The Gardasil Vaccine – Is it Safe and Effective?

The decision made by all but one New Zealand District Health Board to roll out the vaccine programme through schools means that Boards of Trustees have been involved in deciding whether or not to provide the vaccine through their schools. Different schools have reached different decisions for different reasons. The main purpose of this article is to focus on key facts and findings regarding the safety and efficacy of the Gardasil vaccine with a view to assisting schools in reviewing the decisions they have made as well as providing some guidance for parents who face this decision in the near future. Concluding comments will highlight a number of unresolved questions regarding the HPV vaccination programme.

Background

Cervical cancer is well known to be the second most common cancer in women worldwide. Every year in New Zealand 160 women are diagnosed with cervical cancer and approximately 60 women will die from this disease (1). It is encouraging that, over the past few decades, the death rate from cervical cancer has been decreasing in first world countries due to the success of the cervical smear ("Pap Test") programme which can detect abnormal changes in the cervix before they progress to cancer. However, for a variety of reasons, not all women have access to, or choose, cervical screening. Furthermore, even the less radical forms of treatment for early, pre-cancerous changes are not without their potential complications for subsequent pregnancies. Therefore, medical scientists have continued to look for another way to combat this disease. The fact that the disease is almost always caused by infection from one or more viruses opened up the possibility that a vaccine could be used in the fight against the spread of these viruses.

The viruses that infect and cause changes in the cervix that can sometimes progress to cervical cancer come from the family of viruses known as the Human Papilloma Viruses (HPV). These viruses are transmitted between humans via sexual contact, not necessarily sexual intercourse; genital skin to skin contact can be sufficient for transmission which is why condom usage, whilst reducing the chance of viral transmission, cannot completely eliminate it (2). None of us can afford to be complacent about the HPV viruses as it is estimated that 80% of women are exposed to at least one of these viruses in their lifetime. It has also been estimated that 40% of girls become infected with one of the HPV viruses within two years of becoming sexually active (3). Most will clear the virus from their bodies spontaneously but some will not, particularly those who smoke and/or take the contraceptive pill. If the virus is not cleared then it may invade the cervical cells causing pre-cancerous changes known as Cervical Intraepithelial Neoplasia (CIN). These changes are graded CIN 1, 2 or 3 according to their severity and the treatment required.

While there are over a hundred different types of HPV that can infect humans, the Gardasil ('cervical cancer') vaccine used in New Zealand covers four HPV viruses; HPV 6, 11, 16 and 18. The first two, HPV 6 and 11, cause genital warts and the second two, HPV 16 and 18, cause up to 70% of the cases of cervical cancer. The Gardasil vaccine (marketed by pharmaceutical company, Merck) contains L1 VLPs (Virus Like Proteins) similar to proteins produced by the HPV virus when it invades cells. It is these proteins that stimulate the body to produce antibodies to the virus so as to eradicate it from the body, just as it would if attacked by a common cold virus.

It is important to note that these L1 VLPs are only found in cervical cells in the early stages of HPV infection. This means the high grade, pre-cancerous lesions such as CIN 2 or CIN 3 contain very few L1 VLPs, if any. Hence, giving the Gardasil vaccine to a woman who has CIN 2 or CIN 3 will not help her body to fight these lesions because there will be no proteins against which the antibodies (produced by vaccination) can react. Vaccination can only protect against new HPV infections (provided they are one of the four contained within the vaccine – 6, 11, 16 or 18) or prevent potential spread of the virus from an infected site to a previously uninfected site; it provides little or no protection against advanced or established infections (3). This is important when we come to consider which age group benefits most from this vaccine.

Merck began their clinical development programme for Gardasil in 1997 Development of vaccines is carried out over 3 phases. Phase 1 studies use small numbers of volunteers who are given the vaccine via different modes of delivery and at different dosages to assess safety and immune responses, whilst phase 2 studies use larger numbers of volunteers and compare the new vaccine results with those of a placebo group. When phase 1 and 2 results for Gardasil proved favourable, phase 3 studies were initiated; this involved large, randomized, double blind, controlled trials in a number of countries across the world – the gold standard method for scientific testing of new medicines. The results of these studies were presented to the Vaccine and Related Biological Product Advisory Committee (VRBPAC) which forms part of the American Food and Drug Administration (FDA) in May 2006 (4). Merck had requested a process of 'fast tracking' approval of the vaccine on the grounds that it fulfilled an 'unmet medical need'. The pharmaceutical company felt it was no longer ethical to withhold the opportunity of vaccination to the many women who were included in their placebo group (i.e. the control group of women who did not receive the vaccine in the trials) given the demonstrable outcomes for those in the active arm of the trial. The FDA duly approved Merck's biologics license application for the Quadrivalent HPV vaccine (Gardasil) in June 2006 to be delivered and administered to females aged between nine and 26 years of age (4). When Merck later applied to have the license extended to older women this application was declined in June 2008 (see below).

Is the vaccine safe?

Safety figures vary slightly according to the source accessed but it appears that approximately 10% of vaccine recipients experience some side effects (3, 5). 94% of these side effects or 'Adverse Events' are mild and include localized redness and swelling around the injection site, fainting, headache, fever and fatigue.

The rate of adverse event reporting in Australia, which has used the vaccine in its schools since 2007, is roughly consistent to the reporting rate for other new vaccines (6). Similarly, in New Zealand, the Centre for Adverse Reactions to Medicines based at Otago University has noted nothing of concern regarding the rate or types of side effects seen amongst New Zealand recipients up to January 2009. Although in USA the adverse event reporting for Gardasil is higher than for other new vaccines, it has been postulated that this reflects the higher media coverage that resulted because of some states attempting to make the vaccine mandatory (7).

With regards to more serious adverse events (defined by the US Communicable Disease Centre as any event that was life-threatening, causing permanent disability or death, requiring hospital admission, requiring intervention to prevent permanent impairment or damage, or any other event that required medical attention), it is reassuring to note that such events were evenly divided between the vaccine recipients and the placebo recipients and were not unduly high (3, 5). They included symptoms such as wheezing, gastroenteritis, and allergic reaction. The latter is a recognized and unavoidable phenomenon of any protein injected into the body and current Australian rates of anaphylaxis are 3.2 per million Gardasil injections, which is why any vaccine is administered by trained and fully equipped staff (6). So far, there have been no deaths directly attributed to the vaccine. On balance, it appears that the vaccine is safe within currently acceptable parameters.

That said, it is a little disconcerting to learn that the FDA, after granting Merck their license, requested a post marketing short term surveillance study in the United States of America that would follow up on 44,000 vaccinated subjects for up to six months "subsequent to vaccination for new auto-immune disorders ... Also, a sufficient number of children 11-12 years of age will be studied to permit an analysis of safety outcomes ... The final study report will be submitted by September 30, 2009" (4). Long term follow up studies after the introduction of any vaccine are to be expected, but a short term study is somewhat unusual and its results are awaited with interest.

Some commentators have highlighted concerns about certain new auto-immune, neurological diseases including Guillain–Barré Syndrome and Amyotrophic Lateral Sclerosis. These have a background occurrence rate of approximately 1-2 per 100,000 adolescents in the unvaccinated population, making them very rare. The US Government Communicable Disease Center reports that the incidence of such conditions does not appear to be higher amongst girls who have been vaccinated. In other words, this is likely to be a coincidental occurrence. Further studies will provide more evidence on this question.

The fact that many million doses of Gardasil have now been given around the world points to the vaccine being safe. However, it would be preferable to know that a full analysis of safety outcomes had been completed before the vaccine was made available.

Is the vaccine effective?

To truly establish whether a vaccine against HPV is effective, the clinical endpoint that should be measured is high grade CIN or invasive cancer. However, as these outcomes can develop 15-20 years after HPV infection, scientists have to use surrogate outcomes such as the presence of HPV within cervical secretions, or low grade CIN changes, and assume that if the vaccine decreases the incidence of these, then it should ultimately decrease the incidence of cervical cancer also.

Rambout and co-workers have thoroughly analysed six large, recent controlled trials, including the FUTURE (Females United to Unilaterally Reduce Endocervical disease) and PATRICIA (Papilloma Trial against Cancer in young Adults) trials. They have concluded that the vaccine was effective in preventing the four specific HPV infections and pre-cancerous disease, particularly in women aged 15-25 who received all three doses, had no more than six sexual partners and had no prior abnormal smears (5). What we do not yet know, is whether the vaccine will be just as effective in real life if these conditions are not all fulfilled.

Is the vaccine effective in young girls aged 9-15 years?

In Phase III of the initial trials for Gardasil, almost 1000 girls aged between 9-15 years were vaccinated and their antibody levels to HPV were checked following each vaccination. The participants showed good immune responses (5). From this it was inferred the vaccine would be effective in this group. For obvious reasons, follow-up with cervical smears is not desirable in this age group in the short term.

The length of efficacy of the vaccine is also important, particularly for girls in the 9-15 age group. At present, follow up studies and government recommendations (1, 3) suggest that protection lasts for at least five years. Further follow up will determine whether or not booster doses are required after this. If boosters were required after five years, this may have a significant impact on the decision making of parents of 12 year old girls. For example, if vaccine protection has waned by the age of 17 and a girl has not become sexually active by then, she would have had the vaccine unnecessarily.

It is usual for vaccines to give long lasting protection and the Gardasil vaccine is unlikely to be an exception to this. Nevertheless, as detailed above, much of the hope placed in this vaccine is currently based upon presumed hypotheses. Whilst many of these presumptions are reasonable, the lack of hard evidence may give pause to parents considering whether or not to consent for their daughters to receive a vaccine that works in such a sensitive area of human behaviour.

The New Zealand policy of giving the vaccine to girls as young as twelve reflects the fact that the vaccine will not prevent cancer in those who have already been infected with the HPV virus and who have high grade cervical dysplasia; vaccination, if it is to be most effective, is best given prior to them becoming sexually active (8).

Is the vaccine effective in older women over 26 years of age?

A very recent paper in the Lancet (June 2009) based on a group of 4,000 women aged 24-45 gives some reason to believe that the HPV vaccine will be less efficacious in older women than in the young, HPV naive girls referred to above (9). Nearly all the 4,000 women in the trial "seroconverted" (produced antibodies) after vaccination. However, close analysis shows that while those in the ideal "per protocol" population (i.e. those who had no evidence of previous HPV infection and received all three doses of vaccine) did indeed have efficacy rates of 92%, women in the "intent to treat population" (the real world, who may have had previous HPV infections and/or did not receive all three doses) showed efficacy rates of only 30%.

On this basis the authors themselves concluded that the public health benefits of vaccinating older women are likely to be smaller than vaccinating HPV naive adolescents. This supports the FDA decision to refuse to license Gardasil for women older than 26, even though an earlier study had concluded that the vaccine was worth giving to older women even if they already had evidence of HPV infection (10, 11). In this study it was argued, and will continue to be argued by some, that the vaccine prevents these women from being infected with new viruses.

At one stage concerns had been raised that the vaccine might actually enhance pre-existing high grade cervical disease in the older population group. However, the consensus at the present time is that while it does not make the disease worse, neither does it have any therapeutic effect on pre-existing disease (4).

Summary

While it is fairly easy to assess efficacy and safety data for this vaccine, there are still uncertainties regarding its long term benefits for the population as a whole. Research shows that the Gardasil vaccine is most effective in the younger age group who have not yet become sexually active, that is, prior to their exposure to HPV viruses. For this group, current best evidence suggests that the vaccine can minimise the risks of developing cervical cancer by providing immunisation against the two HPV viruses that are linked with 70% of all cases of cervical cancer. It also appears to be safe within currently acceptable parameters, although there will be welcome additional evidence provided on these questions when the results of the United States post marketing study are available in September 2009 (4).

For older women, the vaccine is unlikely to become available in the near future; the cost-benefit ratio is simply not conducive to widespread application in this age group, many of whom may already be undergoing treatment or follow up for abnormal smear tests. Nonetheless, Merck are due to present the results of a 48 month study in older women to the FDA at the end of this year in a fresh attempt to get the licence extended to this age group (12). Like many health professionals, they may argue that if sexually transmitted diseases, including HPV, continue to increase in the older age group then vaccination is worth it to prevent new HPV infections. Whether government purses are willing to stretch that far remains to be seen.

Questions that remain regarding Gardasil

While not denying the fact that the Gardasil vaccine offers protection against the consequences of some of the HPV viruses, the vaccination programme raises a number of other important questions of a financial, political, medical and moral nature:

• Why is it that women alone are being targeted with the vaccine when evidence shows that men are also carriers of HPV and are at risk of developing penile and anal cancer due to HPV infection? Is it acceptable that boys/men are excluded from the benefits (and burdens) of the vaccine? What are the health and financial implications of this?
• Might it be the case that in time the viruses that cause the remaining 30% of cervical cancer become the dominant ones given the way in which nature tends to fill a vacuum?
• Will the vaccine actually save money and angst when women still need to have cervical smears because of the risk of infection from other HPV viruses not covered by the vaccine?
• If fewer women have smears, erroneously thinking they are safe, might this, paradoxically, lead to an increase in cervical cancer cases? Efforts must be sustained to ensure vaccinated women continue to receive regular cervical smears.
• Will the positive evidence currently provided by the measurement of surrogate outcomes be borne out in real terms by a reduction of cases of cervical cancer in the decades ahead?

Some of these questions may be answered by the long term Nordic studies that are due to be completed in 2013, but some will only become apparent in a decade or more, highlighting the fact that we are called to make decisions about the vaccination programme on the best evidence available but without knowing absolutely whether it will be truly effective in the long run.

It has also been suggested that there is a moral connection between the willingness to vaccinate and an attitude of sexual promiscuity amongst young persons. This perception is ultimately naïve; at the root of such behaviours there lie many complex and emotional factors which makes it unreasonable to postulate a necessary or simple link between the use of the vaccine and irresponsible sexual behaviour. Sadly, in our time, even genuine human intimacy carries certain real physical dangers – the HPV virus does not discriminate on the basis of moral behaviour, and with 80% of all women being exposed to this virus at some stage, there is a very real risk of infection for all persons entering into any kind of sexual relationship, including marriage. The vaccine programme arises out of a basic need for persons to be protected as much as possible from the terrible consequences of the HPV virus, and particularly cancer.

From a Catholic perspective, the willingness to vaccinate our young children and young women must occur as part of continuing efforts to promote amongst all people, and from a young age, the Catholic vision for sexual intimacy. Both home and schools need to contribute to this Catholic vision, with school programmes on human development and sexuality and Religious Education classes complementing and reinforcing the teaching of the home . Without such an integrated vision (which stresses that the proper place for sexual intimacy is in a permanent and married relationship) the introduction of the vaccine could too easily become just another aspect of the 'safe-sex campaign', perpetuating further a false sense of 'safety' from the sexually transmitted diseases that are all too prevalent. Without doubt, the most effective way to minimise the risk of contracting the HPV virus is to abstain from casual sexual relations and to keep sexual intimacy within marriage.

To conclude, the advent of the HPV vaccination programme presents us with the opportunity to reflect on many questions. Amidst a rightful concern to protect our young people, we must not lose sight of the question about our effectiveness in promoting the Catholic-Christian truth about sexual love in all its beauty and freedom. The responsibility for keeping our young people and ourselves 'safe' involves much more than the parental decision whether or not to vaccinate against the HPV virus.

References

1. See Ministry of Health. (2008). Immunisation: Human papillomavirus. Retrieved 24 July, 2009, from http://www.moh.govt.nz/moh.nsf/indexmh/immunisation-diseasesandvaccines-hpv
2. Winer, R., Hughes, J., & Feng, Q. e. a.-. (2006). Condom use and the risk of genital HPV infection in young women. New England Journal of Medicine, 354(25), 2644-2654.
3. Advisory Committee on Immunization Practices. (2006). Record of the meeting of the Advisory Committee on Immunization Practices, February 21-22, 2006. Retrieved 24 July, 2009, from http://www.cdc.gov/vaccines/recs/acip/downloads/min-feb06.pdf
4. See Clinical Review of Biologics License Application for Human Papillomavirus 6, 11, 16, 18 L1 Virus Like Particle Vaccine (S. cerevisiae) manufactured by Merck, Inc. Retrieved 24 July, 2009 from www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm111287.pdf
5. Rambout, L., Ferguson, D., & et al. (2007). Prophylactic vaccine against HPV infection and disease in women: A systematic review of randomized controlled trials. Canadian Medical Association Journal, 177(5), 469-479.
6. Therapeutic Goods Administration. (2009, 5 May). Human papillomavirus vaccine (GARDASIL): Advice. Retrieved 24 July, 2009, from http://www.tga.gov.au/alerts/medicines/gardasil.htm
7. John Iskander, Associate Director for Immunization Safety, quoted in Kotz, D. CDC Takes Closer Look at Gardasil and Paralysis. USNews, 2009. Accessed 14 May 2009. Available from http://health.usnews.com/blogs/on-women/2009/03/20/cdc-takes-closer-look-at-gardasil-and-paralysis.html
8. Lewis, H. The potential impact of mass HPV vaccination on cervical cancer prevention: population and clinical perspectives . National Screening Unit, 2007. Accessed 17 July 2009. Available from http://www.nsu.govt.nz/Files/NCSP/HPV_article.pdf
9. Manoz, N., Saah, A., & et al. (2009). Safety, immunogenicity and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 Years: A randomized, double blind trial. The Lancet, 373, 1949-1957.
10. FUTURE II Study Group. (2007). Prophylactic efficacy of a quadrivalent HPV vaccine in women with virological evidence of HPV infection. Journal of Infectious Diseases, 196(10), 1438-1446.
11. Hildesheim , A., & Herrero, R. (2007). Human papillomavirus vaccine should be given before sexual debut for maximum benefit. Journal of Infectious Diseases, 196(10), 1431.
12. Merck. (2009, 26 May). Product News: Gardasil® is first cervical cancer vaccine to receive WHO pre-qualification. Retrieved 24 July, 2009, from http://www.merck.com/newsroom/press_releases/product/2009_0526.html

Jane Mair, a mother of four, is a UK registered doctor who has worked in General Paediatrics. She currently serves on the board of trustees for a Catholic Primary School in the Hutt Valley.

The writer acknowledges valuable feedback provided by John Kleinsman and Associate Professor John France in the preparation of this article.

©
2009