Since infection with HPV is the main cause of most cervical cancer, the obvious solution is to vaccinate children against it.1
Cervical screening detects cellular abnormalities early, but this is only secondary prevention. It is also important to realise that HPV avoids the host immune system, and, therefore, natural immunity. Antibody levels following natural HPV infections are low and many people do not become seropositive.
HPV vaccines have a key role to play in preventing cervical cancer
Most viral vaccines are based on an attenuated form of the virus, but developing an attenuated HPV vaccine has been difficult because there is no effective culture system to propagate HPV.
An attenuated vaccine might also cause disease in vaccinated subjects. The solution has been to manufacture virus-like particles (VLPs) using the L1 and/or L2 virus coat proteins. VLPs have the outward appearance of the virus and generate a powerful immune response, but are harmless as they contain no DNA.
There are potentially 15 cervical cancer HPV types and two prophylactic vaccines against types 6, 11, 16 and 18 have shown promise in clinical trials, with efficacy against HPV 16 and 18-related high-grade cervical intra-epithelial neoplasia and genital warts approaching 100 per cent.2
Gardasil, which contains all four HPV types and would thus protect against genital warts as well as the commonest cervical cancer HPV types (16 and 18) has been approved by the US FDA and the EMEA in Europe, as well as in other countries. Gardasil is licensed for children and women aged from nine to 26 years.
Cervarix, which contains types 16 and 18 and targets cervical cancer alone, was approved by the EMEA in 2007 and is licensed for girls and women from the age of nine upwards.
Although superficially similar, there are differences between the two vaccines. The VLPs are manufactured differently, and the adjuvants used are also different.
While Gardasil contains aluminium hydroxyphosphate sulphate, Cervarix is adjuvanted with ASO4, which is aluminium hydroxide with monophosphoryl lipid A. The ASO4 adjuvant has been used previously in a hepatitis B vaccine (Fendrix), where it was shown to generate a stronger and longer lasting immune response than the vaccine containing aluminium hydroxide alone.3
In this context, it is interesting that the antibody response to HPV 18 appears to be maintained at high levels for longer with Cervarix than Gardasil.3
A related issue is that of cross protection. It had been thought unlikely that this would occur, yet both vaccines have shown early evidence of such an effect. In the extended phase II trials at 6.4 years, Cervarix has shown 78 per cent (95 per cent CI 39-93) protection against incident infections with HPV 45, which is HPV 18-related, and 60 per cent (95 per cent CI 20-81) protection against incident infections with HPV 31, which is HPV 16 related.4
In the interim analysis of the phase III trial, Cervarix has shown cross protection against persistent infections at six months for HPV-45 (59.9 per cent, 95 per cent CI 2.6 - 85.2), type 31 (36.1 per cent, 95 per cent CI 0.5 - 59.5) and type 52 (31.6 per cent, 95 per cent CI 3.5 - 51.9).
The extent of sustained cross-protection against persistent infections, abnormal cytology and precancerous lesions remains undetermined. A laboratory study of antibody cross neutralisation with Gardasil suggested cross protection against types 31, 45, 52 and 58,2 while more recent data suggest protection against both persistent HPV infection and cervical intra-epithelial neoplasia associated with a bank of non-vaccine HPV types (31, 33, 45, 52 and 58).5
However, interestingly, in the Canadian summary of product characteristics, dated March 2008, the level of protection against individual HPV types is given; here there is no cross protection against HPV type 45.6
Although the clinical significance of this is unknown, it is interesting that there appears to be a consistently weaker effect of Gardasil on HPV 18 and its related type, 45. Cross-protection is important, as it may raise overall protection significantly.
Age for vaccination
For optimal protection, vaccines should be administered prior to the onset of sexual activity. It is also important to note that antibody responses induced by all vaccines are higher pre-puberty compared with post-puberty.
We do not know how long immunity lasts: ideally, such a vaccine would be administered with other childhood vaccines. However, that would depend on immunity lasting for decades, or boosters being given.
The FDA has recommended vaccination of 11- to 12-year-olds, with a catch-up to age 26. In England, the DoH has said it will fund a vaccination programme for 12- to 13-year-olds, with a catch-up to age 18. The basic programme is to start in autumn 2008, with the catch-up programme to begin in autumn 2009.
Studies are also under way to evaluate the benefit of vaccinating women over 25 years old. In a group of previously HPV-negative women aged 24-45, recently presented data suggest Gardasil was highly effective in preventing both persistent HPV infection and disease associated with the HPV types in the vaccine.7
If efficacy in older women is confirmed, vaccination of a wider age range could have a more immediate impact on rates of cervical cancer.
Efficacy in men
The issue of whether to vaccinate boys is still under debate and data on efficacy are awaited.
Most mathematical models suggest vaccination of girls alone is the most cost-effective strategy. However, this would not benefit men who have sex with men, who are at increased risk of HPV infections and anal cancer. In addition, this strategy focuses attention on women in relation to a sexually transmitted virus, which is not a useful public message not a useful public message.
Choice of vaccine
In recent weeks, the announcement has been made that Cervarix has been chosen by the DoH for its programme.
Although this decision might at first seem surprising there are valid scientific issues that may have influenced the decision.
In theory, an HPV vaccine could prevent almost all cervical cancer, thus eliminating the need for screening. It is noteworthy that vaccines should be effective against cervical adenocarcinoma, which is not detected effectively by screening and appears to be on the increase.
There is potential for a significant reduction in this cancer. However, until the number of HPV types in the vaccine is increased, there will still be cancers that it does not prevent.
In addition, there is at least one generation of women for whom the vaccines have come too late to precede sexual activity, and who will continue to require screening. It is, however, clear that screening programmes will need to adapt when HPV vaccination becomes widespread.
It is likely that cytology will become less useful as the number of abnormalities in the population decreases, and cytologists struggle to maintain their skills. HPV testing of some kind is likely to be the way forward, but this raises many issues - not least the high transient positivity rates in women under 35, and the probable need for HPV typing tests, which are not yet commercially available, to monitor long-term vaccine efficacy. These are issues which will need to be addressed in the next 15 years in the UK.
- Dr Szarewski is a clinical consultant and honorary senior lecturer at Cancer Research UK
- A vaccine against types 16 and 18 alone could prevent 70-80 per cent of cervical cancers.
- Vaccines against HPV have shown high efficacy in clinical trials.
- Differences between the two vaccines are beginning to emerge.
- Cervarix has been chosen for the UK vaccination programme.
1. Szarewski A. Prophylactic HPV vaccines. Eur J Gynaec Oncol 2007; (28): 165-9.
2. Stanley M. HPV vaccines: where are we now? J Fam Plann Reprod Health Care 2007; 33: 227-9.
3. Einstein M H. Acquired immune response to oncogenic human papillomavirus associated with prophylactic cervical cancer vaccines Cancer Immunol Immunother 2008; 57: 443-51.
4. Harper D. Cross protection against HPV 45 and 31; incident infection up to 6.4 years.
Presentation SGO, Tampa, Florida, March 9-12, 2008. Gynecologic Oncology 2008; 109: 158-9.
5. Brown D. HPV Type 6/11/16/18 Vaccine: First Analysis Of Cross-Protection Against Persistent Infection, Cervical Intraepithelial Neoplasia (CIN), And Adenocarcinoma In Situ (AIS) Caused By Oncogenic HPV Types In Addition To 16/18
Presented at: 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Chicago, September 17-20, 2007. abstract G-1720b 19.09.07.
6. Gardasil Product Monograph 08.05.08 www.merckfrosst.ca/mfcl/en/corporate/products/gardasil.html
7. Luna J, Saah A, Hood S, Barr E. Safety, efficacy and immunogenicity of quadrivalent HPV vaccine (Gardasil) in women aged 24-45.
Presented at; 24th International Papillomavirus Congress, November 3-9, 2007, Beijing. Abstract PA1-04.