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Vaccination against cervical

cancer

RCOG Scientific Advisory Committee
opinion paper 9
Feb 2007
Dr Raymond Arhin
BACKGROUND
The licensing of the first vaccine designed to prevent
cervical cancer recently made headline news across the
world.
The vaccine was shown to be 100% effective in the
short term at preventing type specific premalignant
disease of the cervix.
The potential of such a vaccine to reduce the worldwide
incidence of cervical cancer is immediately apparent.
This paper reviews the rationale for a vaccination
approach to the - prevention of cervical cancer,
- details the progress made so far and
-outlines some of the important
challenges that remain.
The scale of the problem

In the UK, the number of deaths from cervical cancer
has been reduced by over 50% in the 1980s and 1990s,
following the introduction of the National Health Service
Cervical Screening Programme (NHSCSP).
In poorly resourced settings, where screening services
are not available cervical cancer remains a significant
cause of mortality among women.
In fact, without further preventative measures, deaths
from cervical cancer are predicted to jump four-fold to
over a million a year by 2050 as a result of the explosion
in human papillomavirus (HPV) infection rates across the
world.

The Case for Vaccination
Vaccination as a means of primary prevention has
obvious advantages in countries where screening
programmes are not established
but may also offer advantages in countries like the UK,
where secondary prevention by screening and treating
premalignant lesions is not only expensive but
sometimes imprecise, resulting in unnecessary anxiety
and intervention for some women, while at the same
time failing to detect lesions in others.
Despite the success of screening programmes, cervical
cancer still occurs in a proportion of screened women.

HPV is the principal causal factor

The papillomaviruses infect epithelial cells.
Lowrisk types, such as HPV-6 and -11, cause benign
genital warts and respiratory papillomatosis,
while persistent infection with high-risk oncogenic types
(HPV-16 and -18) is associated with a hugely increased
relative risk of developing high grade cervical
intraepithelial neoplasia (CIN).
HPV infections by oncogenic types are extremely
common in young sexually active women but while most
clear spontaneously without ever causing dysplasia, a
proportion develop a persistent infection.

Cervical cancer can therefore be regarded
as a rare consequence of persistent
infection with one or more high risk types,
HPV-16 and -18 together account for up to
70% of cervical cancers across the world.
Other high risk types, including HPV-31, -
33 and -45, are also important, although
the proportion of cancers caused by each
type varies from country to country.8
HPV prophylactic vaccination
2.1 Rationale
Women previously infected with a particular HPV type are unlikely to
become reinfected by the same type, because of immunity largely
provided by antibodies targeted against the major papillomavirus
capsid protein L1.
These antibodies block the interaction between infectious virions
and their epithelial receptor, preventing viral access. When made in
the laboratory, L1 protein self-assembles into virus-like particles
(VLPs) that are morphologically identical to HPV and highly
immunogenic but not in themselves infectious because they lack the
viral genome.
Animals immunised with these VLPs generated high titres of virus-
neutralising antibodies and were subsequently protected against
infection by the same papillomavirus type.

2.2 Vaccination trials

Three HPV prophylactic vaccines have now
been tested in humans in large randomised
double-blind placebo-controlled trials.
SINGLE Vaccine -HPV16
BIVALENT Vaccine HPV16 AND 18
QUADRIVALENT Vaccine HPV -6,11,16 &18
Koutsky et al.11 vaccinated over 1500 women between the ages of
16 and 23 years with either an HPV-16 VLP vaccine (Merck) or
placebo in the form of adjuvant and followed them up for an average
period of 17 months.
The results of this trial established proof of principle for HPV
prophylactic vaccination. During follow-up, all 41 cases of persistent
HPV-16 infection and all nine cases of HPV-16-positive CIN (five
CIN1 lesions and four CIN2 lesions) occurred in the placebo group.
Twenty-two further cases of CIN associated with other HPV types
were seen in each of the placebo and vaccine groups.
This indicates that protection against CIN offered by vaccination
was type-specific.
To make a significant impact on cervical cancer mortality, an HPV
prophylactic vaccine should ideally offer protection against several
high risk HPV types
Harper et al.12 tested a bivalent HPV-16 and -18 VLP vaccine in
over 1000 women aged between 15 and 25 years during a 27-month
follow-up period.
Vaccine efficacy and immunogenicity studies have subsequently
been reported for an extended follow-up period of up to 48 months.
The vaccine (Cervarix, GSK Biologicals), which incorporates a
novel adjuvant (AS04) was shown to be significantly effective (over
88%) against incident and persistent HPV-16 and -18 infections up
to 4 years following vaccination.
It demonstrated significant protection against cytological
abnormalities and 100% efficacy against CIN associated with HPV-
16 and/or -18.
There was also some evidence for vaccine-related cross protection
against incident HPV-45 and -31 infections, the third and fourth most
common HPV types associated with cervical cancers.
Gardasil (Merck), a quadrivalent vaccine offering
protection against HPV types 6, 11, 16 and 18, was
initially tested in a trial involving over 500 women
between the ages of 16 and 23 years over a 36-month
follow-up period.
Persistent infection with one of the four HPV types was
reduced by 89% in the vaccinated women.
Genital warts and type-specific CIN were seen in six
placebo and none of the vaccine-treated women,
although the study was not powered to assess vaccine
efficacy for disease endpoints.
Vaccination resulted in high titres of HPV type 6-, 11-,
16- and 18-specific antibodies, although the longevity of
this immune response varied, with only 76% of
vaccinees showing detectable antibody responses to
HPV-18 36 months after immunisation.
Gardasil is now being tested in a large phase III study
involving over 25 000 women from 33 different countries
across the world.
An interim analysis found the vaccine to be 100%
effective in the short term at preventing high-grade CIN
and cervical adenocarcinoma in situ (AIS).
There is also preliminary evidence of cross-protection
against infection with related HPV types such as 31 and
45.
Furthermore, Gardasil has demonstrated efficacy
against high-grade vulval and vaginal intraepithelial
neoplasia caused by the virus types targeted by the
vaccine.
Following on from this success, Merck submitted a successful
Biologics License Application for Gardasil to the US Food and
Drug Administration. Subsequently, Gardasil received a European
licence and is now available in the UK.
Cervarix, the bivalent HPV-16 and -
18 VLP vaccine, is currently under
investigation in a large multicentre
phase III study and is also likely to be
licensed in the near future.
3. Challenges for universal HPV
prophylactic vaccination
3.1 Public acceptability
Despite the huge success of HPV prophylactic vaccines in clinical
trials, worldwide vaccination programmes are still years from
realisation.
One important consideration is whom to vaccinate.
In order to have maximum impact, a prophylactic vaccination
programme would need to target young women prior to the onset of
sexual activity.
Sensitive public health campaigns would be required to convince
parents to allow their teenage daughters to be vaccinated against a
sexually transmitted infection. Some pro-abstinence and religious
groups may be opposed to the vaccination of young girls, fearing
that it may promote promiscuity.
Others are changing their position, admitting that women who are
celibate until marriage may still contract HPV from husbands who
are not.
3.1 Public acceptability
Parental attitudes are likely to vary across cultures.
A Manchester study found 80% of parents to be
supportive, provided that the vaccine were proven to be
safe and effective.
It also reported that many parents thought that the
decision to be vaccinated would need to be joint with the
child, which would require the child to acquire some
understanding.
By contrast, in India, where the incidence of cervical
cancer is high, extreme social pressure may preclude
parents from vaccinating their unmarried daughters.2
3. Challenges for universal HPV
prophylactic vaccination
3.1 Public acceptability
Whether boys should be vaccinated is still unresolved.
Including boys is likely to be important for the
development of group immunity.
A vaccine that additionally provided protection against
HPV-6 and -11 (such as Gardasil) may act as an
incentive for male vaccination, since genital warts
commonly affect men as well as women and are
unpleasant and can be difficult to cure.
Vaccinating males may also prevent anal cancer, an
increasing problem in the homosexual HIV population.
3.2 Duration of protection

. HPV-specific antibodies generated by vaccination may wane with time,
although current data indicate that immune responses persist through 5
years.
The need for booster immunisations to maintain protection against
infection will only become apparent after prolonged periods of follow-up.
It is also unclear whether the strength of immunity generated by
vaccination is affected by the number of HPV types included in the
vaccine. Villa et al.15 found that HPV-18-specific antibody levels were
only detectable in 76% of vaccinees 36 months following immunisation
with the quadrivalent vaccine.
Further research is necessary to determine what factors influence the
longevity of protection provided by HPV vaccines, thus enabling the
generation of vaccines that offer an extended period of protection.


(It is noteworthy that booster doses are not required for hepatitis B and
hepatitis A vaccination.20,21 )
3.3 Reaching women in
underdeveloped settings

The need for HPV prophylactic vaccines is greatest in
underdeveloped countries where the incidence of
cervical cancer is high and there is an extreme shortage
of screening and treatment facilities
. The logistics of delivering an HPV prophylactic vaccine
to these parts of the world should not be underestimated.
The vaccines are expensive to produce, require
continuous refrigeration and must be given in repeated
injected doses.
Already overstretched budgets that are struggling to
deliver fresh food, clean water and basic health care to
its people may make HPV prophylactic vaccination
unaffordable without a reduced tier of pricing and foreign
aid to deliver the vaccine.
3.4 What about screening?
.
An HPV prophylactic vaccine is unlikely to benefit
women who have already been exposed to the relevant
virus type.
It may therefore take a generation before all women at
risk of cervical cancer can be vaccinated and even then
a proportion will remain unvaccinated.
It is not clear to what extent older women with prior HPV
exposure could be protected by vaccination. Cervical
screening will, therefore, continue to play an important
role in the fight against cervical cancer.
HPV prophylactic vaccination may not be 100% effective
and will probably not protect against all HPV types.
There will, therefore, be a need for continued cervical
screening in a vaccination era.
Future
Future screening strategies may depend upon
primary HPV testing with cytology being
reserved for those women who are HPV
positive.
Current trials will help inform such a policy.
The additional costs of vaccination may
eventually be substantially offset by a reduction
in the screening budget but the cost
effectiveness of vaccination will be a key
consideration in decisions regarding
implementation of a public vaccination
programme.
4. Conclusions

HPV prophylactic vaccines are now becoming
available.
Their potential to reduce the worldwide
incidence of cervical cancer is unprecedented.
Universal vaccination protocols require careful
strategic and financial planning in both
developed and underdeveloped settings.
In the meantime, the final results and longer-
term results of global trials, as well as
demonstration (phase IV) trials, including
feasibility, will continue to provide valuable
information.







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