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 virusneutralising 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 HPV16 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.

 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. Challenges for universal HPV prophylactic vaccination 3.1 Public acceptability

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 longerterm results of global trials, as well as demonstration (phase IV) trials, including feasibility, will continue to provide valuable information.

THANK YOU