduction in peak proportion of positive rotavirus tests in 2008–2009;• 82% reduction in proportion of positive rotavirus tests in 2009–2010;• 16% reduction in hospitalization rates for any-cause diarrhea in < 5 years in 2007;• 46% reduction in hospitalization rates for any-cause diarrhea in < 5 years in 2008

• 74% against severe and 88%
against very severe rotavirus
gastroenteritis• 52–63% against severe rotavirus
gastroenteritis;• 73–86% against very severe
rotavirus gastroenteritis

TABLE 18. IMPACT OF ROTAVIRUS IMMUNIZATION IN SELECT COUNTRIES106, 107, 108, 109, 110, 111, 112, 113

De Oliveira LH, Danovaro-Holliday C, Sanwogou NJ, et al. Progress in the introduction of the rotavirus vaccine in Latin America and the Caribbean – four years ofaccumulate experience. Pediatr Infect Dis J 2011; 30: s61-s66.
106
Braeckman T, Herck KV, Raes M, et al. Rotavirus vaccines in Belgium – policy and impact. Pediatr Infect Dis J 2011; 30: s21-s24.
107
Buttery JP, Lambert SB, Grimwood K, et al. Rediction in rotavirus-associated acute gastroenteritis following introduction of rotavirus vaccine into Australia’s
national childhood vaccine schedule. Pediatr Infect Dis J 2011; 30: s25-s29.
108
Tate JE, Cortese MM, Payne DC, et al. Uptake, impact, and effectiveness of rotavirus vaccination in the United States – review of the first three years of postlicensure
data. Pediatr Infect Dis J 2011; 30: s56-s60.
109
Tate JE, Patel MM, Steele AD, et al. Global impact of rotavirus vaccines. Expert Rev Vaccines 2010; 9: 395-407.
110
Tate JE, Mutuc JD, Panozzo CA, et al. Sustained decline in rotavirus detections in teh United States following the introduction of rotavirus vaccine in 2006. Pediatr
Infect Dis J 2011; 30: s30-s34.
111
Molto Y, Cortes JE, de Oliveira LH et al. Reduction of diarrhea-associated hospitalizations among children aged < 5 years in Panama following the introduction ofrotavirus vaccine. Pediatr Infect Dis J 2011; 30: s16-s20.
112
Quintanar-Solares M, Yen C, Richardson V, et al. Impact of rotavirus vaccination on diarrhea-related hospitalizations among children < 5 years of age in Mexico.
Pediatr Infect Dis J 2011; 30: s11-s15.
113
Yen C, Armero Guardado JA, Alberto P, et al. Decline in rotavirus hospitalizations and health care visits for childhood diarrhea following rotavirus vaccinations in El
Salvador. Pediatr Infect Dis J 2011; 30: s6-s10.
105

VACCINE FACT BOOK 2012 | 81

As of 2010, 14 countries in Latin America were using rotavirus
vaccines114. Post licensure efficacy trials have confirmed
efficacy in Latin American countries. When co-administeredwith oral polio vaccine in six Latin American countries, vaccine
efficacy was found to be 81% against severe diarrhea andvomiting (gastroenteritis)115.
Image 16. President Bolanos of Nicaragua adminisering afirst dose of rotavirus vaccine.
Source: Merck Vaccines

Impact of Rotavirus Immunization in Nicaragua	
  In 2005, the health system in Nicaragua had been overwhelmed by an outbreak of rotavirus disease. The country
reported over 64,000 cases of diarrhea (from any cause) and 56 deaths from diarrhea116. In 2006, in partnership withMerck, Unicef, and international health organizations, rotavirus vaccine was introduced for the first time in a developing
country. For three years, Merck donated rotavirus vaccine for all infants in Nicaragua.
President Enrique Bolaños administered the first dose of oral vaccine on October 27, 2006117. The vaccine has sinceprevented 77% of very severe cases of rotavirus diarrhea118 in Nicaragua and cut hospital admissions and emergency
room visits by 50%119. In children less than 1 year of age, vaccine was 88% effective against hospitalization fromrotavirus gastroenteritis120.

3.6 Human Papillomavirus (HPV)The Cause
Human Papillomaviruses (HPV) were originally thought tobe benign wart-causing viruses. But in the 1980s, the Nobel
Prize winning Harald zur Hausen hypothesized that HPVs
were likely the cause of cervical cancer.
HPV commonly infects humans and can cause warts andcancers. The virus is made up of two proteins (L1 and L2)
which are assembled in pentameres (See Figure 75).

	
  

L1	
  
L1	
  

	
  
	
  
	
  

L1	
  
L2	
  

L1	
  

L1	
  

FIGURE 75. SINGLE PENTAMERE OF HUMAN PAPILLOMAVIRUS(WHOLE VIRUS HAS 72 PENTAMETERS)De Oliveira LH, Danovaro-Holliday C, Sanwogou NJ, et al. Progress in the introduction of the rotavirus vaccine in Latin America and the Caribbean – four years ofaccumulate experience. Pediatr Infect Dis J 2011; 30: s61-s66.
115
Tregnaghi MW, Abate HJ, Valencia A, et al. Human rotavirus vaccine is highly efficacious when coadministered with routine expanded program of immunization
vaccines including oral poliovirus vaccine in Latin America. Pediatr Infect Dis J 2011; 30: e103-108. http://www.ncbi.nlm.nih.gov/pubmed/21378594
116
Merck. Nicaraguan vaccination program. http://www.merck.com/responsibility/access/access-feature-nicaraguan.html
117
PATH Rotavirus Vaccine Project - Summary Report. http://www.rotavirusvaccine.org/files/RVP_SummaryReport_Final.pdf
118
View Change.Org. Living proof: Nicaragua – a vaccine’s remarkable impact. http://www.viewchange.org/videos/living-proof-nicaragua-a-vaccines-remarkableimpact
119
PATH. Press Room. New evidence on rotavirus vaccines in Asia demonstrate significant protection against the most common deadly form of childhood diarrhea.
Press release. http://www.path.org/news/pr100805-rotavirus-vaccines-Asia.php
120
Mast TC, Espinoza F, Palacio del Carmen L, et al. Effectiveness of the oral pentavalent rotavirus vaccine in Nicaragua. Poster presentation 28th annual meeting of
the European Society for Pediatric Infectious Diseases. May 4 – 8, 2010. http://www.kenes.com/espid2010/posters/Abstract596.htm
114

82 | VACCINE FACT BOOK 2012

3 Public health effectiveness of vaccine implementation

About 80% of women in the US will be infected by at least
one strain of HPV by 50 years of age. There are about 200
types of HPV. More than 40 types cause genital infections.
Types 16 and 18 are now known to cause 70% of cervicalcancers and the majority of genital cancers (See Figure 77).
Types 6 and 11 cause 90% of genital warts. These virus types
are transmitted sexually (See Figure 78).

	  HPV may be cleared by the immune system quickly (weeks ormonths) after infection. But sometimes the virus persists fora long period of time (up to 10 years). It is in these persons
that normal cells may be transformed into cancerous cells.
These transformations occur because viral proteins (E6 andE7) inactivate human tumor suppressor proteins.

FIGURE 72. IMPACT OF ROTAVIRUS ASIA IN THE ABSENCE
OF IMMUNIZATION

Based on their characteristics, HPVs are classified into
four groups. Each group may include several types(See Table 19)121.

Group

Site

Effects

Cancer-causing

Common HPV Types

Benign skin

skin

warts

no

1, 2

Epidermodysplasia
verrucruciformis

skinflat warts

yes

5, 8

Genitalgenitalswarts

no (but can cause precancerous lesions)6, 11High-risk genital

genitalsflat warts

yes (can also cause precancerous lesions)16, 18, 33, 45

TABLE 19. CLASSIFICATION OF HPVs (ADAPTED FROM VACCINES 5TH EDITION)	
  Proportion of High-Risk HPVs by Type
60
50
40
% 30
20
10
0
HPV HPV HPV HPV HPV HPV HPV HPV
16
18
31
33
35
45
52
58

	
  

FIGURE 77. GENITAL AND HIGH-RISK GENTIAL
HPVs ARE TRANSMITTED SEXUALLY. SOURCE: NIH-

FIGURE 78. GLOBAL DISTRIBUTION OF HIGH-RISK HPVs BY TYPE(VALUES ARE APPROXIMATE)

VISUALS OLINE. LABORATORY OF TUMOR VIRUS BIOLOGY

Schiller JT, Frazer IH, Lowy DR, et al. Human papillomavirus vaccines. pp 246. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier,
China, 2008.
121

VACCINE FACT BOOK 2012 | 83

The Impact of the Disease122

The Vaccine127

Globally, cervical cancer is the 2nd or 3rd most common cancer
in women, depending on the country screening practices.
It results in 273,000 deaths / year or 2.7 million years of life
lost123. In Latin America and Eastern Europe, this represents
more life years lost than from tuberculosis and AIDS.

A vaccine for use in humans was developed by using theL1 protein which makes up the shell (capsid) of the virus(See Figure 75). The star shaped L1 proteins (pentameres) self
assemble into virus-like particles (VLPs). The L1 protein canbe produced from a number of cell lines. Currently licensed
vaccines are produced in insect cells or in yeast. Since thevaccine is made from the L1 protein only (and not from thewhole virus) the vaccine is not infectious and cannot cause
cancer-like HPVs.
The two vaccines licensed for use are:

About 70% of young women who become sexually active will
become infected with one or more types of HPV within five
years. About 52–58% of cervical cancers are caused by HPV

Age-related incidence of cervical cancer in the
US

•

20

•

15
10
5
85+

80-84

75-79

70-74

65-69

60-64

55-59

50-54

45-49

40-44

35-39

30-34

25-29

20-24

0
15-19

cases / 100,000	
  years of age
FIGURE 79. AGE-RELATED INCIDENCE OF CERVICAL CANCER IN THE US

type 16, depending on the region. Up to an additional 20%
are caused by HPV type 18. The remainder are caused mostly
by types 31, 33, 35, 45, 52, and 58 (See Figure 78)124.
The incidence of cervical cancer varies considerably, even
within a country. Incidence tends to be higher in developing
countries or in minority populations. Incidence peaks in the
40–44 year age group, in the US (See Figure 79)125. In 2011,about 12,710 new cases of cervical cancer and about 4,290
deaths are expected to occur in the US126.

a bivalent vaccine (types 16 and 18, Cervarix™ from
GSK); and,a quadrivalent vaccine (types 6, 11, 16, and 18,
Gardasil ™ from Merck).

Both vaccines are injectable and given in three doses over
six months. Because vaccines prevent infection and the rateof infection increases rapidly within the first years of sexual
activity, vaccination is focused on girls before they become
sexually active. In the US, the ACIP recommends vaccination
at 11–12 years of age, and up to 26 years of age for catch-up
immunization. In addition to the prevention of cervical cancer,
the quadrivalent vaccine, Gardasil™, is also approved forprevention of vulvar or vaginal cancers in females and for theprevention of genital warts, anal cancers, and precancerous ordysplastic lesions in females and males 9–26 years of age128.
The Impact of the Vaccine
In clinical trials, both vaccines proved highly effective (94–96%)
at preventing persistent infections against corresponding
HPV types. Both vaccines were nearly 100% effective atpreventing cervical intraepithelial neoplasia (CIN) (a precursor
to cervical cancer)129.

Schiller JT, Frazer IH, Lowy DR, et al. Human papillomavirus vaccines. pp 243-257. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders
Elsevier, China, 2008.
123
World Health Organization. Human papillomavirus and HPV vaccines: technical information for policy-makers and health professionals. Department of Immunizations,
Vaccines and Biologicals. 2007. http://whqlibdoc.who.int/hq/2007/WHO_IVB_07.05_eng.pdf
124World Health Organization. Human papillomavirus and HPV vaccines: technical information for policy-makers and health professionals. Department of Immunizations,
Vaccines and Biologicals. 2007. http://whqlibdoc.who.int/hq/2007/WHO_IVB_07.05_eng.pdf
125
National Cancer Institute. Surveillance Epidemiology and End Results. SEER Cancer Statistics Review 2004-2008. http://seer.cancer.gov/csr/1975_2008/browse_
csr.php?section=5&page=sect_05_table.07.html
126
National Cancer Institute. Cervical cancer. http://www.cancer.gov/cancertopics/types/cervical
127
Schiller JT, Frazer IH, Lowy DR, et al. Human papillomavirus vaccines. pp 243-257. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders
Elsevier, China, 2008.
128
MerckVaccines.com. Gardasil indications. http://www.merckvaccines.com/Products/Gardasil/Pages/indications.aspx
129
Schiller JT, Frazer IH, Lowy DR, et al. Human papillomavirus vaccines. pp 243-257. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders
Elsevier, China, 2008.
122

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3 Public health effectiveness of vaccine implementation

Country

Year added toimmunization schedule

Australia

2007

girls and women 12-26 years for an initial period of three years;
routine for girls 12-13 years;

Canada2007

routine for girls 11-14 years

France2007

voluntary for girls and women 14-23 years not sexually active or sexually active < 1 year

Greece2007

mandatory for girls entering grade 7;
available to girls and women 12 – 26 years

New Zealand2008

girls and women born after 1990;
routine for girls in grade 8 or 12 years of age

Norway2009

routine for girls 12-13 years

Sweden2010

voluntary for girls 10-12 years

United Kingdom

2008

routine for girls 12-13 years;
catch-up for girls up to 18 years of age

United States2007

routine for girls 11–12 years;
catch-up for girls and women 13–26 years;
boys 9–26 years (2010)

Immunization schedule

TABLE 20. COUNTRIES WITH HUMAN PAPILLOMAVIRUS VACCINE IN IMMUNIZATION SCHEDULES130

On the basis of clinical trial data, several countries introduced
HPV vaccine into national immunization programs shortly
after they were licensed (See Table 20).
Preventing persistent infection with HPV is presumed to resultin an important reduction in the incidence of cervical cancer.
But this effect will only be observed at some point in the
future because the time required to develop cervical cancer
is 10 or more years. Nevertheless, countries that have already

implemented HPV immunization programs may already beobserving some reductions in incidence in vaccine-eligible
age groups. A study in Australia found that incidence of highgrade abnormalities in girls < 18 years had decreased by 38%
three years after vaccine introduction131, and the prevalenceof genital warts in the vaccinated population has decreasedby 59%132. Evidence is growing for the ability of vaccine
HPV types to cross-protect against some other high-risk
HPV types.

Wikipedia. HPV vaccine. http://en.wikipedia.org/wiki/HPV_vaccine
Brotherton JML, Fridman M, May CL, et al. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study.
Lancet 2011; 377: 2085-2092.
132
Donovan B, Franklin N, Guy R, et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillancedata. Lancet Infect Dis 2010; 11:39-44.
130
131

VACCINE FACT BOOK 2012 | 85

Impact of HPV Vaccination in Australia
Australia introduced HPV vaccine in 2007. Between 2007 and 2009 Australia conducted a national catch-up campaign.
72% of girls aged 14 and 15 and nearly 66% of girls aged 16 and 17 were vaccinated with three doses133.
Australia now routinely administers vaccine to 12- and 13-year-old girls in their high school vaccination program.
Vaccines are provided at no cost to girls and approved for boys 9-15 years of age.
The National HPV Vaccination Program Register monitors the impact on cervical cancer rates and vaccination coverage,
and provides reminders for full immunization.
Because cervical cancer usually occurs several years after infection, the full impact on the incidence of cervical cancer
cannot be measured for several years. Nevertheless, the age-adjusted incidence of HPV type 16 was expected to havedecreased by 56% from pre-vaccine levels, by 2010. By 2050 a 92% reduction in incidence of HPV type 16 infections
is expected134, 135.
How the reduction in infections will impact cervical cancer is difficult to assess. Not all infections result in cancer, andthe measured incidence of cervical cancer depends on the quality of a screening program. But already high-grade
cervical abnormalities in girls < 18 years have decreased by 38%, three years after vaccine introduction136. And theprevalence of genital warts in the vaccinated population has decreased by 59%137.

	
  Australian Government. Department of Health and Ageing. Human Papillomavirus (HPV).
http://www.health.gov.au/internet/immunise/publishing.nsf/Content/immunise-hpv
134
Cancer Council. Questions and Answers: New research on HPV: HPV infections will plummet by 2010.
http://www.cancer.org.au/File/NewsMedia/MediaReleases2008/CERUresearchHPVQ&A.pdf
135
Smith MA, Canfell K,Brotherton JML, et al. The predicted impact of vaccination on human papillomavirus infections in Australia. Intl J Cancer 2008; 123: 18541863.
136
Brotherton JML, Fridman M, May CL, et al. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study.
Lancet 2011; 377: 2085-2092.
137
Donovan B, Franklin N, Guy R, et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillancedata. Lancet Infect Dis 2010; 11:39-44.
133

86 | VACCINE FACT BOOK 2012

VACCINE FACT BOOK 2012 | 87

3.7 Pneumococcal disease

The Cause	
  Pneumococci are bacteria(Streptococcus
pneumoniae) that can inhabit (colonize) the nasopharynx inhumans, but normally do
Figure 80. Pneumococci colonize
not cause disease. Occathe back of the nose. When theysionally these bacteria may
spread to other organs in the bodyspread to the ears, lungs,
they cause illness.
SOURCE: CDC PUBLIC HEALTH IMAGE LIBRARY HTTP://brain, or other organs in
EN.WIKIPEDIA.ORG/WIKI/FILE:PNEUMOCOCCUS_CDC_
PHIL_ID1003.JPG
the body (Figure 80). The
spread of the bacteria may
be localized in the respiratory tract and cause ear or sinus infections. If it spreads beyond, it causes invasive pneumococcal disease (IPD). The disease varies according to the organs
that are affected. Typically IPD manifests as blood poisoning(bacteremia), pneumonia, or meningitis. The young and theelderly are most often affected.
Pneumococci were first
identified in 1881 and wererecognized as cause of lobar pneumonia (See Image17). Today, pneumococci
have been classified in more
Image 17. Chest X-ray showing
than 90 serotypes based onpneumococcal lobar pneumonia
differences in a polysaccharide capsule that surrounds
them. The polysaccharide capsule plays a role in virulence
and in how the bacteria are processed by the immune system. Some serotypes account for more invasive disease thanothers. The top 20 serotypes account for the majority of disease cases.
Pneumococcal infections can be treated with antibiotics, but
in recent years antibiotic-resistant strains of pneumococci
have emerged. Because of their frequency and because of

the severity of the diseases that they cause, pneumococcal
infections are best prevented by immunization.
The Impact of the Disease
Pneumococcal disease is widespread throughout the world,
and is the most important cause of bacterial meningitis,
pneumonia, and ear infections (otitis media) in the US andin many other countries. Nearly everyone will experience apneumococcal infection during childhood.
Pneumococcal disease can complicate viral infections suchas measles or influenza138. Increases in pneumococcal
disease are observed during influenza outbreaks.
Globally, acute respiratory infections account for almost
2 million deaths in children every year, and 1 million deaths
are from pneumococcal pneumonia in children < 5 years
old139. Most other serious cases of pneumococcal disease
occur in persons 50 years and older.
Prior to childhood immunization in the US, 500,000 episodesof pneumococcal pneumonia137 and 63,000 cases of invasive
pneumococcal disease were estimated to have occurredannually140. About 17,000 of these cases occurred in children
under 5 years of age141. The US experienced about 6,100
deaths from invasive pneumococcal disease each year. About
700 cases of meningitis and 200 deaths occurred annually inchildren under 5 years of age (See Table 21).
The incidence of invasive pneumococcal disease is highest in
infants and young children. Table 22 shows the incidence ratesof IPD in select countries before childhood pneumococcal
vaccines were introduced. Differences in surveillance systems
and diagnostics between, or within, countries may accountfor some of the variation seen.

National Foundation for Infectious Diseases. Facts about pneumococcal disease. http://www.nfid.org/factsheets/pneumofacts.shtml
Black S, Eskola J, Whitney C, et al. Pneumococcal conjugate and pneumococcal common protein vaccines. pp 531-567. In Vaccines 5th edition, S Plotkin, W
Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
140
Centers for Disease Control and Prevention. What would happen if we stopped vaccinations? Pneumococcal.
http://www.cdc.gov/vaccines/vac-gen/whatifstop.htm#pneumo
141
Centers for Disease Control and Prevention. Preventing pneumococcal disease among infants and young children. Recommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR 2000; 49 (RR-9): 1 – 35.
142
Centers for Disease Control and Prevention. Pneumococcal disease and pneumococcal vaccines. May 2009.
www.cdc.gov/vaccines/pubs/pinkbook/downloads/Slides/Pneumo11.ppt
138
139

88 | VACCINE FACT BOOK 2012

3 Public health effectiveness of vaccine implementation

Syndrome

number of cases annuallybacteremia

1,300

meningitis

700

death

200

ear infection (otitis media)

5,000,000

TABLE 21. FREQUENCY OF PNEUMOCOCCAL SYNDROMES IN THE US
IN CHILDREN < 5 YEARS, PRIOR TO CHILDHOOD PNEUMOCOCCALIMMUNIZATION142

Country

periodincidence in < 2 years of age

incidence in < 5 years of age

Japan (Chiba Prefecture)

2003 – 2006

19.5 – 23.8

12.6 – 13.8

Japan (Kamikawa and Soya
sub-prefectures)2000 – 2010

79.2

43.1

UK

1980 – 1999

37.8

20

Spain

1988 – 2001

93.5

55.3 – 58.8

Mozambique

2001 – 2003

US

1998

416
167

100

TABLE 22. INCIDENCE OF INVASIVE PNEUMOCOCCAL DISEASE IN YOUNG CHILDREN IN SELECT COUNTRIES143,144,145,146,147

In addition, some ethnic groups may be particularly vulnerable(See Table 23).

Age (years)

incidence (cases / 100,000) US General Population

incidence (cases / 100,000) US Navajo and Apache

<2

167

2,396

2–4

36

227 (2 – 5 years)

5–9

6

54

10 – 19

3

35

TABLE 23. INCIDENCE OF INVASIVE PULMONARY DISEASE IN CHILDREN IN THE US IN 1998, PRIOR TO THE INTRODUCTION OF A CHILDHOOD
PNEUMOCOCCAL VACCINE148

Sakata H. Invasive Streptococcus pneumoniae infections in children in Kamikawa and Soya subprefecture, Hokkaido, Japan, 2000-2010, before the introductionof 7-valent pneumococcal conjugate vaccine. J Infect Chemother 2011; DOI: 10.1007/s10156-011-0264-8
144
Bernaola Iturbe E, Aristequi Fernandez J, Herranz Aquirre M, et al. Study of the incidence of invasive pneumococcal disease in neonates and children aged lessthan 5 years in the Basque country and Navarre [Spain]. An Esp Pediatr 2002; 57: 301-309.
145
Roca A, Sigauque B, Quinto LI, et al. Invasive pneumococcal disease in children < 5 years of age in rural Mozambique. Trop Med Intl Health 2006; 11:1422-1431.
146
Ispahani P, Slack R, Donald F, et al. Twenty year surveillance of invasive pneumococcal disease in Nottingham: serogroups responsible and implication fro
immunization. Arch Dis Child 2004; 89: 757-762.
147
Ishiwada N, Kurosaki T, Terashima I, et al. Incidence of pediatric invasive pneumococcal disease in Chiba prefecture, Japan (2003-2006). J Infect 2008; 57:
455-458.
148
Centers for Disease Control and Prevention. Preventing pneumococcal disease among infants and young children. Recommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR 2000; 49 (RR-9): 1 – 35.
143

VACCINE FACT BOOK 2012 | 89

Next to the very young, the elderly experience the highest
incidence of invasive pneumococcal disease (IPD). In 19981999, incidence rates in the US were 40.8 / 100,000 for
persons 50 years and over, 61.5 / 100,000 for persons 50 – 64
years, and 61.5 / 100,000 for persons > 65 years.

In 2010, a 13-valent conjugate pneumococcal vaccine waslicensed. It contains types 3, 6A, and 19A in addition to thetypes contained in the 10-valent vaccine.

Mortality rates from IPD in the US are approximately 7–28%
for all age groups and as high as 11–44% for the elderly149.
Case-fatality rates for pneumococcal meningitis can reach
40% and cause permanent injury in 30–50% of cases.

Pneumococcal polysaccharide vaccine has been shownto significantly reduce the risk of invasive pneumococcal
disease in immunocompetent adults. Some studies haveshown the vaccine to have an effectiveness of about 75%,
although the age of vaccination may influence the level andduration of effectiveness.

High-risk groups including persons with HIV, persons
without a spleen, persons with chronic heart and / or lungdisease, and cigarette smokers are particularly vulnerable topneumococcal infections.
In the US, there are about 15 million visits to the doctor eachyear for ear infections (acute otitis media) alone. The cost ofthese visits is estimated at about $5 billion. As many as 55%of these visits may be for pneumococcal infections.
The Vaccines
In 1977, a first pneumococcal vaccine was licensed. The first
vaccine was a polysaccharide vaccine against 14 types ofpneumococci. It was replaced in 1983 with a polysaccharide
vaccine against 23 types (23-valent) (See Table 24). The
23-valent vaccine protected against > 85% of the strains thatcaused invasive pneumococcal disease in adults.

The impact of the vaccine

Efficacy from clinical trials for conjugate pneumococcal
vaccine has ranged from over 75% to over 95% against
invasive disease caused by the serotypes contained in thevaccine. Childhood pneumococcal vaccination has had analmost immediate impact on the burden of pneumococcal
disease (See Figure 81)150.
In addition, childhood conjugate pneumococcal immunization
programs have had a herd effect, impacting the incidenceof disease in unvaccinated age groups (See Figure82)151. By 2003, there were 30,000 fewer cases of invasive
pneumococcal disease in the US, including 20,000 fewer inchildren and adults who did not receive the vaccine152!

Pneumococcal serotypes contained in the 23-valent polysaccharide vaccine

But polysaccharide vaccines are typically insufficiently
immunogenic in infants and young children. To renderpolysaccharide vaccines immunogenic in this age group,a protein is coupled to the polysaccharide. This process isknown as protein conjugation.
A conjugate pneumococcal vaccine was first licensed in
2000. The first conjugate vaccine protected against the seventypes most frequently responsible for invasive pneumococcal
disease in US infants and young children (See Table 25). It
protected against about 90% of IPD in this age group.
In 2009, a 10-valent (decavalent) conjugate pneumococcal
vaccine was licensed. It contains types 1, 5, and 7F, in addition
to the types in the 7-valent vaccine. These three serotypes are
more prevalent in developing countries.

1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F,
20, 22F, 23F, 33F
TABLE 24. PNEUMOCOCCAL TYPES CONTAINED IN 23-VALENTPNEUMOCOCCAL POLYSACCHARIDE VACCINE

Pneumococcal serotypes contained in the 7-valent conjugate vaccine

4, 6B, 9V, 14, 18C, 19F, 23F

TABLE 25. PNEUMOCOCCAL TYPES CONTAINED IN 7-VALENTPNEUMOCOCCAL CONJUGATE VACCINE

Black S, Eskola J, Whitney C, et al. Pneumococcal conjugate and pneumococcal common protein vaccines. pp 531-567. In Vaccines 5th edition, S Plotkin, W
Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
150
Centers for Disease Control and Prevention. Pneumococcal disease and pneumococcal vaccines. May 2009.
www.cdc.gov/vaccines/pubs/pinkbook/downloads/Slides/Pneumo11.ppt
151
Simonsen L, Taylor RJ, Young-Xu Y, et al. Impact of pneumococcal conjugate vaccination of infants on pneumonia and influenza hospitalizations and mortality inall age groups in the United States. mBio 2011; 2(1):e00309-10.
149

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3 Public health effectiveness of vaccine implementation

A decline in antibiotic-resistant serotype invasive
pneumococcal infections has also been observed in the US.
Conjugate pneumococcal vaccination has reduced
incidence of vaccine-preventable serotypes by 99–100% asdemonstrated in post-licensure studies. Since the first
vaccine was licensed in 2000, most industrialized countries
have introduced conjugate pneumococcal vaccination for
infants where incidences have also declined remarkably. The
use of these vaccines in developing countries, where theburden of pneumococcal disease is very high, is expected tosave millions of lives.
The vaccine has been highly cost effective, costing about$7,800 / life-year saved in the US when accounting for a herd
effect. The herd effect and reduction of infectious pulmonary
disease in adults is even greater than the direct impact
on children.

	  FIGURE 81. DIRECT IMPACT OF CONJUGATE PNEUMOCOCCAL IMMUNIZATION ON INCIDENCE OF
PNEUMOCOCCAL DISEASE IN < 5 YEARS OF AGE	  FIGURE 82. IMPACT OF CHILDHOOD PNEUMOCOCCALVACCINE FACT BOOK 2012 | 91

3.8 Varicella Zoster virus (VZV)The Cause153

The Impact of the Disease

Varicella zoster virus (VZV)
causestwodiseases:varicella (chickenpox) andherpes zoster (shingles).
Varicella is a disease
resembling smallpox (SeeImage 18). It wasn’t until
1767 that varicella wasrecognized as distinct fromsmallpox. A century later,
Steiner proved that varicellawas infectious. In 1892,
Bokay suggested that there
Image 18. Typical pustular lesions
was a link between varicellaof varicella in a child.
SOURCE: CDC PUBLIC HEALTH IMAGE LIBRARY
and herpes zoster and that
HTTP://PHIL.CDC.GOV/PHIL/DETAILS.ASP
these were two different
diseases that result from the same virus154.

	  Varicella
Almost all humans are infected by the fourth decade of life, but
the incidence of the disease peaks in early childhood. Prior
to immunization in the US, the annual incidence of disease
was approximately 1,500 – 1,600 / 100,000 (See Table 26).
There were approximately 4 million cases of varicella annually
and about 11,000 to 13,500
hospitalizations in the US.
	
  Varicella is transmitted by the viruses contained in the skinlesions, or from the upper respiratory tract through air (SeeFigure 83). There is only one serotype of Varicella zoster virus
and the disease is exclusive to humans.

Varicella predisposes togroup A Streptococcus
infections and can lead topneumonia in the young.
Image 19. Herpes zoster showing
The case- fatality rate in thevesicular rash localized over theright chest.
US prior to immunization
SOURCE: FISLE HTTP://EN.WIKIPEDIA.ORG/WIKI/
approximated 2.6 deaths
FILE:HERPES_ZOSTER_CHEST.PNG
per 100,000 cases. But
fatality rates are 20 times
higher in adults and 50 times higher in developing countries.
In countries with high HIV sero-prevalence, fatality rates may
be higher.

A first infection results in varicella. The virus then remains
dormant in the body. When the body’s immune system isweakened, for any number of reasons, the virus can bereactivated and cause herpes zoster.

The major economic impact of the disease is from school
and workdays missed due to parents caring for sick children.
Hospitalization rates in industrialized countries may average
4.0 - 4.5 / 100,000 population.

Herpes zoster is a painful vesicular rash localized to a portionof the body such as around the waist (See Image 19).
Figure 83.
Transmissionof varicellazoster virus
from varicella isairborne from skinlesions or upper
respiratory tract.
SOURCE: E PALMER CDC
PUBLIC HEALTH IMAGE
LIBRARY HTTP://PHIL.CDC.
GOV/PHIL/DETAILS.ASP	  Country

Cases of varicella / 100,000 population

United Kingdom

240 - 880

Scotland480 - 790

France1,000 – 1,350

United States

1,500 – 1,600

TABLE 26. INCIDENCE OF VARICELLA IN SELECT COUNTRIES PRIOR TO
THE INTRODUCTION OF VARICELLA VACCINATION152

Centers for Disease Control and Prevention. What would happen if we stopped vaccinations? Pneumococcal.
http://www.cdc.gov/vaccines/vac-gen/whatifstop.htm#pneumo
153
Gershon AA, Takahashi M, Seward JF. Varicella vaccine. pp 915-958. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier,
China, 2008.
154
Gershon AA, Takahashi M, Seward JF. Varicella vaccine. pp 915-958. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier,
China, 2008.
152

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3 Public health effectiveness of vaccine implementation

Herpes zoster

The impact of the vaccine

Prior to immunization, by 40 years of age more than 99%of the population had been infected with varicella-zoster
virus. The at-risk population for herpes zoster was therefore
enormous. The annual incidence of herpes-zoster in the US,
in the general population, was 120 – 480 / 100,000, but 720-1,180 frequency / 100,000 for persons 60 years and older155.
This represented > 1 million cases / year.

Immunogenicity to varicellavaccine is excellent andvaccineefficacyfromclinical trials has been
evaluated at more than
90% from a single doseand over 98% after two
doses. Effectiveness trialsof vaccines post-licensure
confirm rates as high as
100% against moderate orsevere disease156.

The Vaccine
All strains of Varicella Zoster virus used to produce varicellavaccines are derived from the Oka strain of VZV. This strain
and a corresponding vaccine were originally developed byMichiaki Takahashi in Japan, at the University of Osaka.
The vaccine was first introduced in Japan, in 1988. It waslicensed in the US in 1995. It is available from several suppliersin a monovalent form, or in combination with Measles,
Mumps, Rubella vaccine. The quadrivalent vaccine (MMRV)
was licensed in the US in 2005.
A higher-dose VZV vaccine for the prevention of herpes zoster
was licensed in the US in 2006.
VZV vaccines are believed to impart long-lasting immunity (10– 20 years). They may result in mild rash and fever in about
5% of vaccine recipients.

Countries using childhood
varicella vaccine
Australia
CanadaGermany
Israel
Italy
Korea, South
Qatar
Uruguay
United States
TABLE 27. COUNTRIES THATHAVE UNIVERSAL CHILDHOOD
VARICELLA IMMUNIZATIONPROGRAMSThe US was the first
country to introduce a
universal childhood varicellaimmunization program, in
1995, but close to a dozen other countries now have similar
programs (See Table 27).
The US ACIP recommends a two-dose policy for varicellain children, similar to MMR vaccine. Since the introductionof varicella vaccine in the US, the incidence of varicellahas declined by as much as 90% and hospitalizations havebeen reduced by > 90% in children (See Figure 85)157. Direct
expenses for hospitalizations and care for varicella had
decreased by 74% by 2005.

FIGURE 84. IMPACT OF VARICELLA IMMNIZATION BY AGE IN TWO SURVEILLANCE CENTERS IN THE US.

Levin MJ. Zoster vaccine. pp 1057-1068. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
Gershon AA, Takahashi M, Seward JF. Varicella vaccine. pp 915-958. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier,
China, 2008.
157
Gershon AA, Takahashi M, Seward JF. Varicella vaccine. pp 915-958. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier,
China, 2008.
155
156

VACCINE FACT BOOK 2012 | 93

3.9 Hepatitis B

The Cause158
Hepatitis B virus infects the liver and alters liver function. The
disease can be both acute and chronic. In acute disease,viral infection results in raised liver enzyme levels after about
60 days and causes jaundice about 90 days after infection.
The liver becomes large and painful and about 40% of
infections lead to hospitalization, in the US. About 0.5 – 1% of
infections may result in a fulminant form of disease (very rapid
progression) leading to liver failure. In the fulminant form, up
to 33% of cases result in death.

20. CT scan showing	  Imageenlargement of the liver as often
occurs in chronic hepatitis B
infections.
SOURCE: HTTP://UPLOAD.WIKIMEDIA.ORG/
WIKIPEDIA/COMMONS/F/FE/SE000.JPG

In chronic infections, there
is an initial period of viral
replication in the liver. Thisis followed by a period oflow (or no) viral replicationand no liver disease.
But hepatitis B surface
antigen (HBsAg) persist in
the blood for at least six
months. Chronic hepatitis
B increases the risk ofhepatocellular
carcinoma(cancer of the liver) andcirrhosis (See Image 20).

The virus spreads by transmission from mother to child atbirth, close contact, sexual contact and direct contact withmucosa, blood or body fluids (See Figure 85). In the US,
about 24,000 infants are born to Hepatitis B-infected mothers.
About 50% of new cases in the US are acquired by sexual
contact, and 15% from injection-drug use.

	
  Figure 85. Transmission of hepatitis
B virus is from body fluids andsexual contact
SOURCE: E PALMER CDC PUBLIC HEALTH IMAGESLIBRARY HTTP://PHIL.CDC.GOV/PHIL/DETAILS.

The risk of developing chronic infection is greatest when
acquired perinatally or in early childhood. At a young age
most infections are asymptomatic.
The Impact of the Disease
Globally, about 2 billion people have been infected, and 350
million are living with chronic hepatitis B infection. About
600,000 die each year from the consequences of chronic
hepatitis B infection (See Figure 86)159. 25% of adults withchronic hepatitis B who became infected during childhood
will die of liver cancer or liver cirrhosis.
600,000 deaths each year
from chronic hepatitis B
infections
350 million livingwith chronic
hepatitis B
infections

2 billion hepatatis B infections

FIGURE 86. GLOBAL IMPORTANCE OF HEPATITIS B

In the US, prior to hepatitis B immunization, about 200,000–
300,000 persons were infected each year. There are about
1.25 million chronic hepatitis B infections in the US, resulting
in 4,000–5,000 deaths each year160.
The prevalence of chronic infections is much higher in theseregions: East Asia, Southeast Asia, the Middle East, theAmazon basin, the Pacific Islands and Africa. In these regions,the lifetime risk of developing hepatitis B is > 60%. Before
immunization was introduced in East Asia and Southeast
Asia, as many as 30–50% of chronic infections in children
were the result of transmission from the mother to the childat birth.

Mast EE, Ward JW. Hepatitis B vaccine. pp 205-241. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
World Health Organization. Media center. Hepatitis B. Fact sheet n°204. August 2008. http://www.who.int/mediacentre/factsheets/fs204/en/index.html
160
Mast EE, Ward JW. Hepatitis B vaccine. pp 205-241. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
158
159

94 | VACCINE FACT BOOK 2012

3 Public health effectiveness of vaccine implementation

The Vaccine
The first hepatitis B vaccine developed and licensed in 1981
was produced from the plasma of persons chronically infectedwith hepatitis B. Hepatitis B surface antigen was filtered fromthe plasma and served as the vaccine antigen. In 1986 a
recombinant protein vaccine was licensed. The recombinantvaccine was manufactured from hepatitis B surface antigen
produced in yeast cells.
The vaccine is given in three or four doses in a primary series
by injection. More than 150 countries now recommend
hepatitis B vaccination. Hepatitis B vaccine is commonly
administered in combination with other childhood vaccines.

FIGURE 87. IMPACT OF ROUTINE INFANT HEPATITIS B IMMUNIZATION IN
THE US162

	  Serious adverse events are extremely rare, but local transient
mild reactions occur. Pain (3-29%) and fever (1-6%) are mostcommon reported.
The impact of the vaccine
Recombinant hepatitis B vaccines are 80-100% effectiveat preventing hepatitis B infections and 70-95% effective atpreventing perinatal infections if the first dose is given within
12 hours of birth161.
Everywhere they have been used, hepatitis B vaccines havesignificantly reduced the incidence of acute hepatitis B.
In the US, reports of acute hepatitis B have continued to
decline since the introduction of routine infant hepatitis B
vaccination in 1991. However, because many infections are
asymptomatic or go unreported, reports of acute hepatitis B
may underestimate the true number of new infections (SeeFigure 87).

FIGURE 88. EFFECTIVENESS OF HEPATITIS B VACCINES AT REDUCING
THE PREVALENCE OF CHRONIC HEPATITIS B INFECTIONS IN SELECTCOUNTRIES163	  In addition to reducing the incidence of acute hepatitis B
infections, routine infant hepatitis B immunization has also
been found to be effective at reducing the incidence ofchronic hepatitis B infections (See Figure 88).

Mast EE, Ward JW. Hepatitis B vaccine. pp 205-241. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
Centers for Disease Control and Prevention. Viral hepatitis statistics and surveillance. Disease burden from viral hepatitis A, B, and C in the United States.
http://www.cdc.gov/hepatitis/Statistics/index.htm
163
Mast EE, Ward JW. Hepatitis B vaccine. pp 205-241. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
161
162

VACCINE FACT BOOK 2012 | 95

4 Vaccines in use

4.1 GloballyMore than 40 vaccines have been developed for the preventionof human diseases. Several vaccines protect against multiple
serotypes of virus or bacteria (e.g. polio types 1, 2, and 3).
Several vaccines are delivered in combination to protect
against multiple diseases.
Most countries routinely use only a portion of vaccines
available to them. The selection of vaccines for use in a nationalschedule is based on the local epidemiology and the risks
associated with each specific vaccine-preventable disease.

In resource-poor countries, the WHO recommended theprioritization of childhood immunization and the protectionof women of child-bearing age. For more than 20 years,
the EPI targeted only six diseases: tuberculosis, polio,
measles, diphtheria, pertussis and tetanus. Now WHO
recommendations are part of an overarching strategy andvision for immunization that promotes routine immunization of
all age groups and includes several additional target diseases(See Table 28).

In 1974, the World Health Assembly resolved to build on the
success of the smallpox eradication program and ensurethat all children benefited from the ability of vaccines to save
lives. In 1977, the WHO set a goal of providing universal
immunization for children by 1990, through the Expanded
Programme on Immunization (EPI)164.

Universal recommendations
AntigenChildrenBCG (tuberculosis)√

Hepatitis B

√

Polio

√

Diphtheria, Tetanus, Pertussis√

Haemophilus influenzae
type b (Hib)√

Pneumococcal conjugate√

Rotavirus√

Measles√

Human Papillomavirus
TABLE 28. WORLD HEALTH ORGANIZATIONRECOMMENDATIONS FOR IMMUNIZATION165

Regional recommendations

AdolescentsJapanese
Encephalitis Virus√

Yellow Fever√

For high risk or notpreviously immunized

Td booster種Td booster

booster

Some High-Risk recommendations
Typhoid

Primary series and booster

CholeraPrimary series and booster

Meningococcal A√

Hepatitis A

Primary series

RabiesPrimary series

Recommendations for some immunization programs
Mumps

√

Rubella√Or adolescent girls and women ofchild-bearing age

Influenza√

Revaccinate annuallyGirls only

Mast EE, Ward JW. Hepatitis B vaccine. pp 205-241. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds, Saunders Elsevier, China, 2008.
World Health Organization. Immunization service delivery and accelerated disease control. Expanded programme on immunization.
http://www.who.int/immunization_delivery/en/165
World Health Organization.Table 1. Recommended Routine Immunization – Summary of WHO Position Papers. October 21, 2010.
http://www.who.int/immunization/policy/Immunization_routine_table1.pdf
163
164

96 | VACCINE FACT BOOK 2012

4.2 USIn the US, immunization has been classified as one of the top
10 public health achievements of the 20th century. Vaccinepreventable diseases are now at a record low. In addition,for every dollar the US spends on immunization against 10
vaccine-preventable diseases (diphtheria, tetanus, pertussis,
polio, hepatitis B, Haemophilus influenzae type b, measles,
mumps, rubella, and varicella), it saves $5.30 and society
saves $16.50166. Every 26 days, the US saves the equivalentof its entire investment in the smallpox eradication programfrom savings on treatment of disease alone167.
In 1977, the US launched a national immunization initiative.
Its goals were to achieve national vaccination coverage of
90% by 1979 and establish a permanent system to provide
immunization services to the annual US birth cohort of3 million. At that time, an estimated 20 million children were
not fully immunized.
In 1991, a new objective was set: to ensure that 90% ofchildren had completed the full series of vaccinations by
their 2nd birthday. And in 1993, the Childhood Immunization
Initiative was launched to improve the quality and quantityof vaccine delivery services, expand access to vaccines,
enhance community involvement, improve the measurementof immunization coverage and surveillance of vaccinepreventable diseases, simplify the immunization schedule,
and improve vaccines.

“
In 1991, a new
objective was set:to ensure that
90% of children
had completed
the full series ofvaccinations by their
2nd birthday.

The number of vaccine-preventable diseases covered by
the current childhood immunization schedule in the US has
doubled, from eight to 16 diseases, in the last 20 years (SeeTable 29).

Orenstein, WA, Rodewald LE, Hinman AR, et al. Immunization in the United States. pp 1479-1510. In Vaccines 5th edition, S Plotkin, W Orenstein and P Offit, Eds,
Saunders Elsevier, China, 2008.
167
Brilliant LB. The management of smallpox eradication in India: a case study and analysis. Ann Arbor, University of Michigan Press, 1985.
166

VACCINE FACT BOOK 2012 | 97

Age of administration
AntigenBirth

2months1 month4
months6months12months15
months18
months19-23
monthsInfluenza

4-6
years

7-10
years

11-12
years

13-18
years

Annually

Inactivated
Polio

√

√

Pneumococcal
conjugate

√

√

√

√

Haemophilus
influenzae type
b

√

√

√

√

√

Diphtheria,
Tetanus,acellular
Pertussis√√√

Rotavirus√√√

Hepatitis B

2-3
years

√

√
Pneumococcal polysaccharide high-risk√√

Tetanus,diphtheria,acellular
pertussis√√

TABLE 29. CHILDHOOD IMMUNIZATION SCHEDULE IN THE US (EXCLUDING CATCH-UP SCHEDULE)168

Age of administration
AntigenBirth

1 month2
months4months6months12months15
months18
months19-23
months

2-3
years

4-6
years

Measles,
Mumps, Rubella√√

Varicella√√

Hepatitis A
Meningoccal
conjugate
Human
Papillomavirus

7-10
years

11-12
years

13-18
years

high-risk√
high-risk

√

girls

Centers for Disease Control and Prevention. Vaccines & Immunizations. Recommendations and guidelines: 2011 child and adolescent immunization schedules for
persons aged 0 – 6 years, 7 – 18 years, and “catch-up schedule”.http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm
168

98 | VACCINE FACT BOOK 2012

4 Vaccines in use

The Adult Immunization Schedule, in addition to providing
for boosters of childhood vaccines, also provides for
immunization against varicella zoster, an excruciatingly
painful and potentially neurologically damaging condition(See Table 30).

Antigen19-26 years

27-49 years

Influenza60-64 years≥ 65 years

1 dose annually

Tetanus, Diphtheria, Acellular Pertusis /Tetanus, Diphtheria

1dose of Tdap then Td every 10 years

Varicella
Human Papillomavirus

50-59 years

Td every 10 years

2 doses if no evidence of immunity
3 doses (females) if
not yet received

Herpes zoster
Measles, Mumps, Rubella
Pneumococcal polysaccharide

1 dose1 or 2 doses

1 dose high-risk
1or 2 doses high-risk

Meningococcal polysaccharide

1 or more doses high-risk

Hepatitis A

2 doses high-risk

Hepatitis B

3 doses high-risk

1 doseTABLE 30. ADULT IMMUNIZATION SCHEDULE IN THE US169

US Department of Health and Human Services and Centers for Disease Control and Prevention. Recommended adult immunization schedule United States 2011.
http://www.cdc.gov/vaccines/recs/schedules/downloads/adult/adult-schedule.pdf
169

VACCINE FACT BOOK 2012 | 99

4.3 European Union

√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√

√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√

√
√
√
√
√
√
√
√
√
√
√
√
√
√

√

√
√
√
√

√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√

√
√

√

√
√

√
√

√

√

√
√

√

√
√

√

√
√
√

√
√

√
√

√
√
√

√
√
√

√
√
√

√
√

√
√

√
√

√

√
√

√
√
√
√
√
√
√

√

√
√

√
√

√

√

√

√
√

√
√
√

Euvacnet. National childhood vaccination schedules. http://www.euvac.net/graphics/euvac/vaccination/vaccination.html

100 | VACCINE FACT BOOK 2012

√

√
√

√

√
√
√
√
√

TABLE 31. CHILDHOOD VACCINES USED IN EUROPEAN COUNTRIES (LAST UPDATE OF SCHEDULE RANGE FROM DEC 2006 – JULY 2011)170

170

Meningococcal C

Varicella

Diphtheria, Tetanus,
Acellular Pertussis

Tetanus

Diphtheria, TetanusInactivated Polio√

Rotavirus

√
√
√

Human
Papillomavirus

√
√
√
√
√
√
√
√

Diseases typically targeted by immunization in Europe areshown by country in Table 31 below.

Diphtheria, Tetanus

√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√*
√
√
√
√
√
√
√
√*
√

related to immunization. The EURO policy framework targets
a number of diseases for prevention by vaccination.

Measles, Mumps,
Rubella

√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√

Pneumococcal
Conjugate

√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√*
√
√
√
√
√
√
√
√
√

Hepatitis B

Inactivated Polio

√
√
√
√

Haemophilus
iinfluenzae type b

Austria/08
Belgium/11
Bulgaria/10
Croatia/08
Cyprus/09
Czech/10
Denmark/09
Estonia/09
Finland/11
France/10
Germany/10
Greece/07
Hungary/10
Iceland/10
Ireland/10
Italy/08
Latvia/11
Lithuania/08
Luxemburg/08
Malta/10
Netherlands/06
Norway/10
Poland/07
Portugal/09
Romania/10
Slovakia/11
Slovenia/09
Spain/08
Sweden/10
Switzerland/08
Turkey/10
United Kingdom/11

Diphtheria, Tetanus,
Acellular Pertussis

Country / year last
updatedBCG (tuberculosis)

European countries do not have a unified vaccination policy.
The number and types of vaccines used in European countries
varies from one country to the other. However, the European
Union’s European Center for Disease Prevention and Control(ECDC) and the WHO’s European Regional Office (EURO)do provide common guidance to member states on matters

√

√
√
√

4 Vaccines in use

4.4 Australia

The Australian childhood immunization schedule closely
resembles that of the US (See Table 32).

Age of administration
2
months4months6months12months

√

√

√*

√*

Rotavirus√√√

Diphtheria, Tetanus,
Acellular Pertussis

√

√

√

Haemophilus influenzae
type b√√√Pneumococcal conjugate

√

√

√

Antigen

Birth

Hepatitis B

√

1
month

18
months4 years

10
years

12
years

13
years

15-17 years√

Tetanusdiphtheria,acellular
pertussis√√

Pneumococcal
polysaccharide
Inactivated Polio

24
monthshigh-risk
√

√

√

√
Aboriginalhigh-risk

Influenza
Measles, Mumps, Rubella√√

Varicella√

Hepatitis A

high-risk

Meningococcal C conjugate√√

Human Papillomavirus

girls

TABLE 32. AUSTRALIAN CHILDHOOD IMMUNIZATION SCHEDULE

171

The adult Australian immunization schedule provides forpneumococcal and influenza vaccines. Influenza is not part of
the routine childhood immunization schedule (See Table 33).

Antigen15 - 49 years

50 years and over

65 years and over

Influenzahigh-risk Aboriginal

Aboriginal

√

PPV23

high-risk Aboriginal

Aboriginal√

TABLE 33. AUSTRALIAN ADULT IMMUNIZATION SCHEDULE172
Australian government. Department of Health and Ageing. National Immunisation Program Schedule (Valid from 1 July 2007).
http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/E875BA5436C6DF9BCA2575BD001C80BF/$File/nip-schedule-card-july07.pdf
172
Australian government. Department of Health and Ageing. National Immunisation Program Schedule (Valid from 1 July 2007).
http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/E875BA5436C6DF9BCA2575BD001C80BF/$File/nip-schedule-card-july07.pdf
171

VACCINE FACT BOOK 2012 | 101

4.5 Japan

Like in many industrialized countries, vaccines in thechildhood immunization schedule in Japan are provided at no
cost in public health centers. But Japan has been slow to
adopt many of the newest vaccines from the last 10 – 15 years
and its immunization schedule resembles the schedule of a

Gross National Income / capita (US$)
BCG (tuberculosis)

country of much lower economic status. A table of Japan’schildhood immunization schedule relative to countries in theregion with comparable or much lower levels of wealth isshown in Table 34 below.

Japan

Australia

Korea, South

Singapore

Indonesia

ThailandUSA

37,78043,77018,83037,2202,230

37,76047,240

√

√

√

√

√

√

√

√

√

Diphtheria, Tetanus, Pertussis
Diphtheris, Tetanus, Acellular Pertussis√

Oral Polio√

Inactivated Polio
Haemophilus influenzae type b

√

√

√
√

√

Hepatitis B

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

√

Tetanus
Diphtheria, Tetanus√√

Measles. Mumps, Rubella
Japanese Encephalitis Virus√√

Measles
Measles, Rubella or combination

√

√
√

√

Tetanus, Diphtheria√

Tetanus, Diphtheria, Acellular Pertussis
Pneumococcal conjugate√

Varicella√Meningococcal C conjugate

√

√
√

√

√

√

√

√

Meningococcal A,C,W,Y conjugate

high risk√

Human Papillomavirus

√

√

√

Rotavirus√√√

high risk√

Hepatitis A
Typhoid
Influenzahigh risk√

high risk

high risk√√

TABLE 34. JAPAN’S CHILDHOOD IMMUNIZATION SCHEDULE COMPARED TO OTHER COUNTRIES IN THE REGION AND THE US

173

World Health Organization. WHO Vaccine Preventable Diseases Monitoring System.
http://apps.who.int/immunization_monitoring/en/globalsummary/countryprofileselect.cfm
173

102 | VACCINE FACT BOOK 2012

4 Vaccines in use

4.5.1 Current situation in Japan

Japan was one of only a few pioneering countries in vaccine
development. Several vaccines were developed first in Japanand later produced or further adapted in other countries.
Ironically, Japan has lagged behind most countries ofsimilar economic development in both vaccine policy andimplementation. Over the last several decades, the US andcountries in the European Union have outpaced Japan indeveloping policies and practices for the introduction of new
vaccines.
Initiatives, such as the Childhood Immunization Initiative of theearly 1990s, helped the US to develop systems to efficiently
achieve public health objectives for disease prevention.
These systems include the provision of vaccines for children
who are uninsured or otherwise would not have access toimmunization.
Likewise, the WHO’s Vision and Immunization Strategy,
launched at the start of the 2000s, was developed toassist developing countries to further develop policies andimmunization objectives. At the start of the 2000s, many
developing countries had not updated their immunization
programs and policies from the 1970s when they were firstlaunched. The WHO’s overarching strategy for immunization
has evolved to include several new vaccines that have become
available since the 1970s. It also includes new target groups,
such as adolescents and adults, for specific immunizations.
The relatively high incidence of deafness from mumps in Japan,
when the US and countries in Europe have virtually eliminatedthe disease, highlights the divergence in immunization policy
and implementation between Japan and countries of similar
economic status. In the absence of a renewed or reinvigoratedemphasis on immunization in Japan, the contrast in publichealth outcomes may become increasingly apparent. With
clear objectives, solid policies, and robust implementation
systems, Europe and the US have been very quick to adopt
recently licensed vaccines. These investments in prevention
are expected to have net advantages over curative care thatwould otherwise be required, particularly at a time of budgetary
constraint and austerity.
Therefore, Japan has recently undertaken to reform vaccine
policy and practice, as evidenced by the activities of the Vaccine
Committee of the Ministry of Health, Labor and Welfare.

VACCINE FACT BOOK 2012 | 103

5 Vaccines in development

Vaccine research and development is lengthy and risky. Fromdiscovery to license requires 10 to 15 years. Approximately
one out of 10 vaccines that enter clinical development willreach the market. Which vaccines will be successfully
developed is impossible to predict.

In 2011, the global leaders in vaccine research anddevelopment reported the vaccines shown in Table 35 to beunder clinical development.

Over 100 vaccines are currently under development. A few ofthese may reach the market in the next decade.

Manufacturer

Phase I

Phase II

Phase III

Pneumococcal conjugate

9-valent Human Papillomavirus
inactivated Herpes Zoster
6-valent pediatric combination (diphtheria, tetanus,
pertussis, polio, hepatitis B, and Haemophilus
influenzae type b)

Merckcell-cultured influenza vaccine; pediatric influenza
vaccineNovartis

Pfizercytomegalovirus

Pseudomonas aeruginosagroup B Streptococcus

meningococcal B

HIVcell-cultured influenza

pneumococcal

conjugate meningococcal A, B, C, Y, W135

3 and 4-valent
Staphylococcus aureas

Alzheimer’s diseaseadolescent and infant meningococcal B

rotavirus

6-valent pediatric combination (diphtheria, tetanus,
pertussis, polio, hepatitis B, and Haemophilus
influenzae type b)

4-valent pediatric combination (diphtheria, tetatnus,
pertussis, polio)

pneumococcal

Clostridium difficile

6-valent pediatric combination (diphtheria, tetanus,
pertussis, polio, hepatitis B, and Haemophilus
influenzae type b)

Pseudomonas
aeruginosarabies post-exposure prophylaxis

4-valent inactivated influenza

tuberculosis

rabies4-valent dengue

Sanofi Pasteur

4-valent meningococcal a, C, Y, W135 conjugate

GlaxoSmithKline

cell-cultured influenza

7-valent pediatric combination (diphtheria, tetanus,
pertussis, polio, hepatitis B, Haemophilus influenzae
type b, and meningococcal C conjugate)

4-valent inactivated influenza

HIVmeasles, mumps, rubella

Herpes Zoster

pneumococcal conjugateHIVtuberculosis
TABLE 35. VACCINES UNDER DEVELOPMENT BY GLOBAL VACCINE LEADERS, BY CLINICAL PHASE OF DEVELOPMENT174,175,176,177,178
Merck. Merck pipeline. July 29, 2011. http://www.merck.com/research/pipeline/home.html
sanofi pasteur. sanofi pasteur R&D portfolio. Feb 9, 2011.
http://www.sanofipasteur.com/sanofi-pasteur2/front/index.jsp?siteCode=SP_CORP&codePage=PAG_22_1288245984593&lang=EN&codeRubrique=22
176
Pfizer. Pfizer pipeline – our medicines in development. Aug 11, 2011. http://www.pfizer.com/research/product_pipeline/product_pipeline.jsp
177
Novartis. Welcome to Novartis vaccines. Pipeline. 2011. http://www.novartisvaccines.com/products-diseases/pipeline.shtml
178
GlaxoSmithKline. Product development pipeline. Feb 2011. http://www.gsk.com/investors/product_pipeline/docs/gsk-pipeline-2011.pdf
174
175

104 | VACCINE FACT BOOK 2012

In addition, in its report of 2006, the WHO noted vaccine
research and development in specific disease areas (SeeTable 36). Some of these trials have now been completed.
Others have been discontinued. Some have progressed to afurther stage of development.

Disease Area

VaccineCholeraEscherichia coli

Diarrheal diseases

Rotavirus
Shigella“
Vaccine researchand development
is lengthy and risky.
From discovery to
license requires
10 to 15 years.
Approximately oneout of 10 vaccinesthat enter clinicaldevelopment willreach the market.

Typhoid fever
Influenza
Parainfluenza virus type 3
Respiratory syncytial virus
Respiratory diseases

Severe Acute Respiratory Syndrome(SARS)
Pneumococcal
Tuberculosis
Anthrax
Meningococcal A, C, Y, W135

Bacterial diseases

Meningococcal B
PlagueGroup A Streptococcus
Group B Streptococcus
Chlamydia trachomatis

Sexually transmitted diseases

Herpes simplex type 2HIV
Dengue fever

Vector-borne diseases

Japanese encephalitis
West Nile virus
Hookworm

Parasitic diseases

Leishmania
Malaria
Schistosomiasis
Helicobacter pylori
Hepatitis B

Hepatitis and cancers

Hepatitis C
Hepatitis E
Human Papillomavirus
Epstein-Barr virusEnterovirus

Polio

TABLE 36. VACCINE RESEARCH AND DEVELOPMENT BY DISEASE AREA179

World Health Organization. Immunizations and Vaccine Research. New vaccines against infectious diseases: research and development status. Updated Feb 2006.
http://www.who.int/vaccine_research/documents/en/Status_Table.pdf
179

VACCINE FACT BOOK 2012 | 105

This project was supported by MSD, Novartis Pharma K.K., Pfizer, and Sanofi Pasteur.