HUMAN PAPILLOMA VIRUS (HPV) VACCINATION
Human papillomavirus (HPV) is a double
stranded DNA virus, that infects
squamous
epithelia including the skin and mucosae of the upper respiratory
and
anogenital tracts. There are
approximately 100 types of HPV, of which
about 40 infect the genital tract (McCance, 2004).
Although most infections
are asymptomatic and self-limiting, genital infection
by HPV is associated
with genital warts and anogenital cancers in both men
and women. HPV
viruses are classified as either ‘high-risk’ or
‘low-risk’ types depending on
their association with the development of cancer.
Genital HPVs are transmitted by sexual contact with an
infected individual,
primarily through sexual intercourse. The risk
therefore, is related to the
number of sexual partners, the introduction of a new
sexual partner, and the
sexual history of any partner. Studies of incident HPV
infection, based on HPV
DNA detection, demonstrate that acquisition of at least
one type of HPV
infection often occurs soon after sexual debut with
almost 40% of women
being infected within two years (Winer et al., 2003; Winer et al., 2008).
The use of condoms reduces but does not
eliminate the risk of sexual
transmission. Non-sexual routes of HPV transmission include
vertical
transmission
from mother to newborn baby.
Persistent infection by high-risk HPV types is
detectable in more than 99%
of cervical cancers (Walboomers et al., 1999). Of these
high-risk types,
HPV16 is responsible for almost 60% and HPV18 for more
than 15%, of all
cervical cancers in Europe (Smith et al., 2007). A further 11
high-risk types
have been described (WHO IARC, 2007, 1 Including
types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66). In addition to
cervical cancer,
HPV is causally associated with other less
common cancers, including
cancer
of the vulva, vagina, penis and anus, and some cancers of the head
and
neck (Parkin et al., 2006; Stanley, 2007).
Infection by multiple types is
common (Cusheri et
al, 2004).
The majority of HPV infections are transient and cause
no clinical problems.
Around 70% of new infections will clear within one year
and approximately
90% will clear within two years (Ho et al., 1998; Franco et al., 1999). The
median duration of a new infection is eight months.
Persistent infection by a
high-risk HPV type is the most important causal factor
for the development of
cervical pre-cancerous and cancerous lesions. Persistence
and disease is more
common
for infections by HPV types 16 and 18 than for other high-risk types.
The
time span between infection by HPV and the development of CIN3 or
cervical
cancer varies from one to ten years (Moscicki et al., 2006).
Although high-risk HPV infection is a risk factor for
the development of vaginal
or vulval lesions, unlike cervical cancer, only
approximately 40% are associated
with HPV infection (Munoz et al., 2006). The natural
history of vaginal and
vulval cancers is not completely understood. HPV
infection is associated with
80-90% of all anal squamous cell cancers and HPV types
16 and 18 are found in
the majority of HPV-related anal cancers (Munoz et al., 2006). Around 40% of
cases of penile cancer are attributable to HPV
infection (Rubin et al., 2001). For
all sites, the evidence for a causal association is greater
for HPV types 16 and 18
than for other HPV types, and the
majority of HPV related cancers are associated
with types 16 and 18.
Low-risk HPV types are responsible for genital warts,
which is the most
commonly diagnosed viral sexually transmitted infection
in the UK (Fenton et
al., 2004),
(HPA, 2012). HPV types 6 and 11 cause the majority of all genital
warts (Lacey et
al., 2006; Garland et al., 2007). Genital
warts appear from three
weeks
to eight months after primary infection (most commonly two to three
months)
(Oriel, 1971). In the absence of treatment, up to 30% of individuals
clear
the infection in the short term (Tyring
et al., 1998;
Edwards et al.,
1998).
The rate of spontaneous regression in the long term is
not known. Treatments
focus
on removal of the warts, but do not necessarily eliminate infection, which
may
persist sub-clinically, and be a source of recurrence and continuing viral
transmission.
Genital warts are not life threatening, but they can cause significant
morbidity.
HPV infection has been associated with cancerous
and non-cancerous lesions
outside the ano-genital area including laryngeal
papillomas, (Stamataki et al.,
2007) and some head and neck cancers (Psyrri et al., 2008).
The HPV vaccination
HPV vaccines are sub-unit vaccines made
from the major protein of the
viral-coat or capsid of HPV. Virus-like particles
(VLPs) are prepared from
recombinant proteins grown in either yeast or baculovirus
infected insect
cells (the latter derive from a type of moth). VLPs
mimic the structure of the
native virus but do not contain any viral DNA. There are
currently two
different
HPV vaccine products. Cervarix® contains VLPs
for two HPV types
(16
and 18 – bivalent vaccine) and Gardasil® contains VLPs
for four HPV
types
(6, 11, 16 and 18 – quadrivalent vaccine). The VLPs used in Cervarix®
are adjuvanted by AS04 containing
3-O-desacyl-4'- monophosphoryl lipid A
(MPL) adsorbed on aluminium hydroxide. The VLPs used in
Gardasil® are
adsorbed on amorphous aluminium hydroxyphosphate
sulphate adjuvant.
The above vaccines do not contain thiomersal. They do not
contain live
organisms
and cannot cause the diseases against which they protect.
HPV vaccines are highly effective at preventing the
infection of susceptible
women with the HPV types covered by the vaccine. In
clinical trials in young
women with no evidence of previous infection, both
vaccines are over 99%
effective at preventing pre-cancerous lesions
associated with HPV types 16
or 18 (Harper et
al., 2006; Ault et
al., 2007; Lu et
al., 2011). Current studies
suggest that
protection is maintained for at least seven years. Based on the
immune responses, it is expected that protection will
be extended further;
long-term follow-up studies are in place. Some other
high-risk HPV types
are closely related to those contained in the vaccines,
and vaccination has
been shown to provide some cross-protection against
infection by these types
(Brown et al., 2009; Lehtinen et al., 2012). Gardasil® is also 99% effective at
preventing genital warts associated with vaccine types
in young women
(Barr et al., 2007).
Cervarix® was the HPV vaccine offered
from September 2008 to August
2012 with Gardasil® being
offered from September 2012 (Department of
Health, 2011).
Storage
Vaccines should be stored in the original
packaging at +2°C to +8°C (ideally
aim for 5°C) and protected from light. All vaccines are
sensitive to some
extent to heat or cold. Heat speeds up the decline in
potency of most
vaccines, thus reducing their shelf life. Effectiveness
cannot be guaranteed
for vaccines unless they have been stored at the
correct temperature. Freezing
Human
papillomavirus
(HPV) July 2012
may cause increased reactogenicity and loss
of potency for some vaccines. It
can also cause hairline cracks in the container,
leading to contamination of
the contents.
Presentation
HPV vaccines are all supplied as suspensions
of VLPs in pre-filled syringes.
During storage, a white precipitate may develop and the
vaccines should be
shaken before use to form a white cloudy liquid.
Dosage and schedule
The two vaccine products are not routinely
interchangeable and, ideally, one
vaccine
product should be used for the entire course (see below). Following
the introduction of Gardasil® as
the vaccine for the national immunisation
programme, there will continue to be a supply of
Cervarix® available for a
further six months to allow girls who started the
schedule with Cervarix® but
missed vaccinations to complete the course.
The Summaries of Product Characteristics for
Cervarix® and Gardasil®
allow flexibility in their administration.
Schedule for Cervarix® (containing
HPV types 16,18)
● First dose
of 0.5ml of Cervarix® HPV vaccine.
● Second dose of 0.5ml, one to two and
a half months after the first dose.
● A third dose of 0.5ml at least five months
after the first dose.
Schedule for Gardasil® (containing
HPV types 6,11,16,18)
● First dose
of 0.5ml of Gardasil® HPV vaccine.
● Second dose of 0.5ml at least one
month after the first dose.
● A third dose of 0.5ml at least three
months after the second dose.
For
planning purposes, a vaccination schedule of 0, 1, 4-6 months is
appropriate
for both vaccines. All three doses should be ideally given within
a
12-month period. If the course is interrupted, it should be resumed (using
the
same vaccine) but not repeated, ideally allowing the appropriate interval
between
the remaining doses.
Minimum interval for the third dose of HPV vaccine
There is no clinical data on whether the
interval between doses two and three
can be reduced below three months. Where the second
dose is given late and
there is a high likelihood that the individual will not
return for a third dose
after three months or if, for practical reasons, it is
not possible to schedule a
third dose within this time-frame, then a third dose
can be given at least one
month after the second dose. This applies to both
Cervarix® and Gardasil®.
Whenever possible, immunisations for all individuals
should follow the
recommended 0, 1, 4-6 month schedule.
Previous incomplete vaccination with Cervarix®
– advice
for girls and young women covered by the
national
HPV vaccination programme
The advice below applies to those girls and
young women who are eligible to
receive HPV vaccination as part of the national HPV
immunisation
programme as described in the guidance issued by the
Department of Health
(PL/CMO/2008/4).
If an individual has started a course of Cervarix®, then
this course should,
where possible, be completed with Cervarix®. In
instances where this is not
possible or where the make of the initial vaccination
is not known, then the
vaccination course can be completed with Gardasil® to
three doses in total.
The course should be completed according to a
vaccination schedule of 0, 1,
4-6 months. As there is no evidence on the
interchangeability of the two HPV
vaccine products, this advice is based on expert
judgement of the data from
partial courses of each vaccine.
It is not advisable to implement a three-dose course of
Gardasil® following a
partial or complete course of Cervarix® as
there are no safety data on
individuals who receive mixed courses of vaccines
involving four or more
HPV vaccine doses.
The primary purpose of the national immunisation
programme is to protect
against cervical cancer. It would not be appropriate,
therefore, as part of the
NHS programme, to offer Gardasil® to
those who have had a full course of
Cervarix® with the aim of providing
additional protection against genital warts.
Human
papillomavirus
(HPV) July 2012
Administration
Vaccines are routinely given intramuscularly
into the upper arm or
anterolateral
thigh. This is to reduce the risk
of localised reactions, which are
more common when vaccines are given subcutaneously
(Mark et al., 1999;
Zuckerman, 2000; Diggle et al., 2000). However, for
individuals who have a
bleeding
disorder, vaccines should be given by deep subcutaneous injection
to
reduce the risk of bleeding.
HPV vaccines can be given at the same time as
other vaccines such as Td/
IPV, MMR and hepatitis B. A trend of lower anti-HPV
titres has been
observed when Gardasil® is
administered concomitantly with dTaP, dT/IPV
and dTaP/IPV vaccines, though the clinical significance
of this observation
is unclear. The vaccines should be given at a separate
site, preferably in a
different limb. If given in the same limb, they should
be given at least 2.5cm
apart (American Academy of Pediatrics, 2006). The site
at which each
vaccine was given should be noted in the individual’s
records.
Recommendations
for the use of the vaccine
The objective of the HPV immunisation
programme is to provide three doses
of HPV vaccine to females before they reach an age when
the risk of HPV
infection increases and puts them at subsequent risk of
cervical cancer.
Prevention of HPV infection in those eligible for
vaccination and in others
outside of the routine programme should include advice
on safer sex. All
women, whether vaccinated or not, should be strongly
encouraged to attend
routine cervical screening at the scheduled age.
Cervarix® and Gardasil® are licensed for individuals from nine years old.
Vaccination of girls of this age is not covered by the national HPV vaccination
programme.
Females aged 12 to 13 years
From September 2008, HPV vaccination was routinely recommended for all
girls at 12 to 13 years of age (school year 8 or S2 in Scotland or school year 9
in Northern Ireland). The course of HPV vaccination should be administered
according to the guidance given in the dosage and schedule section. If the
course is interrupted then it should be resumed but not repeated, ideally
allowing the appropriate interval between the remaining doses.
Females aged 13 to under 18 years
Girls aged 13 years to under 18 years, who are in or have completed school
year 9 (S3 in Scotland or school year 10 in Northern Ireland), should have
been offered HPV vaccine as part of the routine programme, or catch-up
programmes run in 2008/09, 2009/10 and 2010/11. For girls with unknown or
incomplete immunisation status see below.
Females aged 18 or over
Vaccination for females over the age of 18 years is not covered by the
national HPV vaccination programme. However, for girls who commenced,
but did not complete vaccination in the catch-up programmes (born after
1 September 1990), it is reasonable to complete their HPV vaccination
course after the age of 18 years.
Vaccination of females with unknown or incomplete
immunisation status
Where a female in the target cohort aged over 12 and under 18 years presents
with an inadequate vaccination history, every effort should be made to
clarify what doses she has had. A female who has started but did not
complete the schedule before reaching the age of 18 years, should complete
the vaccination course at the minimum interval (see above) where possible.
The course of HPV vaccination should be administered according to the
guidance given in the dosage and schedule section. If the course is interrupted
then it should be resumed but not repeated, ideally allowing the appropriate
interval between the remaining doses. Females coming to the UK from
overseas and registered with a GP practice may not have been offered
protection against HPV in their country of origin and should be offered
vaccination if they are aged under 18 years. If they are aged 18 years or over,
and commenced, but did not complete vaccination, it is reasonable to
complete their HPV vaccination course.
http://www.who.int/vaccines/globalsummary/immunization/scheduleselect.cfm
Vaccination of boys and young men
Males of any age are not covered by the national HPV vaccination programme.
ccontraindicationContraindications
There are very few individuals who cannot receive HPV vaccine. Where
there is doubt, appropriate advice should be sought from an immunisation
coordinator or consultant in health protection rather than withholding
vaccination.
The vaccine should not be given to those who have had:
● a confirmed anaphylactic reaction to a previous dose of HPV vaccine, or
● a confirmed anaphylactic reaction to any components of the vaccine.
Yeast allergy is not a contraindication to the HPV vaccine. Even though
Gardasil® is grown in yeast cells, the final vaccine product does not contain
any yeast (DiMiceli et al., 2006).
Minor illnesses without fever or systemic upset are not valid reasons to
postpone immunisation. If an individual is acutely unwell, immunisation
may be postponed until they have fully recovered. This is to avoid confusing
the differential diagnosis of any acute illness by wrongly attributing any
signs or symptoms to any possible adverse effects of the vaccine.
Pregnancy and breast-feeding
There is no known risk associated with giving inactivated, recombinant viral
or bacterial vaccines or toxoids during pregnancy or whilst breast-feeding
(Atkinson et al., 2008). Since inactivated vaccines cannot replicate they
cannot cause infection in either the mother or the foetus. However, on a
precautionary basis, HPV vaccine is not advised in pregnancy. If a woman
finds out she is pregnant after she has started a course of HPV vaccine, she
should complete her pregnancy before finishing the three-dose schedule.
This precaution is not due to any known risk associated with giving HPV
vaccine during pregnancy, but due to absence of data. Limited data are
available because pregnant women were specifically excluded from clinical
trials of HPV vaccine. However, despite these exclusion criteria some
women were inadvertently immunised whilst pregnant or shortly before
becoming pregnant (many pregnant women have also now been vaccinated
following the introduction of HPV vaccination programmes). No specific
safety concerns have been identified in the women who have been given
HPV vaccine, either for the outcome of pregnancy or fetal development,
when compared with women who received a placebo or control vaccine.
Routine questioning about last menstrual period and/or pregnancy testing is
not required before offering HPV vaccine.
Girls aged under 18 years in the target cohort who are known to be sexually
active, including those who are or who have been pregnant, may still be
susceptible to high-risk HPV infection and could therefore benefit from
vaccination according to the UK schedule. If pregnant, they should be
offered vaccine as soon as possible after pregnancy. If high-risk sexual
activity continues during pregnancy, and the opportunity for vaccination
after pregnancy is uncertain, the benefit of vaccination during pregnancy is
likely to outweigh any potential risk.
Termination of pregnancy following inadvertent immunisation should not be
recommended. The available evidence on the use of HPV vaccine in
pregnancy should be discussed with the prospective parents.
Due to the relatively limited experience of HPV vaccine in pregnant women
to date, it is important to record and follow up such cases of inadvertent
administration during pregnancy to provide further data on the outcome.
Surveillance of vaccination in pregnancy is being conducted by the
Immunisation Department at HPA Colindale, to whom such cases in England
and Wales should be reported via the website (http://www. hpa.org.uk) or by
telephone (01788 540298 or 0208 327 7471). Cases in Scotland should be
reported to Health Protection Scotland on 0141 300 1100, Immunisation
Department. Cases in Northern Ireland should be reported to the Public
Health Agency Duty Room (028 9055 3997).
Immunosuppression and HIV infection
Individuals with immunosuppression or with HIV infection (regardless of
CD4 count) should be considered for HPV vaccines in accordance with the
recommendations above. However, individuals who are immunosuppressed
may not develop a full antibody response. Clinical trials to study the
effectiveness of HPV vaccination in immunosuppressed individuals are in
progress. Re-immunisation should be considered after treatment is finished
and/or recovery has occurred. Specialist advice may be required.Adverse reactions
As with all vaccines and medicines, healthcare professionals and parents/
carers are encouraged to report suspected adverse reactions to the Medicines
and Healthcare products Regulatory Agency (MHRA) using the Yellow Card
reporting scheme (www.mhra.gov.uk/yellowcard).
The most common adverse reaction observed after HPV vaccine
administration is mild to moderate short-lasting pain at the injection site. An
immediate localised stinging sensation has also been reported. Redness has
also been reported at the injection site.
Other reactions commonly reported are headache, myalgia, fatigue, and low
grade fever.
A detailed list of adverse reactions associated with Cervarix® and Gardasil®
is available in the Summary of Product Characteristics (SPC) for each
vaccine, which are available from the European Medicines Agency website
http://www.ema.europa.eu.
Syncope (vasovagal reaction), or fainting, can occur during any vaccination,
most commonly amongst adolescents. Some individuals may also experience
panic attacks before vaccination. The clinical features of fainting and panic
attacks are described in detail in Chapter 8 of the Green Book. Fainting and
panic attacks occurring before or very shortly after vaccination are not
usually direct side effects (adverse reactions) of the vaccine but events
associated with the injection process itself.
Only reactions suspected to be related to the vaccine (and not those
associated with the injection process) should be reported via the Yellow Card
Scheme.
Reporting anaphylaxis and other allergic reactions
Anaphylaxis is a very rare, recognised side effect of most vaccines and
suspected cases should be reported via the Yellow Card Scheme (www.mhra.
gov.uk/yellowcard). Chapter 8 of the Green Book gives detailed guidance on
distinguishing between faints, panic attacks and the signs and symptoms of
anaphylaxis. If a case of suspected anaphylaxis meets the clinical features
described in Chapter 8, this should be reported via the Yellow Card Scheme
as a case of 'anaphylaxis' (or if appropriate 'anaphylactoid reaction
of less severe allergic reactions (i.e. not including the aforementioned
clinical features for anaphylaxis) should not be reported as anaphylaxis but
as 'allergic reaction'.
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