Volume 1/Issue 1/115e150

Contents lists available at ScienceDirect

CHAPTER 5
Understanding Modern Vaccines:
Perspectives in Vaccinology

Vaccine development
Authors: Geert Leroux-Roels, Paolo Bonanni,
Terapong Tantawichien, Fred Zepp

Key concepts
n Vaccine development is a complex multistep process
n From concept to licensure, it takes many years to develop a vaccine
n Following authorisation to market, it may be necessary to provide evidence of economic value prior to governments
approving the implementation of a new vaccination programme
n Safety is a major issue for any vaccine; it is assessed at every step of vaccine development and safety
surveillance continues indefinitely after licensure
n Sometimes an adverse reaction is observed after a vaccination. It is important to determine whether a temporal
association between the adverse event and the vaccination is causal, rather than a random chance occurrence
(coincidental). Otherwise, vaccination programmes are halted for risks that are only theoretical, thus
endangering people’s health through not being vaccinated
n Clinical and epidemiological studies indicate that licensed vaccines have a benefiterisk profile where the
benefits of vaccines clearly outweigh the risks of adverse effects

Ó 2011 Elsevier B.V. Open access under CC BY-NC-ND license.

doi:10.1016/j.pervac.2011.05.005
116 UNDERSTANDING MODERN VACCINES

Overview
Vaccine development is a complex and lengthy process that
has evolved and expanded especially over the last few decades.
Early on, the focus of the vaccine development process was the
immunogenicity and efficacy of the vaccines, which were
generally developed for diseases with significant burdens of
morbidity; often with high mortality as well. As once-prevalent
deadly diseases have become uncommon, or even eliminated,
the focus of vaccine development has shifted to place even
greater emphasis on benefiterisk profiles, with increased
attention paid to the safety of vaccines. Moreover, the general
public has become increasingly sensitive to potential safety
issues of vaccines, as it no longer fears the diseases for which
the vaccines were developed. As a consequence, the need to
demonstrate vaccine safety requires more investigations today
than was necessary in the past. This need is reflected in more
comprehensive regulatory and licensing procedures aiming to
ensure that a new vaccine has a benefiterisk profile where the
benefits are many times greater than the risks.
Economic considerations also play an increasing role in vaccine
implementation. The older vaccines could be introduced to market
primarily based upon mortality reduction arguments; however,
nowadays there is a shift towards economic argumentation where
the implementation of a new vaccine depends upon the perceived
value of the programme outweighing the cost.
It was the introduction of the first conjugate pneumococcal vaccine
that heralded economic evaluation of vaccines. Interestingly, this
vaccine was initially determined not to be cost-effective; however
this was challenged when the indirect benefits (herd protection
effects) of vaccination were included. While more complex vaccines
are developed, calculation of the overall investment/return ratio
is important for governments and healthcare providers, as they
evaluate the desirability of introducing a particular vaccine. This
chapter gives an overview of the key considerations and processes
involved in vaccine development, licensure and implementation,
 VACCINE DEVELOPMENT 117

and will highlight where experience has led to changes that have
improved development processes.

Principles of vaccine development

There are many groups with an interest in vaccine development; this
includes patient groups, medical professionals, policy makers,
governments and payers (eg government funds, health insurance
companies, public or private health maintenance organisations
etc). Many factors and points of view are therefore considered when
deciding to develop or implement a new vaccination programme.
Some of the key points are discussed here.

ASSESSMENT OF DISEASE BURDEN

The initial step in vaccine development is determining the disease

burden and defining the target population for a new vaccine (the
population that will gain the most from vaccine introduction).
Disease burden is the impact of a health problem in a region or
population, dependent upon the frequencies of the disease, the
impact on quality of life (mortality and morbidity), healthcare
resource use and other indicators such as financial cost to society.
These factors, which vary among diseases, are often quantified in
terms of quality-adjusted life years (QALYs) and costs (from the
healthcare provider or broader societal perspective). The QALY
combines the burden due to both death and morbidity into one
index, which then provides a way of comparing the social utility of
various vaccines and vaccine candidates in different populations.
The overall costeburden of a disease can also be calculated and
will depend upon how the disease is currently managed, which in
turn is dependent upon the healthcare arrangements. The overall
costeburden can then be compared with that for other diseases
and in other target populations. A health problem or disease can
have a relatively low incidence, but have a high case-fatality or
case-disability incidence and treatment costs, resulting in a high
burden of disease. Conversely, some mild illnesses, in spite of
a very high prevalence, cause a much smaller burden of disease.
118 UNDERSTANDING MODERN VACCINES

Assessing disease burden should also take into account

the pathophysiology of the disease, the pathogenicity of the
responsible agent and the ease with which an infection spreads
within the community. Highly transmissible infections that cause
high morbidity and mortality are associated with a high burden of
disease. The disease burden will also differ greatly between the
developing world and developed countries due to differences in
healthcare, sanitation and other contributing factors, such as
access to preventive measures of communicable diseases,
antibiotics or supportive care, and socioeconomic factors.

Medical need and economic resources

Advances in biotechnology and immunology can bring to the
market new vaccines to protect against previously unpreventable
disease. However, just as in the case for new therapeutic products,
resources are scarce so judgements must be made in order to
secure funding for those interventions that deliver the best value.
One accepted method is to look at the investment cost for the
public health gain anticipated upon implementation of the new
vaccine. The World Health Organization (WHO) CHOICE
(CHOosing Interventions that are Cost-Effective) project has the
objective of providing policy makers with the evidence for deciding
on the interventions and programmes which maximise health for the
available resources (http://www.who.int/choice/description/en/).

Funding vaccine programmes

Vaccine programmes can be funded by national bodies; however,
supranational organisations also play a key role. For example, the
introduction of the Haemophilus influenzae type b (Hib) vaccine to
national immunisation programmes has, in most developing
countries in Africa, Central and Southeast Asia, only been possible
with support from the Global Alliance for Vaccines and
Immunisation (GAVI). GAVI is a global health partnership between
the private and public sectors, committed to the mission of saving
children’s lives and protecting people’s health by increasing access
to immunisation in poor countries. In Latin America, a Revolving
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Fund for Vaccine Procurement was developed by the Pan American

Health Organization in 1979 for the purchase of vaccines, syringes/
needles and cold chain equipment for countries in Latin America
and the Caribbean. A major benefit of the Fund’s role has been to
ensure access to vaccines and thereby significantly improve
population health.
Through a system of bulk purchasing for countries in the region, the
Fund has for the past 20 years secured a supply of high-quality
vaccines for national immunisation programmes at affordable
prices. It has been instrumental in the introduction of measles,
mumps, rubella (MMR), Hib and hepatitis B vaccines in the region’s
regular immunisation programmes and has also allowed for the
orderly planning of immunisation activities.
In recent years, the focus of these organisations has been to
provide faster access to newly licensed vaccines for people in need,
through advanced market commitments (AMCs). AMCs are
a guarantee that committed donors will buy a certain number of
vaccine doses at a pre-fixed price for an agreed number of years.
This gives vaccine manufacturers a return on their development
costs, followed by availability of the vaccine in the market at an
affordable price. Governments of developing countries are able to
budget and plan for immunisation programmes, knowing that
vaccines will be available in sufficient quantity, at a price they can
afford, for the long term.
Today, the medical needs and cost-effectiveness of vaccination
programmes are central to new vaccine development and
implementation since they guide vaccine manufacturers and public
health authorities in better targeting vaccines to those who are most
in need.

Recent science and technology discoveries

As summarised in previous chapters, advancements in our
understanding of immunology, hostepathogen interactions, antigen
development and presentation to the immune system through
adjuvant technology and novel delivery systems, provide new
120 UNDERSTANDING MODERN VACCINES

opportunities for innovative vaccines and make previously unmet

disease challenges more amenable to vaccination strategies. An
increase in the use of innovative technologies in vaccine development
is likely to play a substantial role in the way vaccines will be designed
and tested, and will impact the productivity of the global vaccine
industry as well.

Steps in vaccine development

Vaccines have many challenges to overcome before they become
licensed products. Vaccine development requires many steps e the
preclinical step may take 5e15 years to complete with clinical
development also ranging from 5 to 15 years. Following vaccine
development, an ongoing commitment to post-licensure analysis of
safety is required. Taking post-licensure safety commitments into
account, the whole process can take approximately 10e30 years to
complete (Figure 5.1).

PATHOGEN IDENTIFICATION AND ANTIGEN SELECTION

As discussed in Chapter 1 e Vaccine evolution and Chapter 3 e
Vaccine antigens, during the preclinical development stage the
pathogens responsible for diseases are the starting point for
new vaccine candidates. Antigen selection is guided by the need
to stimulate a protective immune response that is comparable or
superior to the immune response induced by infection (see
Chapter 2 e Vaccine immunology).

PRECLINICAL EVALUATION
Overview
Before investigational vaccines enter clinical trials, it is important to
identify the lead vaccine candidates through relevant in vitro studies
and in vivo animal models. Many candidate vaccines will not
progress beyond this stage due to unacceptable reactogenicity in
animal models or a lack of immunogenicity.
To satisfy regulatory requirements, candidate vaccines must be
assessed in a number of ways including, but not limited to, analysis
 VACCINE DEVELOPMENT 121

Figure 5.1 The multifactorial vaccine development process. The vaccine development process can be lengthy and involves many steps and
regulatory checks. Each of these steps can be broadly categorised into three stages: preclinical, clinical and post-licensure development.
These milestones are built into the process to ensure the safety and immunogenicity/efficacy of the final licensed product.
Ag, antigen; GMP, good manufacturing practice; IND, investigational new drug; GLP, good laboratory practice.

I I I I I I I

I I I I I II
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I II
I
I I I
I
I I I II I
I I I
I
I
I
I
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I I
III
I II I I I
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of all the known physical and chemical parameters of the

immunogen that are relevant to the performance of the immunogen
(quality assurance or QA) toxicology testing, dose-ranging and
quality control (QC) testing. Preclinical testing includes in vivo
animal studies that assess reactogenicity and/or characterise
further the action of the antigen and any adjuvant.
122 UNDERSTANDING MODERN VACCINES

At this point, the vaccine manufacturing process is also defined.

Compulsory initial submissions are made to regulatory
authorities, such as an Investigational New Drug (IND)
application to the Food and Drug Administration (FDA) in the
USA, in order to begin clinical development. The information
included in these initial submissions must show the proper
identity, strength or potency, quality and purity of the vaccine.
The type and amount of information depends on the phase
of the clinical investigation, the extent and duration of
the clinical study, as well as the nature and source of the
vaccine material, and the dosage form. For instance, the quality
and safety of Phase I material are controlled, by having
appropriate QA and QC procedures in place and following
current good manufacturing practices (cGMP). This will also
facilitate the manufacture of equivalent or comparable IND
vaccines for future clinical trials. Adherence to cGMP during
manufacture of Phase I investigational drugs is achieved mostly
through well-defined written procedures, adequately controlled
and calibrated (certified) equipment and manufacturing
environment, and accurately and consistently recorded data
from manufacturing testing.

Preclinical safety evaluation

Pharmacological and toxicological effects of new vaccines must be
assessed before initiation of human studies and continued
throughout clinical development. Both in vitro and in vivo data are
used to assess preclinical safety. The goals of preclinical safety
evaluation include evaluation of single-dose toxicity; repeated-dose
toxicity; primary pharmacodynamics (immunogenicity); secondary
pharmacodynamics (safety); pharmacokinetics and local tolerance.
For the in vivo phase of preclinical testing, selection of the relevant
animal species, age of test animals, their physiological state,
vaccine delivery (including dose, route of administration and
treatment regimen) and stability of the test material under the
conditions of use are necessary information to submit to regulatory
authorities before clinical studies begin.
 VACCINE DEVELOPMENT 123

CLINICAL EVALUATION
Overview
Clinical development involves studies of the effects of vaccines on
healthy volunteers for safety, immunogenicity and efficacy through
a staged process. As shown in Figure 5.1, there are three distinct
phases in the clinical development programme following preclinical
acceptance of a vaccine candidate. Phase I clinical studies are
mainly safety studies, with some of them looking at dose-ranging as
well. Phase II trials include immunogenicity proof-of-concept (and in
some cases, efficacy) and dose-ranging, and carry the vaccine
forward in increasing numbers of volunteers. Larger Phase III clinical
trials are then conducted to determine the ability of a new vaccine to
produce a desired clinical effect at an optimum dose and schedule
with an acceptable safety profile. These are conducted and
completed alongside consistency lot studies (for consistency of
vaccine physicochemical and biological quality and effect among
different vaccine lots). In addition, post-licensure trials, also known
as Phase IV trials, include studies on new indications of use and
safety surveillance studies (pharmacovigilance). Phase IV
surveillance studies, because of the large sample size involved, are
designed to detect very rare adverse events (AEs) that are difficult
to pick up in Phase III studies. Due to the prophylactic nature of
most vaccines and since licensed vaccines are generally given to
large populations of healthy people including infants and children,
in addition to showing considerable benefits, the risks associated
with vaccination have to be minimal in order to maximise
acceptance, thereby achieving expected public health benefits.
This may differ from therapeutic vaccines or drugs, where the
potential improvement of an existing clinical condition may increase
a patient’s tolerance or acceptance of certain AEs.
The success of clinical studies is based on precise and relevant
immunological and clinical endpoints (these are essential if the
immune correlates of protection are not known); accurate estimates
of sample size based on disease incidence; appropriate numbers
of subjects (to allow for the estimated drop-out rate); and rigorous
124 UNDERSTANDING MODERN VACCINES

data management. Safety is an endpoint evaluated throughout all

studies. In order to most accurately determine both efficacy and the
incidence of AEs, Phase III clinical trials usually enrol a large number
of subjects. In these studies Independent Data Monitoring
Committees (IDMCs) may be put in place to guarantee continuous
surveillance of data produced, and to flag any possible safety
concern arising during the study. An example of the importance of
this and post-licensure safety evaluations is described in the
rotavirus vaccine case study (case study 3).

Clinical safety evaluation

As stated earlier, safety is integral to all aspects of vaccine
manufacture and, as such, is continually assessed throughout the
entire vaccine development (Figure 5.2). As with all areas of medical

Figure 5.2 Vaccine safety is important at all stages of development. Safety is assessed at all points of the vaccine development process e from
preclinical toxicology studies using cell cultures and animal models through to rigorous assessment in clinical studies. Post-licensure, safety is still
of prime concern and is the major focus of post-licensure surveillance studies.
AEs, adverse events.
 VACCINE DEVELOPMENT 125

research, the development of new vaccines builds on the

experience gained in the development of earlier products.
Safety is the main endpoint of Phase I clinical trials, and
continues to be an important endpoint for all further stages of the
clinical development process and post-licensure assessments.
Vaccines licensed within the last few years have well-established
safety profiles due to the extensive studies and rigorous safety
checks to which new vaccines must now be subjected. This is
described in the human papillomavirus (HPV) case study below.

CASE STUDY 1 Licensed, AS04-adjuvanted HPV-16 and HPV-18 vaccine

Background
New generation vaccines containing novel adjuvants seek to improve on existing vaccines
and/or increase the number of diseases that can be targeted by vaccination, as described in
Chapter 4 e Vaccine adjuvants. Adjuvants are used to enhance and modulate the immune
response to the vaccine antigen.

Safety assessment of AS04-adjuvanted HPV vaccine

As a result of increasing scrutiny of vaccine safety, especially for new vaccines formulated
with novel adjuvants to increase the magnitude of the immune response, the clinical
development plan for the AS04-adjuvanted HPV-16 and -18 vaccine included enhanced
safety assessments. Investigators and vaccinees were solicited to actively report events
requiring medical attention, eg new onset of chronic disorders (NOCDs) and autoimmune (AI)
diseases. In addition, the inclusion and exclusion criteria and study design were standardised
and harmonised across the HPV clinical plan (to allow for pooling of safety data from the entire
database). This effectively increased the sample size of vaccine recipients in order to
maximise the chance of detecting a rare adverse event.
To further assess safety, an integrated safety analysis was performed to evaluate the type
and rate of serious adverse events (SAEs) reported (Verstraeten et al., 2008). The analysis
included clinical studies conducted with all candidate and licensed vaccines containing AS04,
eg vaccines against HPV, HBV (a hepatitis B vaccine for pre-haemodialysis and haemodialysis
patients) and herpes simplex virus (HSV), providing a database of 68,512 subjects. The sample
therefore included different study designs, target populations and vaccine formulations. Due to
the heterogeneity of studies included, the integrated safety analysis was performed only to
identify possible safety signals and not to rule out a cause and effect relationship. All analyses
performed from the HPV pooled clinical studies or from the AS04-adjuvanted vaccines showed

Continued on next page

126 UNDERSTANDING MODERN VACCINES

an acceptable safety profile. The reporting rate of SAEs and, in particular, of AI diseases in the
group receiving the adjuvanted vaccines, was very similar to the control group and the relative
risk was very close to 1 (0.98 [95% confidence intervals 0.80, 1.21]) (a relative risk, or risk ratio,
of 1 means there is no difference in risk between the two groups).
As with all vaccines, an extensive post-licensure surveillance system is also in place and has
so far confirmed the acceptable benefiterisk profile of the vaccine.

Testing the adjuvant

Mode of action studies have also been performed, in vivo and in vitro, in order to characterise
the adjuvant, alone or combined with the antigen. This has been undertaken to also support
and explain the safety profile of the AS04-adjuvanted HPV vaccine in humans. These studies
support the clinically acceptable safety profile seen with this adjuvanted vaccine. They
demonstrated that the effects of the adjuvant are limited in time (a few hours or days) and
localised at the injection site and the draining lymph node with no systemic activation.
Furthermore, the effects are dependent on the presence of antigen at the same site
(Didierlaurent et al., 2009).

Highlights
New-generation vaccines containing novel adjuvants are subject to increased safety testing
throughout the vaccine development process. The safety assessment has been enhanced
with additional preclinical mode of action studies and active soliciting of SAEs, in particular of
AI diseases. All safety assessments performed have the objective of increasing the likelihood
of identifying possible safety concerns and consequently of taking the necessary measures to
remove or minimise them.

Vaccine production
The selection and production of different types of vaccine antigens
are discussed in more detail in Chapter 3 e Vaccine antigens. Here,
the principles of the production of each type of antigen are briefly
described. Vaccine manufacturing processes can be split into bulk
manufacturing and finishing operations (Figure 5.3). For bulk
manufacturing, the first step is the propagation of vaccine-strain
viruses, bacteria or other microorganisms in culture. The starting
point for bacterial vaccines may be the growth of the organism on
agar gels which can then be expanded in large-scale liquid/
suspension culture. Vaccine-strain viruses are expanded by culture
 VACCINE DEVELOPMENT 127

Figure 5.3 Large-scale vaccine manufacture. Bulk

manufacture of vaccines may be facilitated using
large-scale fermentation.

Courtesy of Sartorius Stedim Biotech.

through a eukaryotic cell line. Cell culture may be derived from

primary cells (including eggs and primary monkey kidney cells),
diploid cells (such as MRC-5 [a diploid line from normal human lung
fibroblasts], WI-38 [Wistar Institute; a diploid line from normal
human lung fibroblasts] and FRhL-2 [a cell line from foetal rhesus
monkey lung]), yeast and other continuous cell lines (CCLs). Once
the cell cultures are established, the vaccine-strain virus is seeded
and cultivated.
128 UNDERSTANDING MODERN VACCINES

In the case of microorganisms that are not able to grow in vitro,

recombinant antigens have been produced through expression
systems (eg yeast or baculovirus/insect cells) used to generate
the protein antigen from gene sequences inserted into the
expression system and under the control of a promoter sequence
(see Chapter 3 e Vaccine antigens).
Recovery of antigens from the culture media involves a combination
of optimised processes, including microfiltration, purification,
homogenisation and batch clarification using ion-exchange resins.
Vaccines based on whole living organisms/pathogens can be
made using a genetically altered (thus attenuated) organism grown
in the culture system or by attenuating the viral pathogen itself.
Attenuation can be achieved by repeatedly propagating the microbial
pathogen in human and/or non-human cell lines grown in culture,
which reduces their efficiency at replicating in human cells or alters
other virulence properties. Whole pathogen antigens can be
inactivated by methods including chemical or heat treatment to
produce whole killed formulations. Pathogens can be split or
fractionated to produce subunit antigens, which may be subsequently
purified to retain highly selected antigenic components. Vaccine
polysaccharide antigens may also be conjugated to protein carriers
once they have been isolated, to produce vaccines for diseases
caused by encapsulated bacteria such as Meningococci (see
Chapter 2 e Vaccine immunology and Chapter 3 e Vaccine antigens).
Finishing operations include sterilising/clarifying filtration, freezing,
freeze drying, glassifying (drying vaccines in the presence of sugars
or other stabilisers) after formulation with adjuvants, stabilisers,
preservatives (if required), filling syringes or vials, and labelling and
packaging the products. All procedures need to be conducted
according to strict cGMP regulations.

VACCINE QUALITY CONTROL

QA and QC are performed at every step of the vaccine

manufacturing process. Production of a vaccine, whether by
fermentation, cultivation, isolation or synthesis, usually starts with
 VACCINE DEVELOPMENT 129

raw materials. Subsequent steps of the procedure involve

preparation, characterisation and purification of intermediates
eventually resulting in the bulk material. The quality and purity
cannot be assured solely by downstream testing, but depends on
proper control of the manufacturing and synthetic process as well.

VACCINE APPROVAL
There are three principal licensing procedures for vaccines in
the European Union (EU): the centralised procedure, the
mutual recognition procedure and the decentralised procedure
(Figure 5.4). These review procedures are expected to be
completed within 210 days after receipt of a valid application.

The centralised procedure

Once the manufacturer has submitted the required dossier
containing technical, preclinical, and clinical safety and efficacy
data, the European Medicines Agency (EMA) will complete its
scientific evaluation within 210 days. Following this, a Committee for
Medicinal Products for Human Use (CHMP) opinion is issued (the
advisory committee is responsible for preparing the opinions on all
questions concerning medicinal products for human use for the
EMA). If the CHMP opinion is positive, the vaccine will normally
obtain a licence from the European Commission (EC) which will
allow use of the vaccine throughout the EU.

The mutual recognition and decentralised procedures

The mutual recognition and decentralised procedures are
European authorisation procedures which give rise to national
licences, instead of an EC decision. These procedures are based
on the principle of recognition of the assessment by the Reference
Member State (RMS).
In the case of the mutual recognition procedure, the RMS has
already issued a marketing authorisation. The RMS’ assessment
report forms the basis for requesting the other Member States’
mutual recognition of the marketing authorisation (including the
130 UNDERSTANDING MODERN VACCINES

Figure 5.4 Licensing procedures for vaccines in the EU. There are three separate vaccine licensing procedures in the EU. The processes
involved in acquiring a licence vary depending on whether a licence covering several countries or an EU-wide licence is applied for.
EU, European Union.
 VACCINE DEVELOPMENT 131

Summary of Product Characteristics [SmPC], package leaflet and

labelling text). Member States have 90 days to review and approve
the RMS’ assessment report and related documentation. The RMS
records the agreement of all parties, closes the procedure and
informs the applicant accordingly.
The decentralised procedure may be used to obtain a marketing
authorisation in several Member States when the applicant does
not yet have a marketing authorisation in any country of the EU. The
applicant requests one country to be the RMS in the procedure.
Within 120 days of receiving a valid application, the RMS prepares
the draft assessment report and sends it to the Member States
along with the SmPC, package leaflet and labelling text etc. The
Member States have 90 days to review and approve the RMS’
assessment report and related documentation. The RMS records
the agreement of all parties, closes the procedure and informs the
applicant accordingly.
A summary of all the products that have been accepted through the
decentralised and mutual recognition procedure is published in the
European Product Index on the website of the Heads of Medicines
Agencies (HMA).
In the USA, the development of vaccine candidates is regulated
through an Investigational New Drug (IND) application which is
filed with the FDA, specifically the Center for Biologics Evaluation
and Research (CBER). After completion of the pivotal clinical trial
and meeting with CBER, a dossier containing all the clinical, safety
and technical information to support a Biologics License
Application (BLA) is filed for review. The Standard Review period
for an initial BLA is 10 months. However, if the drug has the
potential for a significant improvement or prevention of a serious or
life-threatening disease, it may be eligible for priority review
(6-month review period). At the end of the review period, the FDA
issues an action letter. If all parts of the dossier are satisfactory,
approval is granted; if not, the sponsor must respond to CBER
formally; then additional review cycles of 4e6 months are
undertaken until all aspects, including manufacturing (QA, QC and
132 UNDERSTANDING MODERN VACCINES

consistency), testing, stability, safety and efficacy are finally

considered satisfactory. Prior to approving most vaccine BLAs, the
CBER will convene an external advisory committee to review and
evaluate the data concerning the safety, effectiveness and
appropriate use of the vaccine candidate. This committee, known
as the Vaccines and Related Biological Products Advisory
Committee (VRBPAC), is made up of external experts who meet in
a public forum and provide their advice to CBER.
In addition to the regulatory processes that provide quality assurance
for vaccines manufactured and procured in the EU and USA, the
WHO has a system for the prequalification of vaccines destined for
countries without functional National Regulatory Authorities (NRA).
This is provided as a service to the United Nations Children’s Fund
(UNICEF; and other UN agencies that purchase vaccines) to
determine the acceptability, in principle, of vaccines from different
sources for supply to these agencies. This service assesses whether
vaccines are effective, have acceptable safety profiles and comply
with the regulations of the functional NRA of the producing country,
including details of QA and QC methods and GMP compliance. This
service also provides assurance of continued acceptability through
reassessments, testing of lots and follow-up of complaints and AEs
following immunisation.

SPECIAL VACCINE APPROVAL PROCESS:

PANDEMIC INFLUENZA
Authorisation of a new vaccine within the EU typically takes at least
1 year; however, in the event of a pandemic, such a time delay
would be unacceptable. As a result, many countries have
implemented alternative authorisation procedures which speed up
the availability of vaccines. For pandemic vaccines in the EU, the
two primary procedures used for authorisation are described below.

The ‘mock-up procedure’

The ‘mock-up procedure’ allows a vaccine to be developed and
authorised in advance of a pandemic, based on information
 VACCINE DEVELOPMENT 133

generated with a virus strain that could potentially cause

a pandemic (Figure 5.5). Once the actual virus strain causing the
pandemic is identified, the manufacturer can substitute this strain
in the mock-up vaccine (for which regulatory approval has
previously been granted) and apply for it to be authorised as a ‘final’
pandemic vaccine. The mock-up vaccine is specially designed to
mimic the final vaccine in the way it is constructed, ie the methods
used to prepare the virus, as well as the composition of the vaccine
and the way it is administered. Information from mock-up vaccines
can, in addition, be used to predict the safety and efficacy of the
final vaccines. Such information includes the mock-up vaccine’s

Figure 5.5 EU authorisation of pandemic influenza vaccines using the ‘mock-up procedure’. A mock-up vaccine is a type of influenza vaccine
that is developed before a pandemic has started using a strain of influenza virus that is a possible candidate to start a pandemic, since it has
infected small clusters of subjects and to which the majority of the population does not have pre-existing immunity. Data on safety,
immunogenicity and manufacturing quality can be generated using a mock-up vaccine. The mock-up vaccine strain is then replaced with
the pandemic strain once a pandemic is declared. New data generated from the final vaccine are submitted on a rolling review basis.
EU, European Union; CHMP Committee for Medicinal Products for Human Use; EC, European Commission.
134 UNDERSTANDING MODERN VACCINES

ability to trigger the production of antibodies against the virus

according to criteria laid down by the EMA for vaccine licensure.
Once the actual pandemic strain is introduced into the formulation,
any new data produced (clinical, stability, dosage data etc) are
continuously submitted to the authorities and the label is
continuously updated as needed.

Figure 5.6 EU authorisation of pandemic influenza vaccines using the ‘emergency procedure’. In addition to the mock-up procedure, the EMA
has also set up the ‘emergency procedure’ that allows for fast-track approval of a new vaccine developed after a pandemic has already been
declared. In contrast to the mock-up procedure, the authorisation of vaccines submitted via the emergency procedure requires submission of
a new, full dossier of information that may take more time compared with working from a mock-up dossier.
EU, European Union; EMA, European Medicines Agency; CHMP Committee for Medicinal Products for Human Use; EC, European Commission.
 VACCINE DEVELOPMENT 135

The ‘emergency procedure’

The ‘emergency procedure’ allows for fast-track approval of a new
vaccine developed after a pandemic has already been declared
(Figure 5.6). Authorisation of these pandemic vaccines is quicker
than for a normal vaccine, as the information submitted by the
manufacturer is assessed in an accelerated timeframe (around 70
days instead of 210 days).
In contrast to the approach of the ‘mock-up procedure’, vaccines
licensed according to the ‘emergency procedure’ must submit a full
dossier of information. However, in recognition of the need for the
issuance of a licence rapidly, manufacturers use the ‘rolling review’
process, supplying data on vaccines under development as they
become available, rather than waiting until they have collected the
full data set. This allows the CHMP to evaluate the data as it is
produced to expedite vaccine approval.
Once sufficient data to evaluate the benefiterisk ratio have been
collected, the manufacturer makes a formal application to the EMA
for marketing authorisation. The CHMP assesses the dossier and
gives an opinion to the EC, which will then issue a final decision
within approximately 25e40 days. The vaccine will be given
‘conditional approval’, which means its benefits outweigh its risks,
but full data to support its authorisation are not yet available e these
must be provided by further post-licensing studies. Influenza
pandemic vaccines licensed via the ‘mock-up procedure’ or the
‘emergency procedure’ are shown in Table 5.1. TABLE 5.1. PANDEMIC INFLUENZA
As both rapid authorisation routes abbreviate or miss out some of VACCINES LICENSED IN EUROPE VIA
THE ‘MOCK-UP PROCEDURE’ OR
the typical stages in the approval process, special procedures are
‘EMERGENCY PROCEDURE’
in place to monitor the immunogenicity, efficacy and safety of
Product Company
pandemic vaccines once they are in use. As it is not always possible
to predict the impact of a given pandemic, it is imperative that ArepanrixÔ GSK Biologicals
procedures are in place to facilitate the rapid production of CelvapanÔ Baxter

vaccines, while maintaining quality and safety standards. The H1N1 DaronrixÔ GSK Biologicals
pandemic influenza case study provides a good example of how FocetriaÔ Novartis

the clinical and safety profiles of pandemic vaccines have been HumenzaÔ Sanofi Pasteur
continuously monitored and assessed. PandemrixÔ GSK Biologicals
136 UNDERSTANDING MODERN VACCINES

In the USA, licensure of pandemic influenza vaccines may be

sought from the FDA through the submission of a BLA. If
a manufacturer holds a USA licence for an approved BLA for
a seasonal inactivated influenza vaccine (including post-marketing
data), and the manufacturing process is the same, then clinical
immunogenicity trials are needed to determine the dose and
regimen of the pandemic influenza vaccine candidate. These
trials should also include an assessment of safety. For the most
part, the new BLA references the original BLA, including the
non-clinical, chemistry, manufacturing and controls data.

Post-licensure surveillance e vaccine

pharmacovigilance
Continuous post-licensure surveillance is used to confirm the
safety of vaccines in the general population, including people with
a variety of health backgrounds. Post-licensure studies of safety
and effectiveness of vaccines are now considered increasingly
important and are often based on national immunisation
programmes and safety surveillance. Due to the nature of
surveillance methods, such as patient registers and call-backs,
post-licensure data may not appear in the literature until 5e10
years after a vaccine has been granted a licence.
It is important to assess the background incidence in
non-vaccinees of rare conditions and AI disorders that might be
possibly diagnosed in temporal association with vaccination
(Table 5.2). The background incidence is required to determine
whether temporal associations with vaccination are in line with
the natural expected incidence rate or if there is an increased
incidence that may suggest a causal link with the vaccine, as
described in the rotavirus case study (see case study 3).
Vaccine pharmacovigilance is defined by the Council for
International Organizations of Medical Sciences as ‘the science
and activities relating to the detection, assessment,
understanding, prevention and communication of AEs following
 VACCINE DEVELOPMENT 137

TABLE 5.2. ADVERSE EVENTS OF SPECIAL INTEREST e RARE CONDITIONS TO MONITOR IN POST-AUTHORISATION
STUDIES OF PANDEMIC INFLUENZA VACCINES
l Convulsions (generalised seizures)
l Bell’s palsy
l Encephalitis
l Transverse myelitis
l GuillaineBarré syndrome
l Demyelination (acute disseminated encephalomyelitis and multiple sclerosis, separately)
l Optic neuritis
l Vasculitis (severe)
l Anaphylaxis (multi-organ involvement)
l Thrombocytopenia
l Sudden death and sudden infant death syndrome/sudden unexpected death in infancy
l Spontaneous abortion and premature birth
This table refers to the adverse events of special interest requested by the EMA. It is not specific to any particular pandemic vaccine.
EMA, European Medicines Agency.

immunisation, or of any other vaccine- or immunisation-related

issues’. This covers many activities such as continuous
benefitecost assessment, risk management or communication
activities to improve vaccine safety.
Pharmacovigilance activities include the collection, analysis and
reporting of AEs following authorisation. These reports are
received from different sources, with the most frequent being
healthcare professionals. Reporting to the competent authorities
can be expedited or periodic. The expedited reporting of serious
unexpected suspected adverse events (SUSARs) to regulatory
authorities should be done no later than 15 days from their receipt.
In Europe, life-threatening or fatal events must be reported within
7 days. Periodic safety reporting, which in Europe takes the form
of a periodic safety update report (PSUR), should be submitted to
regulatory authorities at 6-monthly intervals until a full 2 years of
marketing experience has been completed, then one is due every
year for the following 2 years and every 3 years thereafter.
Examples of assessments, requirements and timings in vaccine
pharmacovigilance are summarised in Figure 5.7.
138 UNDERSTANDING MODERN VACCINES

Figure 5.7 Vaccine pharmacovigilance. Considerations for vaccine pharmacovigilance include acquiring an understanding of
baseline events, continuously assessing benefits and risks, and the collection and reporting of AEs within the times stipulated by
regulatory authorities.
AEs, adverse events; SAEs, serious adverse events.
 VACCINE DEVELOPMENT 139

CASE STUDY 2 Vaccines for a pandemic situation undergo fast-track approval but still
follow stringent regulation processes to ensure safety and immunogenicity
Background
At the beginning of summer 2009, the WHO declared a pandemic alert due to an outbreak of
a swine-origin influenza A virus (H1N1). As of August 2010, more than 214 countries had
reported a total of at least 18,449 deaths.

Safety assessment
In addition to a progressive submission of clinical data and the rolling review by CHMP,
specific active surveillance systems were put in place in the EU, by the EMA and health
authorities, to rigorously assess the safety profile of new pandemic vaccines; the EMA also
issued pandemic influenza vaccine risk management guidance. This guidance was
updated after the appearance of the H1N1 pandemic virus to include monitoring of
immunocompromised people, children and pregnant women as these groups were found to
have a higher risk of severe disease after infection. The EMA also introduced the active
surveillance of AEs of special interest (AESI), including problems affecting the nervous
system, anaphylaxis (severe allergic reactions) and vaccination failure, and intensified the
periodic reporting of SAEs after pandemic influenza vaccines (Table 5.2). The EMA required
the influenza vaccine manufacturers to carry out additional safety studies and to put special
pandemic risk management plans in place once their pandemic vaccines were administered
to the general population. The EMA also required companies to confirm efficacy in preventing
pandemic influenza in all age groups and ‘at risk’ groups after authorisation.

In the USA, the FDA published a briefing document in July 2009 specifically for H1N1 influenza
vaccines, stating that post-marketing evaluation of AEs would be monitored ‘through reports to
the Vaccine Adverse Event Reporting System (VAERS), as well as through diagnoses and
related data in the Vaccine Safety Data (VSD) link system, the Department of Defense (DoD),
Centers for Medicaid and Medicare Services (CMS), the Veterans’ Health Administration (VHA),
and other population-based health care organizations’.

Therefore, pandemic vaccines can be licensed under a fast-track procedure; however, they
must follow comprehensive and stringent safety assessments and immunogenicity/efficacy
requirements to allow a close monitoring of their benefiterisk profile.

The Global Advisory Committee on Vaccine Safety (GACVS), an expert clinical and scientific
advisory body established by the WHO, conducted a safety review from data generated
between September and December 2009 following the administration of tens of millions of
doses of the pandemic (H1N1) 2009 vaccine. The committee concluded that the safety data
were reassuring; reporting mechanisms had been enhanced (see above) and most AEs that
were reported after immunisation were expected and not serious (WHO, 2009).

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140 UNDERSTANDING MODERN VACCINES

Highlights
Even vaccines produced in emergency situations are subject to stringent regulations and
procedures to ensure that their immunogenicity, efficacy and safety are thoroughly and
continuously evaluated. The pandemic influenza vaccines’ assessment, which is the most
comprehensive ever done for influenza vaccine has, thus far, confirmed the clinically
acceptable benefiterisk profiles of pandemic influenza vaccines.

CASE STUDY 3 The importance of understanding the background incidence of events that
could be related to vaccination
Background
Rotavirus infection in infants and young children can rapidly lead to severe diarrhoea and
dehydration, electrolyte imbalance and metabolic acidosis. In developing countries, severe
gastroenteritis caused by rotavirus is a leading cause of childhood illness and death. Eighty
two per cent of the annual rotavirus deaths in children occur in low income countries, most
likely due to limited healthcare infrastructure and inadequate domestic sanitation conditions.
Rotavirus causes a substantial disease burden; natural infection with one or several serotypes
of rotavirus does not afford 100% protection against subsequent infection, although it can
mitigate the severity of subsequent attacks. The burden of disease is largely associated with
children below 5 years of age, with a higher rate of severe cases in children below 2 years of
age (mostly in infants). In older children, previous encounters with rotaviruses make
individuals less susceptible to infection and more likely to develop a milder form of disease.
Therefore, a realistic goal for a vaccine candidate would be to provide at least the degree of
protection that follows natural infection at an earlier age, ie to prevent the severe and
life-threatening complications of rotavirus diarrhoeas in infancy.
Previous attempts at rotavirus vaccination
In August 1998, rhesus rotavirus tetravalent vaccine (RRV-TV) (RotashieldÔ) was licensed by
the FDA and recommended for inclusion in the regular childhood immunisation schedule.
The efficacy and safety of this vaccine, which incorporated three reassortant (human/simian)
rotaviruses, was tested in seven large efficacy trials in which approximately 7000 infants
received the vaccine. The data showed efficacy against rotavirus disease and the only
significant safety outcome of note was fever. In the first year following licensure of the
vaccine in the USA however, 15 cases of intussusception (a reversible invagination of
a section of the small intestine into itself) occurred among infants who had received RRV-TV
(13 following the first dose, two within 1 week of any dose). Background estimates of the

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 VACCINE DEVELOPMENT 141

incidence of intussusception before RRV-TV licensure ranged from 39 to 74 per 100,000

person-years among children
12 months of age. A study was performed to identify other
cases occurring in vaccinees, using hospital discharge records and other databases, and
then intussusception rates were compared between vaccinees and non-vaccinees,
correcting for variables such as age and time elapsed since vaccination (Centers for
Disease Control and Prevention, 1999). The rate of intussusception mainly after the first
dose among vaccinated children was significantly higher compared with children who
were not vaccinated (125 versus 45 per 100,000 person-years). Subsequently, the
recommendation for RRV-TV immunisation in infancy was reversed and the vaccine was
voluntarily withdrawn from the market by the manufacturer, thereby prompting the need for
other candidate vaccines.

Recent attempts at rotavirus vaccination

Rigorously designed large-scale clinical trials were designed to assess new candidate
rotavirus vaccines. Given that the rate of cases of intussusception following RRV-TV was
estimated at 1 per 5000 doses of RRV-TV, studies of new rotavirus vaccines following
RRV-TV needed to be sufficiently powered to detect and rule out a similar effect, if indeed it
existed with previous candidate vaccines.

Two live oral rotavirus vaccines e RotaTeqÔ (RV5) and RotarixÔ (RV1) e were tested in
two large clinical trials (Ruiz-Palacios et al., 2006; Vesikari et al., 2006), each of which
included over 60,000 infants. Neither vaccine was shown during clinical development to
induce an increased rate of intussusception (ie the incidence of intussusception in those
who received the rotavirus vaccine and those who did not was comparable) or other SAEs.
Since 2006, the two vaccines have been licensed for use in many countries. Their licensure
has been followed by rigorous post-licensure surveillance monitoring including an
enhanced review of AEs reported to VAERS. Intensive post-licensure surveillance is
necessary to assess the safety of this vaccine with regard to intussusception, as
occurrences of this rare event are expected to occur by chance following, but not caused
by, vaccination e in the USA, the VSD is being used for this purpose and to evaluate any
other possible associations. Reports of intussusception after vaccination have been
received for both licensed vaccines. A clustering of 18 hospitalisations was identified
following intussusception (none of which were associated with fatality) in the period 1e7
days after the first dose in Mexico; no clustering was observed after the first dose in Brazil.
This would translate to a risk of approximately 20e40 additional cases per year nationwide
at current vaccination rates (approximately 2 million). Australian post-marketing surveillance
studies found no increased risk of intussusception up to 9 months of age with either
RotarixÔ or RotaTeqÔ vaccines. US data (from a smaller population compared with the
Mexico data) do not show evidence of an increased risk of intussusception with RotaTeqÔ.

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142 UNDERSTANDING MODERN VACCINES

If these data are confirmed, the level of risk with the two current vaccines is substantially
lower than the risk of one case of intussusception in 5000e10,000 vaccinees seen with the
withdrawn RRV-TV vaccine (WHO, 2011).
Highlights
Occasionally, unexpected rare vaccine-related events, which were not detected during the
pre-licensure clinical programme due to their low incidence rate, are detected once a vaccine
is approved and administered to large numbers of individuals. Continuous and thorough
collection and evaluation of safety data prior to and post-licensure is paramount to
continuously assess and re-evaluate the benefiterisk profile of vaccines.

Challenges in vaccine development

Hurdles facing vaccine developers today can be practical, such as
the search for immune correlates of protection, but also perceptual.
Both issues are discussed below.
MEASURING PROTECTIVE EFFECTS
As discussed in detail in Chapter 3 e Vaccine antigens, defining
immunological correlates of protection is an important aspect of
vaccine design. For several pathogens, antibodies have been found
to represent a reliable correlate of protection and therefore the efficacy
of a proposed vaccine can be measured in the absence of clinical
endpoints using seroprotection rates (eg number of subjects with
antibody response above a pre-specified cut-off). Two examples of
vaccines with accepted serological correlates of protection are HBV
and hepatitis A virus (HAV) vaccines. An antibody response against
the HBV surface protein (anti-HBs) 10 mIU/mL was observed to
correlate with protection from hepatitis in efficacy studies in healthy
subjects. For HAV, the correlates of protection are defined by a level
of anti-HAV antibodies against the HAV structural proteins above
the assay cut-off level demonstrated to correlate with protection
from hepatitis.
The search for immune correlates of protection is difficult for
diseases with complex hostepathogen interactions or pathogenesis.
 VACCINE DEVELOPMENT 143

The presence of antibodies is not a correlate of protection for some

diseases such as pertussis or human immunodeficiency virus (HIV),
where exposed individuals may develop antibodies without being
protected against subsequent infection or disease. Generally, it is
harder to establish cell-mediated correlates of protection than it is to
detect protective antibody responses. This is linked to both the assay
methods available to detect such effects and to difficulty in linking an
observed response with a known protective benefit, ie prevention of
infection and/or disease.
Without knowing the immunological correlates of protection, the best
method of assessing vaccine efficacy is through large, randomised
controlled clinical trials that include well-defined clinical endpoints.
Increasingly, vaccine studies focus on these types of endpoints,
since many of the remaining targets for vaccination are complex or
do not have established correlates of protection. However, when
conducting such randomised controlled trials, consideration must be
given to the variability of the disease incidence in the test population.
Some vaccine trials have failed not necessarily because of a lack of
protection by the vaccine but because the seasonal incidence of the
target disease changed and there were not enough incidences of
infection in the placebo group to draw meaningful conclusions.
Designing clinical trials to avoid such an eventuality adds to both the
size and cost of the trial.

CASE STUDY 4 Developing a vaccine using immune correlates of protection

Background
Hepatitis A is an acute, usually self-limiting disease of the liver caused by HAV. This is
transmitted from person to person, primarily by the faecaleoral route or via contaminated
water or food. The incidence of HAV is closely related to socioeconomic development, such
that the prevalence of anti-HAV antibodies in the general population varies from 15% to nearly
100% in different parts of the world. While infection with HAV induces lifelong immunity in all
cases and is mostly asymptomatic in children, it is often symptomatic in adolescents and
adults causing acute hepatitis and may, therefore, represent a substantial medical and
economic burden.

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144 UNDERSTANDING MODERN VACCINES

Passive immunisation
Prior to the development of HAV vaccines, human plasma immunoglobulin (Ig) from pooled
donor IgG was administered as a pre- or post-exposure prophylactic measure, demonstrating
the protective role of anti-HAV antibodies in humans. The concentrations of antibody
achieved after passive transfer of immunoglobulin (or active induction by vaccination) are 10
e100-fold lower than those produced in response to natural infection, but are sufficient to
protect against overt HAV disease.
Active immunisation
Experience regarding passive immunisation with Ig showed that individuals were protected
with anti-HAV concentrations of 10e20 mIU/mL. However, since no absolute protective level
has been defined for HAV, generally the lower limit of detection of the assay being used has
been considered as the protective level. With this serological correlate of protection,
candidate vaccines against HAV were rapidly developed and licensed; subsequently their
efficacy has been confirmed in a number of studies and immunisation campaigns.

Highlights
Immune correlates of protection, when validated by a demonstrated clinical benefit, are
extremely useful to the development of efficacious vaccines.

AUTOIMMUNITY AND VACCINES

In clinical terms, an AI disease may be defined as a disease in

which tissue damage is mediated by T cells and/or antibodies,
resulting from a failure of self-tolerance. AI diseases may be
organ-specific or systemic, depending on the organs and tissues
affected. However, this is sometimes not a simple distinction,
particularly in cases where there is apparent organ specificity
despite autoreactive immune responses that target ubiquitous
antigens. The innate immune system may contribute to the initial
induction of antigen-specific autoreactivity and may participate in
the effector mechanisms responsible for tissue damage, but
activated T cells, antibodies, or both must also be detected to
establish a diagnosis of AI disease.
From an immunological perspective, there is little evidence that
vaccinations cause AI diseases e the pathological mechanisms
underlying these diseases include complex features such as
 VACCINE DEVELOPMENT 145

a genetic predisposition and chronic inflammation. Damage to

target organs and tissues is usually the result of infiltration by
activated immune cells and their subsequent cytokine production e
the immune response is no longer regulated, leading to systemic
disruption of physiological functions.
The increasing knowledge on how vaccines induce an immune
response and the recent evidence for the mechanism of action of
(novel adjuvanted) vaccines provide reassurance as they indicate
that the induction of immune responses and the triggering of
cytokine release are limited to the injection site and local draining
lymph node, with no infiltration of distant tissues or organs. In
addition, vaccines with novel adjuvants enhance the presentation
of antigen, and a more specific modulation of the adaptive
immune response. This evidence is further supported by the
clinical profiles of licensed vaccines, which show no evidence of
AI disease induction in vaccinees (see case study 1 and
Chapter 4 e Vaccine adjuvants).

TEMPORAL ASSOCIATIONS BETWEEN ADVERSE EVENTS

AND VACCINATION
Although there are case reports of temporal associations between
the administration of vaccines (or common vaccine components)
and events that trigger safety alerts, these associations alone do
not establish a causal link. Vaccine manufacturers and regulatory
bodies must be careful to monitor reports of temporally associated
events so that these can serve as possible signals for unexpected
rare AEs. These signals can then be further evaluated by additional
data collection and appropriate analyses. With the objective of
further improving the safety profile of a vaccine, action may be
taken as a precautionary or definitive measure as illustrated in the
case of the rhesus rotavirus (RRV-TV) vaccine (case study 3).
Some of the specific issues that have arisen in relation to vaccines
and vaccine components are described here, along with action
taken by vaccine manufacturers and regulatory authorities to
address concerns.
146 UNDERSTANDING MODERN VACCINES

CASE STUDY 5 A temporal association between an adverse event and vaccine is not
sufficient to establish a cause and effect relationship
Background
Measles is a virus that causes a rash, cough and fever in the majority of patients, but can less
commonly lead to pneumonia, seizures, encephalitis and even death. Mumps is a virus that
causes fever, headache and swollen salivary glands (mainly parotid glands), but in more
serious cases can lead to deafness, viral meningitis and orchitis. Rubella, also known as
German measles, is generally a mild disease, but can result in serious birth defects in children
born to mothers infected in the early stages of pregnancy.

Vaccine
The MMR three-component live-virus vaccine is a combination vaccine delivered in a single
injection, designed to provide protection against measles, mumps and rubella. Originally
developed in the 1970s, the MMR vaccine is currently used in over 100 countries. A small
minority of vaccinees experience minor-to-moderate side effects including fever, rash and
joint pain, which subside within a few days.
Controversy
Since the MMR vaccine was introduced in the early 1970s, the number of children
experiencing each of the diseases and their complications has dramatically decreased.
However, controversy ensued upon publication of a paper in The Lancet in 1998, which
hypothesised a potential association between receiving the MMR vaccine and the
subsequent development of autism in children in their second year of life. This was
published by the primary author, after observing a small number of children with
inflammatory bowel disorders and neurological development disorder a few weeks or
months after they had received the MMR vaccination. The publication of this report and,
perhaps more poignantly, the subsequent negative media coverage surrounding the
publication led to a dramatic decrease in MMR vaccination rates and loss of public
confidence in the combined MMR vaccine. Subsequently, a number of serious
methodological flaws in this report coupled with improper or non-existent disclosures of
interest were revealed and The Lancet, and all but a single author, retracted the report.
The subsequent effects and present status
In the years following the original publication in The Lancet, many studies were designed
by different research groups to address this issue using different methodologies. Overall,
more than 25 studies were performed, all of which concluded there was no association
between autism and MMR vaccines; these studies have provided a clear answer to the
scientific community. However, it is taking some time to regain public trust in the MMR
vaccination. Statistics from a UK National Health Service (NHS) publication indicated that
coverage of the MMR vaccine in children up to 2 years of age in England fell from 92% in

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 VACCINE DEVELOPMENT 147

1995e1996 to 82% in 2002e2003 (the WHO recommends maintaining population immunity

levels of around 95% to prevent outbreaks of disease). Uptake is now on the rise (85% in
2008e2009), but cases of measles have increased due to the reduced population
coverage with the vaccine. The Republic of Ireland saw more than 1220 cases of measles
in 2000 including two deaths. New vaccination campaigns have been conducted to
increase MMR vaccination coverage including the launch of an MMR catch-up campaign in
the UK which began in August 2008.

Highlights
The occurrence of events with a temporal association with vaccines is not sufficient to
establish a cause and effect relationship e to show this, specific studies must be performed. If
the temporal coincidence is misinterpreted as being causal, consequences may be more
significant. The MMR case reflects the serious consequences of elevating a hypothesis of risk
above the real risk of vaccine-preventable diseases.

Safety concerns linked to

vaccine ingredients
Thiomersal, also known as thimerosal in the USA, is a preservative
that has been used in several vaccines since the 1930s. It is
a mercury derivative metabolised or degraded into ethylmercury
and thiosalicylate. In vaccines, thiomersal meets the requirements
for a preservative, established by worldwide pharmacopoeias, and
has a long record of well-tolerated and effective use. It is utilised in
very small concentrations, typically at 0.003e0.010%.
In the late 1990s, exposure to thiomersal and accumulation of its
metabolites was reviewed by USA regulatory authorities in order to
reduce exposure to mercury from all sources, considering the
toxicity shown with a different mercury derivative e methylmercury.
As a precautionary measure, many regulatory agencies worldwide
issued a statement urging vaccine manufacturers to reduce or
eliminate thiomersal in vaccines as soon as possible to help control
overall exposure to mercury, especially in infants. Studies were
initiated to investigate whether exposure to thiomersal in vaccines
was associated with an increased risk of neurodevelopmental
148 UNDERSTANDING MODERN VACCINES

disorders, including autism, but did not produce any evidence of

a causal link. The request by authorities to remove thiomersal
caused fear amongst the general public concerning the toxicity of
vaccine components, and negatively impacted overall vaccine
uptake and acceptance. In the subsequent years, following
authority guidance, vaccine manufacturers have removed
thiomersal from most paediatric vaccines and reduced the amount
of thiomersal in the few remaining vaccine formulations in
a common effort to remove mercury from vaccines and
re-establish public confidence in immunisation programmes.
However, the WHO acknowledges that making changes to the
thiomersal content of licensed vaccines containing this preservative
is a complex issue requiring careful consideration. Any change in
the formulation of thiomersal-containing vaccines may have an
important impact on the quality, safety and efficacy of the vaccine
and therefore any decision regarding the elimination or reduction
of thiomersal in vaccines should be based on a demonstrated
adverse effect.

Continuous improvement in vaccine

safety assessment
New-generation vaccines are subject to increased safety
testing throughout the vaccine development process. The safety
assessment has been enhanced throughout preclinical, clinical
and post-licensure studies. All safety assessments performed
have the objective of increasing the likelihood of identifying
possible safety concerns and consequently of taking the
necessary measures to remove or minimise them. Available data
indicate that licensed vaccines have a benefiterisk profile where
the benefits clearly surpass the risks.

Conclusions
This short overview of vaccine development processes and
post-licensure surveillance describes how clinical development
and assessment of vaccines is constantly improving and evolving.
 VACCINE DEVELOPMENT 149

It also illustrates how changes to the processes over time have

helped to generate the robust data needed to enhance the
benefiterisk profiles of new vaccines.
There is now a large number of diseases for which licensed
vaccines are available (Appendices, Supplementary Table 6),
however, we are still faced with challenges in the form of diverse
populations and complex pathogens; these require further novel
approaches to antigen selection, manufacture, presentation and
delivery. The main areas of new vaccine research are the subject of
Chapter 6 e Vaccines of the future.

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FURTHER READING
de Oliveira LH, Danovaro-Holliday MC, Matus CR et al. Rotavirus vaccine introduction in
the Americas: progress and lessons learned. Expert Rev Vaccines 2008;7:345e353

Godlee F, Smith J, Marcovitch H. Wakefield’s article linking MMR vaccine and autism
was fraudulent. BMJ 2011;342:c7452

Offit P. Autism’s false prophets: Bad science, risky medicine and the search for
a cure. New York: Columbia University Press; 2008
150 UNDERSTANDING MODERN VACCINES

Stanberry LR, Barrett ABT. Vaccine Development Pathway. In Barrett ADT, Stanberry LR
(eds). Vaccines for Biodefense and Emerging and Neglected Diseases. London:
Saunders Elsevier; 2009 p 45e54

Taylor K, Nguyen A, Stéphenne J. The need for new vaccines. Vaccine 2009;27(Suppl. 6):
G3e8

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RotaTeqÔ is a trademark of Merck Sharp & Dohme Corp; ArepanrixÔ, DaronrixÔ,
PandemrixÔ and RotarixÔ are trademarks of the GlaxoSmithKline group of companies;
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