No 2 - 2016

Novel HPV vaccine in the childhood vaccination programme

As previously described, EPI-NEWS 49/15, a new HPV vaccine, Cervarix®, shall be used in the childhood vaccination programme as from 1 February 2016.

The background for this is the result of the statutory vaccine tender. The vaccine tender is used for publicly funded vaccines not produced by Statens Serum Institut. The criteria applied in the assessment of tenders received for the HPV vaccine are available here.

The tender includes pre-established tender criteria relating to efficacy , adverse events, side-effects (in this context protection against condyloma is weighted) and price. On the basis of an overall assessment, the Cervarix® vaccine was chosen. The tender period is 1 year, followed by two optional 1-year extensions of the period. The tender material and process is assessed regularly by the Legal Advisor of the Danish Government (Danish: Kammeradvokaten).

All girls who receive HPV vaccination under the childhood vaccination programme as from 1 February 2016 shall therefore initiate vaccination with Cervarix®.

About the vaccine

Cervarix® contains virus-like protein particles (VLP) from HPV types 16 and 18. The virus-like particles are produced in cells from cabbage looper (Trichopulsia ni) through recombinant DNA technology and is adjuvanted by adjuvant system AS04 and adsorbed on hydrated aluminium hydroxide.

The HPV vaccine does not contain genetic material from the virus and therefore cannot infect cells or cause infection in the vaccinee. Animal studies have shown that the effect of the vaccine is largely mediated by the development of a humoral immune response.

Cervarix® protects against the two oncogenic HPV types (16 and 18) that cause 70% of all cases of cervical cancer. Protection against cervical cancer and the adverse event profile of Cervarix® are comparable with those of the previously used vaccine; Gardasil®. In contrast to Gardasil®, the new Cervarix® vaccine does not provide protection against condyloma.

Cervarix® was approved for use in Europe (EU) in 2007, and so far a total of approx. 57 million doses have been administered globally. The vaccine is used in the childhood vaccination programmes of Holland, Finland, Iceland and Hungary, among others. Some countries use both vaccines in parallel.

Cervarix® is approved for use as from 9 years of age. The Danish Health and Medicines Authority recommends that the vaccine be given in the childhood vaccination programme at 12 years of age.

Upon storage of the pre-filled syringe, a fine white deposit with a clear colourless supernatant may be observed. After well shaking, the vaccine becomes a cloudy, white liquid.

Further information about the HPV vaccine is found in the approved summary of product characteristics, which is available at the SSI website.

Posology and administration

Cervarix® may be used as from 9 years of age for prevention of premalignant genital (cervical, vulvar and vaginal) lesions and cervical cancer, which are causally related to certain oncogenic types of human papilloma virus (HPV).

From 9 years through 14 years of age, two doses each of 0.5 ml are given. The minimum interval separating the two doses is 5 months, and the vaccination series shall have been completed within 13 months. If these intervals are not observed, a total of three doses are to be given. The minimum interval between the second and third dose is the standard 5 months.

From 15 years and upwards a total of three doses each of 0.5 ml are given - at months 0, 1 and 6.

Girls who are immunosuppressed at the time of vaccination are recommended a three-dose programme.

The need for a booster dose has yet to be established.

No data are available on combination vaccination with various HPV vaccines, and it is therefore recommended that persons who have received Cervarix® as their first dose complete the entire vaccination schedule with Cervarix®.

Cervarix® is not recommended for use in girls below 9 years of age due to lack of data on safety and immunogenicity in this age group.

The vaccine is administered intramuscularly to the upper arm (deltoid region). Under no circumstances should the vaccination be administered intravascularly or intradermally. No data are available on subcutaneous administration of Cervarix®.

The vaccine should be shaken well before use.

Protection

Cervarix® only protects against disease caused by HPV types 16 and 18, and to some degree against disease caused by the related oncogenic HPV types 31, 33 and 45.

Immunogenicity:
In the clinical studies, more than 99% of the subjects who were seronegative prior to vaccination had formed antibodies to both HPV 16 and 18 after their third dose.

Clinical efficacy:
Overall, the efficacy of Cervarix® against premalignant genital lesions and cervix cancer is in line with that documented for Gardasil®.

In an end-of-study analysis with a median follow-up of 44 months after the first vaccine dose (and independently of HPV-DNA type), the protection provided by Cervarix® against development of severe premalignant cervical lesions or worse (Cervical Intraepitelial Neoplasia /CIN3+) was 93.2%, and against development of moderate lesions or worse (CIN2+) it was 64.9%. The study was conducted in a cohort of women aged 15-25 years who at their inclusion had a normal cytology, were HPV-DNA-negative to 14 oncogenic HPV types and seronegative to HPV 16 and 18 (HPV naïve).

In the full cohort of vaccinated subjects whose HPV-DNA status, cytology or serological status had not been recorded at inclusion (baseline), the corresponding protection of Cervarix® to development of CIN3+ and CIN2+ was 45.6% and 33.1%, respectively.

For the three oncogenic non-vaccine HPV types 31, 33 and 45, persisting cross-protection against 6 months of persisting infection reached 76.8%, 44.8% and 73.6%, respectively; and against CIN2+ changes a protection of 87.5%, 68.3% and 81.9%, respectively, was reached. Both of the above results were seen in women who had received three doses and who were DNA-naïve to the relevant HPV type at months 0 and 6.

No direct efficacy data are available for girls aged 9-14 years. The approval of the efficacy of the vaccine for this age group was based on so-called immuno-bridging studies. These studies reported a non-inferior immune response for girls aged 9-14 years compared with immunogenicity in women aged 15-25 years.

In clinical studies in girls aged 9-14 years who followed a two-dose programme (months 0 and 6 or months 0 and 12) and young women aged 15-25 years who were given Cervarix® in accordance with the standard programme (months 0, 1 and 6), all subjects seroconverted for both HPV type 16 and 18 one month after the second dose. The immune response after two doses in girls aged 9-14 was non-inferior to the response after three doses in women aged 15-25 years.

Certain data are available on the long-term protection of Cervarix® in a three-dose programme. In 92 persons with a median observation time of 8.9 years, 100% remained seropositive to both HPV 16 and 18.

There are no studies on the effect of a two-dose programme with Cervarix® beyond 5 years, but the effect is expected to be prolonged.

For both programmes, the need for any booster vaccination remains unknown.

Concomitant use with other vaccines

Cervarix® was tested with concomitant use of vaccines containing diphtheria, tetanus and acellular pertussis and with or without inactivated polio vaccine (IPV), hepatitis A and hepatitis B vaccine (and the combined vaccine). Based on common vaccinological principles, it may also be given concomitantly with other vaccines, including the MMR vaccine. When more vaccinations are given simultaneously, they are administered at separate injection sites.

Adverse events

In clinical studies conducted before the marketing authorisation was granted in girls and women aged 10-72 years, Cervarix® was administered to 16,142 subjects, whereas 13,811 subjects received a control vaccine (hepatitis A).

These subjects were followed for serious adverse events over the entire study period. In a pre-defined subset of subjects, all adverse events were followed for 30 days after each injection. The most common adverse event observed after vaccine administration was injection site pain which occurred after 78% of all doses.

The majority of these events were of mild to moderate severity and were not long lasting.

In addition to local pain, very common adverse events (>1/10) included erythema, swelling, and fatigue and also headache and myalgia.

Common adverse events (> 1/100 to < 1/10) were nausea, vomiting, diarrhoea and abdominal pain. Furthermore, pruritus, rash, hives and fever > 38 degrees Celcius.

Uncommon adverse events (>1/1,000 to <1/100) were upper respiratory tract infection, dizziness and other injection site reactions such as induration and local paraesthesia.

Post-marketing, the latest summary of product characteristics from September 2012 informs of the following possible adverse events, the frequency of which cannot be assessed due to spontaneous reporting. Lymphadenopathy, allergic reactions (including anaphylactic and anaphylactoid reactions), angio-oedema and syncope or vasovagal responses during injection, sometimes accompanied by tonic-clonic movements.

For information of any special warnings and precautions concerning the use and contraindications, please see the approved summary of product characteristics .

Strong focus on possible adverse effects of HPV in Denmark

In Denmark, the Danish Medicines Agency is the authority responsible for the monitoring of any adverse effects related to the HPV vaccines. Since 2009, the Danish Medicines Agency has received slightly more than 650 reports of presumed serious adverse effects following HPV vaccines, the vast majority following Gardasil®, which has so far been used in Denmark, both in the childhood vaccination programme and in several catch-up programmes.

This number should be seen in relation to the very large number of Danish girls and women who have received vaccination against cervical cancer in this period. A total of more than 1.6 million vaccines have been sold, and therefore approx. one in every five Danish women has currently been vaccinated.

With a view to describing any association between HPV vaccines and syndromes like POTS (postural orthostatic tachycardia syndrome), CRPS (complex regional pain syndrome) and chronic fatigue syndrome (CFS), the European Medicines Agency (EMA) prepared and published a safety review of both HPV vaccines in 2015 by Danish request.

The review demonstrated that no data indicate any association between the HPV vaccine and the POTS and CRPS syndromes. Furthermore, the EMA placed great emphasis on a population study which found no association between HPV vaccine and CFS or symptoms of chronic fatigue.

By December 2015, the WHO’s Global Advisory Committee on Vaccine Safety (GACVS) published a statement on the safety of the HPV vaccines. In line with EMA, the GACVS assessed that, based on the existing knowledge there is no documentation of any safety issues that give rise to a change in the use of the vaccines.

Several studies have been initiated to contribute to clarify if special characteristics can be demonstrated among girls/women who have been notified with a presumed serious adverse effect. We refer here to characteristics that set these girls/women apart from other women who have been vaccinated, but who have not experienced similar symptoms.

Requirement on notification of all adverse effects

The Danish Medicines Agency continues to monitor the safety/adverse effects of the HPV vaccines and still encourages physicians, patients and relatives who believe that they themselves or their patients or relatives have suffered any adverse effects to report the suspected adverse effects to the Danish Medicines Agency.

As this is the first time Cervarix® is used in the childhood vaccination programme, the Danish Medicines Agency has decided that the vaccine will be comprised by the enhanced duty of notification and therefore all presumed adverse effects of the vaccine shall be reported by physicians (dentists and midwives).

Settlement codes

Before 1 February the Cervarix® settlement codes will be made public.

Transition programme

All girls who receive their first HPV vaccination on 1 February or later shall receive Cervarix®.

All girls who have already received a minimum of one Gardasil® dose shall complete their vaccination series with this vaccine. This should take place before the end of January 2017.

Ordering and supply

Cervarix® is ordered using item number 97187. The vaccine is supplied in 10-dose packages. The vaccine is ordered using Form 6 or Ordre@ssi.dk. We expect to provide any ordered vaccines in Week 4 on the standard supply day. Along with the vaccines, a number of information folders from the Danish Health and Medicines Authority will be provided as well as a copy of this issue of EPI-NEWS.
(P.H. Andersen, P. Valentiner-Branth, Department of Infectious Disease Epidemiology)

The Travel Advice Service (Rejserådgivningen) at Statens Serum Institut will close as from 1 February 2016

Due to cut-backs, the Travel Advice Service for general practitioners offered by Department of Infectious Disease Epidemiology at Statens Serum Institut since the beginning of April 2010 will be closed, EPI-NEWS 11/10.

As from 1 February 2016, we will therefore no longer be providing advice on vaccination and use of malaria prophylaxis for foreign travel, either in the form of risk assessment or other information about the used vaccines. The downsizing comprises advice given over the phone as well as by letter/e-mail. It will still be possible to find information through the SSI website “Travels and Infectious Diseases”

We will continue to provide advice on the childhood vaccination programme, including on adaptation to the programme of children who arrive to Denmark and on childhood vaccines for children who will be staying abroad for longer periods of time.

Following written application, we will also - for a period of time - provide advice on continued vaccination for children who have experienced an adverse effect following vaccination, if the adverse effect was presumably caused by a vaccine produced by the SSI. This type of advice will be discontinued when the SSI's vaccine production is sold off.

We will also be providing advice on risk assessment following exposure to infectious diseases, including on treatment following specific exposure to infection in the form of vaccination and possibly immunoglobulin.

The department may also be contacted in future, if preparedness products are needed, both during the daytime on phone +45 32683037 and during outside normal working hours (after 15.30 on working days, 15.00 on Fridays, and on Saturdays, Sundays and holidays) on phone +45 41317404.

Due to the above measures, the opening hours of the Department’s telephone advice service are limited to working days except Wednesdays 8.30-11.00 and Wednesdays 12.30-15.00.

The new opening hours will apply as from 1 March 2016. In the month of February, the previous opening hours will apply, but we will not be available for travel advice.
(The Consultancy Team, Department of Infectious Disease Epidemiology)

Link to previous issues of EPI-NEWS

13 January 2016