Lucija Tomljenovic*, Judy Wilyman, Eva Vanamee, Toni Bark and Christopher A Shaw
Corresponding author: Lucija Tomljenovic email@example.com
Infectious Agents and Cancer 2013, 8:6 doi:10.1186/1750-9378-8-6
Franco Maria Buonaguro
(2013-05-08 16:14) on behalf of Dr Silvia de Sanjose. Institut Catala d'Oncologia, Barcelona, Spain
Dear Dr Tomljenovic and colleagues.
Thank you for your comment. I agree with the authors that cervical cancer prevention
and control is a very complex issue. The availability of tools to prevent it for over
60 years it makes this disease a target for Public intervention and concern as still
many women will suffer from it or its precursor lesions.
When trying to respond to the 8 questions that the authors bring forward I realized
that Tomljenovic are questioning the whole system of how the public health stake holders
are evaluating research, take decisions and monitor the safety of the population.
It is thus difficult to counter argue so many queries from the part of one researcher.
I am unclear if the debate should go towards analyzing the whole regulatory system
for the introduction of a public health intervention or should I go point by point
showing the best of the available data indicating the HPV vaccines offer an amazing
opportunity to reduce cervical cancer burden in the world. Clearly I will not go for
the first as this would involve to review the organization of agencies such as FDA
or EMEA. As for the second I think that the reports for WHO, CDC, and those of several
countries that have considered the introduction of HPV vaccines are very compelling.
I would just refer to the WHO position paper. This document reflects the work over
2 years of an independent group from the related industry . Its conclusion of recommendation
of the HPV vaccine is fully documented. (1)
Apart from these general consideration I will try to bring forward my personal view
on each one of the specific questions .
1. HPV vaccines have not been demonstrated to prevent any cervical cancers so why
are they being promoted as cervical cancer vaccines?
It is still early to claim that exiting HPV vaccines have prevented a single cervical
cancer. The acquired knowledge of the natural history of cervical cancer indicates
that we will need over a decade to be able to fully estimate the impact of HPV vaccines
in cervical cancer. Data from several clinical trials including a large non industry
based trial have all been consistent of an enormous efficacy in the reduction of target
HPV types and their related pre-neoplasic lesions. These robust data informed us that
if it was possible to remove the etiological factor leading to this cancer, in the
long run this should result in lowering the burden of invasive cervical cancer.
2. If the majority of HPV infections and a great proportion of pre-cancerous lesions
clear spontaneously and without medical treatment and are thus not a reliable indication
of cancer later in life, then how can these end-points be used as a reliable indicator
of the number of cervical cancer cases that will be prevented by HPV vaccines?
In the same way that we do not allow women to get invasive cervical cancer when undergoing
screening, similarly we expect that women with cervical cancer will arise from those
infected that cannot resolve spontaneously the infection. The same argument could
go for any other vaccine.
3. How can the clinical trials make an accurate estimate of the risk associated with
HPV-vaccines if they are methodologically biased to produce type-2 errors (false
negatives [2, 4, 13])?
The risk associated to secondary effects of the vaccines is not exclusively evaluated
on the data generated from trials phase III trials. Additional monitoring is routinely
done to complement the information.
4. Can a passive monitoring system such as that used by most vaccine surveillance
systems world-wide allow the medical regulatory agencies to make accurate estimates
on the real frequency of HPV-vaccine related adverse reactions?
Surveillance systems should be able to allow identification of short and long term
effect for any intervention done in the general population. If the system is wrong
then it needs to be improved but why should this be different for a specific vaccine
with a very good record of safety from the trials.?
5. Can an accurate estimate of the real frequency of HPV-vaccine related adverse
reactions be made if appropriate follow-up and thorough investigation of suspected
vaccine related ADRs is not conducted but instead, these cases are a-priori dismissed
as being unrelated to the vaccine?
To my knowledge, ADR have been fully monitored in many countries with established
surveillance systems. See as a good example the reports of the Vaccine Adverse Event
Reporting System (VAERS) which publishes regularly the information for the US.
6. Why are women not informed of the fact that in some circumstances (i.e., prior
exposure to vaccine-targeted and non-targeted HPV types), HPV vaccination may
accelerate the progression of cervical abnormalities [4, 26-28]?
The most recent data support the fact that women that have a cervical abnormality
and that are vaccinated do not have any acceleration of their abnormalities and that
on the contrary seem to be getting a better prognosis.
7. How can women make a fully informed decision about whether or not to consent to
vaccination if crucial information regarding HPV vaccine efficacy and safety is not
being disclosed to them?
I believe that any program introducing the HPV vaccine massively has promoted the
channels by which women can get information on the safety and efficacy of this vaccine.
See for exemple many Goverment based web sites informing the public http://www.cdc.gov/hpv/vaccine.html
for the US ; http://www.mhra.gov.uk/Safetyinformation/Generalsafetyinformationandadvice/Product-specificinformationandadvice/Product-specificinformationandadvice-G-L/HumanpapillomavirusHPVvaccine/CON023340
for the UK;
8. Should the medical health regulators and authorities rely solely on data provided
the vaccine manufacturers to make vaccine-policy decisions and recommendations [12,
Vaccine manufactures run the necessary trials and should provide their data as requested
by the official agencies in such a way that can be evaluated and contracted. Many
countries provide recommendation on a sum of different aspects of evidence not only
on the manufacture trials but also on independent research studies on the natural
history of the disease, mathematical models and more. Care indeed must be taken that
all this information is adequately traceable.
However it cannot be dismissed that countries with high coverage of the quadrivalent
vaccine have already shown a remarkable reduction of HPV related diseases such as
genital warts. Similarly a reduction of high grade lesions has also been reported
in Australia. It is obvious that we need to follow up the impact
I agree with the authors that cervical cytology suffers of poor repeatability for
some stages of pre-neoplasic lesions and has poor sensitivity if not applied on a
regular bases. Efforts to improve screening tools are regularly deployed by many
research groups. New data coming from large meta-analysis show that probably HPV DNA
detection tools could remove some of the caveats of cervical cytology. Still women
going to screening will be triaged to negative for cervical cancer or positive for
cervical cancer. The proportion of positives through the span of the suitable screening
range (aprox 25-65 years) brings a significant proportion of women to be at a certain
point to be positive with all the side effects that this involves. The whole concept
to prevent the disease is appealing and should then not be dismissed.
It is true that at this point a vaccine to protect against the established high risk
types is not yet available but the reduction of 70% of the cancer burden is a considerable
adequate target in terms of public health reduction. Trial data show that a 70% reduction
is a feasible aim. Probably we have not had better data before any medical intervention
as what is available for HPV vaccine. Despite of this, many groups around the world
are investing many efforts to improve our estimates, to refine the predictions, to
genotype existing HPV related cases or to improve the existing vaccines. Evidence
based medicine is supportive of this intervention providing there exist adequate infrastructure.
Silvia de Sanjose, MD PhD
(1) Human papillomavirus (HPV) vaccine background paper. Geneva: World Health Organization;
2008. Available from: http://www.who.int/immunization/documents/HPVBGpaper_final_03_04_2009.pdf
[accessed 4 April 2012]
Comment published on behalf of Dr Silvia de Sanjose, editor of the Thematic series
on HPV Prevention .
Director of Unit of Infections and Cancer, Cancer Epidemiology Research Programme,
Institut Catala d'Oncologia, Av. Gran Via de l'Hospitalet 199-203, 08908 L'Hospitalet
de Llobregat, Barcelona, Spain
BioMed Central Ltd unless otherwise stated. Part of Springer Science+Business Media.