1) As a world-leading expert in immunization research you have become known as a

key advisor on vaccination policies. Can you explain what attracted you to this area of
research?
I first became involved in vaccine research in 1978, when I joined the then Public Health
Laboratory Service as a medical epidemiologist. I worked on the large post-licensure safety and
efficacy studies of pertussis vaccines that were being conducted following the collapse of the UK
whooping cough immunisation programme in the mid-1970s. This massive decline in vaccine
coverage was the result of allegations that the vaccine caused brain damage based on reports of
children who developed neurological conditions after vaccination. These safety concerns were
amplified by claims that the vaccine was also largely ineffective in protecting against the disease.
Massive nationwide epidemics of whooping cough followed the collapse in coverage and, while
it was relatively easy to demonstrate the efficacy of the vaccine, safety studies were more
difficult to perform. Back then, before the advent of desk top computers and the internet, it was
quite a challenge to conduct large epidemiological studies to test whether a temporal association
between vaccination and the development of a rare clinical condition was due to chance or was
evidence of a causal connection. It therefore took several years to conduct the prospective cohort
and case control studies that eventually confirmed the safety of the vaccine and allowed coverage
to be restored.
The next vaccine safety scare to hit the UK occurred in the 1990s, when claims were made that
MMR caused autism. By this time, it was possible to remotely access computerized health
records and link these with immunization records, which meant that retrospective cohort studies
could be rapidly undertaken with minimal cost. Over the last two decades, our research team has
conducted many studies of vaccine safety using these large linked databases and employing a
novel statistical method that we developed to improve analytic efficiency and minimize
confounding – a potential source of bias in any observational study of association. I have found
this vaccine safety research not only intellectually challenging but also very rewarding in that its
results can directly inform vaccine policy and the risk-benefit evaluation implicit in every
individual’s decision to accept a vaccine.

2) What are the controversies regarding vaccines?

Vaccines differ from other medications as they are given to millions of healthy individuals,
usually children, to prevent diseases that may no longer pose an immediate threat. Concern about
vaccine safety is therefore perfectly legitimate and, when potential safety signals arise, they must
be investigated promptly and rigorously. Many of the concerns about vaccine side effects have
arisen as a result of reports of a temporal association between administration of a vaccine and
development of a rare disease for which the cause is currently unknown. Such case reports are
still the way that most safety signals are generated; indeed, health professionals and parents are
encouraged to report any side effects that they suspect may have been caused by a vaccine to
authorities such as the Centers for Disease Control and Prevention (CDC) in the US or the
Medicines and Healthcare products Regulatory Agency (MHRA) in the UK.
In other instances, signals are generated from ecological associations, where an increase in the
incidence of a disease is noticed to coincide with introduction of a vaccine. Examples of vaccine
safety concerns that have arisen in this way are the alleged association between the combined
MMR vaccine and autism, which was based on both a reported temporal link for some cases and
a suggested ecologic association. This developed into a “controversy”, as despite sound
epidemiological studies showing no excess of autism onsets after MMR vaccine, there remained
a vocal lobby that did not accept the evidence.
The reasons why scientific evidence on vaccine safety is rejected by the so-called ‘anti-vaxxers’
are complex and varied. They include distrust of the scientific ‘establishment’ who generally
promotes vaccination, albeit based on careful risk-benefit analyses, suspicion that those
conducting vaccine safety studies are in the pay of the pharmaceutical industry, sincerely held
personal belief that their child was damaged by a vaccine, or pseudoscientific beliefs such that
vaccination is unnatural and it is better for a child to experience the real disease or that giving
several vaccines to a young child can ‘overload the immune system’. Despite strong scientific
arguments against the immune overload hypothesis and epidemiological studies showing no
increased risk of infections after multiple vaccinations, this idea may seem plausible to parents
who then hesitate to vaccinate their infant believing that deferral until an older age may be in
their best interests. The concept of vaccine hesitancy is one that is now gaining currency as it
recognizes that there is a continuum between those who accept and those who refuse vaccination
and that it is not helpful to characterize all of the latter as anti-vaxxers.

3) What are the health consequences of refusing vaccinations and what are the
implications beyond those who do so?
An implacable rejection of vaccination, despite strong evidence of its safety, is damaging. It
places the individual at increased risk of disease and also of exposing vulnerable contacts. For
example, in a measles outbreak in San Diego in which the index case was an ‘intentionally
unvaccinated’ child who contracted the disease while travelling abroad, 75 % of the secondary
cases were similarly unvaccinated due to refusal, with one hospitalization of an infected infant
who was too young to be vaccinated. In addition to the clinical consequences of such outbreaks,
there are economic impacts because of the extensive public health measures that need to be put
in place to limit transmission and protect vulnerable contacts. However, the consequences can be
even more far reaching than this, as the promulgation of anti-vaccine views via websites and the
media can lead to a decline in vaccine acceptance among others who are not, in principle,
opposed to vaccination. In the case of the MMR controversy, for example, sustained interest in
the alleged association by the British media with extensive coverage of the unsubstantiated
claims of the anti-vaccine lobby and scant attention to the actual scientific evidence resulted in a
critical fall in MMR vaccine coverage in the UK. As a result, measles, which is highly infectious
and can exploit even a small decline in population immunity, returned with savage
consequences. After an interval of 14 years with no acute measles deaths, the resurgence
associated with MMR vaccine refusal led to the deaths of two immunocompromised children
who could not be vaccinated and therefore contracted the disease. Within the European region,
refusal or hesitancy to accept the MMR vaccine because of unfounded safety concerns has been
one of the factors behind its continuing failure to attain the region’s measles elimination goal,
initially set for 2010, then deferred until 2015.

4) How should the risks of not vaccinating be communicated?

There is no blanket approach to communicating with parents who refuse or are hesitant to
vaccinate. In fact, some research has suggested that emphasizing the dangers of not vaccinating
may be counterproductive. In a controlled trial in the US, parents were randomly allocated to a
control group or to receive 1 of 4 interventions, namely (1) information about the lack of
evidence that MMR causes autism from the CDC, (2) information about the dangers of the
diseases prevented by MMR, (3) images of children with diseases prevented by the MMR
vaccine, and (4) a dramatic narrative about an infant who almost died of measles. None of the
interventions increased parents’ intent to vaccinate. Furthermore, amongst those with the most
negative opinions, the interventions actually increased misperceptions or reduced vaccination
intention. Since parents rate their children’s doctor as their most trusted source of vaccine safety
information, it is important that paediatricians and general practitioners have access to the most
up-to-date information. In the UK, for example, during the MMR/autism controversy, the
Department of Health posted each new safety study on its website as it was published, together
with up-to-date information on disease risks.
Tailoring the message to the individual is important as well. In an attempt to provide health
professionals with a framework for communicating with parents, researchers have identified five
distinct parental attitudes, representing a continuum of beliefs regarding vaccination. There are
the ‘unquestioning acceptors’ (30–40 %), who believe in the benefits of vaccination and trust
their healthcare provider to have their child’s best interests at heart, and the ‘cautious acceptor’
(25–35 %), who have some minor concerns but nevertheless proceed with vaccination following
a brief discussion on side effects and disease risks. The ‘hesitant’ group (20–30 %) comprises
those who have significant concerns about vaccine risks. For this group, trust in their doctor or
nurse is key and, if their questions are answered satisfactorily and completely by knowledgeable
health professionals, they will proceed with vaccination. The ‘late or selective vaccinator’ (2–
27 %) group has specific concerns about one vaccine or alleged phenomena, such as immune
overload, and are generally knowledgeable. This group needs the most time, with detailed
information on the risks and benefits of vaccination and, if necessary, another appointment to
reconsider their decision. The outright ‘refuser’ of all vaccines generally comprise less than
<2 % and are often motivated by their religious, philosophical or alternative beliefs. For this
group, even referral to a specialist immunization clinic where they can have dedicated time with
experts is unlikely to change their attitude. This analytic framework supports the concept of
vaccine hesitancy and makes useful distinctions between the tiny minority who are implacably
opposed to vaccination and the broader group of vaccine refusers who can have their views
modified with appropriate discussion and information.

5) Should vaccination be compulsory?

Making vaccination compulsory by law is often seen as a way of improving compliance and
dealing with the problem of vaccine hesitancy or refusal. While individual freedom of choice is
an important principle, those who refuse vaccination not only pose a risk to themselves but also
to others. The philosopher JS Mill, while a staunch proponent of individual liberty, recognized in
his essay On Liberty in 1859, that “the only purpose for which power can be rightfully exercised
over any member of a civilized community, against his will, is to prevent harm to others”, thus
presciently providing an ethical justification for mandatory vaccination. Moreover, vaccine
refusers are now often seen as ‘free loaders’ – exercising their rights to refuse vaccination safe in
the knowledge that the risk to their own child is low because of the herd immunity provided by
others who have their child vaccinated. In the European Union, 14 of the 27 countries have one
or more mandatory vaccination programmes, with the legal consequences of failure to comply
ranging from punitive measures such as pecuniary penalties, difficulty to attend public schools or
even penal consequences for the parents, to milder disincentives such as just necessitating a
formal ‘opt-out’ on religious or philosophical grounds. The rigour with which mandatory
vaccination is enforced also varies and, overall, there is no clear evidence from European
countries that mandatory vaccination necessarily achieves high coverage. In the US and
Australia, however, compulsory vaccination has contributed to the success of immunisation
programmes, but the balance between individual freedoms and public benefits is a fine
judgement and not all countries will make the same decision. In countries such as Sweden,
Norway, Denmark, the Netherlands, and the UK, compulsory immunisation is unlikely to be
acceptable and indeed high coverage has been achieved through other approaches.

6) What can be done to increase transparency in research funded by pharmaceutical

companies, and is enough being done to ensure that data from vaccine trials are being
adequately reported, particularly regarding any adverse outcomes?
There have been significant changes to the regulatory framework in recent years which have
ensured that manufacturers of any medicinal product, including vaccines, operate in a more
transparent manner, with improved systems for detection of adverse events. Firstly, all those
conducting clinical trials of vaccines and therapeutic drugs are encouraged to register them on a
publically accessible website such as ClinicalTrials.gov. In the US, the Food and Drug
Administration Amendment Act requires this by law and the International Committee of Medical
Journal Editors (ICMJE) makes trial registration a condition of the publication of clinical trial
results. The purpose is partly to ensure that potentially eligible participants are made aware of
trials that may be of interest to them and are kept informed of the results, but also to reduce bias
in outcome reporting. When an unexpected but serious adverse event occurs that might possibly
be related to the vaccine or drug (termed a suspected unexpected serious adverse reaction), there
is now a requirement to notify the licensing authority within 7 days so that information can be
rapidly collated across different trials using the same product to assess whether this constitutes a
safety signal. Hiding unfavourable safety results in a trial is not an option as the licensing
authority can audit the conduct of the trial and the compliance of the investigators with Good
Clinical Practice and the regulatory framework. As part of the licensing process, manufactures
must also submit a Risk Management Plan that identifies possible risks of their product,
including any potential pre-licensure safety signals, together with a mitigation strategy to reduce
the risk. Thus, when the second generation of rotavirus vaccines was licensed, manufacturers
were required to conduct large post-marketing studies to assess the risk of intussusception, as
this rare side effect was the cause of the withdrawal of the first licensed rotavirus vaccine. With
novel statistical methods, such as the self-controlled case series, and the increasing availability of
large linked databases, such studies can now be conducted rapidly and with minimal bias.
Despite these improvements, no risk management plan could anticipate a rare and completely
unexpected reaction, for example, narcolepsy following the AS03 adjuvanted H1N1 pandemic
influenza vaccine, which first came to light as a result of observant sleep physicians who noted
an increase in referral of cases, many of whom had recently been vaccinated. While pre-licensure
trials were necessarily limited in size due to the urgency of getting the pandemic vaccine to the
population in time, with a risk as low as 1 in 55,000 largely concentrated in children and
adolescents, conducting a pre-licensure trial large enough to detect such a reaction would not
have been feasible.
While it is important to convey the huge benefits of vaccination, it is also necessary to honestly
acknowledge that the absolute safety of a new vaccine can only be confirmed after it has been
given to hundreds of thousands of individuals and that the decision to vaccinate is a risk-benefit
judgement that requires full informed consent.