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Quadrivalent human papillomavirus vaccine: questions and cautions

HPV infection is necessary for the development of cervical cancer and the vaccine may prevent primary infection with HPV types 16 and 18. However, Abby Lippman, chair of the Canadian Women's Health Network and an epidemiologist at McGill University, and colleagues think that these facts should be assessed within a broad context before immunization policies are implemented.

A careful review of the literature, including that submitted by the manufacturer with its application for approval of Gardasil, revealed a sufficient number of unanswered questions to lead to conclude that a universal immunization program aimed at girls and women in Canada is, at this time, premature and could possibly have unintended negative consequences for individuals and for society as a whole.

General questions and cautions

• There is no epidemic of cervical cancer in Canada to warrant the sense of urgency for a vaccination program.
According to 2006 Canadian cancer statistics, cervical cancer is the 11th most frequent cancer affecting Canadian women and the 13th most common cause of cancer-related deaths, accounting for approximately 400 deaths per year. Both the incidence and mortality of cervical cancer have been declining in Canada, as in other resource-rich countries, although recently at a somewhat slower rate than has been observed in previous decades. However, the incidence and mortality still vary between different groups of women, being notably higher among Aboriginal women than among non-Aboriginal women.

• Invasive cervical cancer typically follows a slowly progressive course that can be halted at one of various stages. The dramatic decrease in deaths from cervical cancer in Canada, even before the development of any vaccine,represents a public health success. Research attributes this to improved reproductive health practices and the widespread availability of publicly funded programs for Papanicolaou smear testing. Consequently, deaths from cervical cancer must be considered as a failure in the adequate support of both the primary care and reproductive health services that would guarantee healthy living conditions for all women. Improvements here, as well as steps to en- sure that all women receive appropriate Pap testing and follow-up, are needed.

• Most HPV infections are cleared spontaneously. Recent research using available molecular detection technologies has suggested that clearance occurs within 1 year for about 70% of infected women, and within 2 years for 90%.Thus, HPV infection and cervical cancer must not be conflated: cervical cancer will not develop in most women who are infected with even a high-risk strain of HPV.
Unfortunately, there are no data on clearance rates among girls, nor even about the actual HPV prevalence rates among youth and children.

• The nature of a vaccination program is necessarily dependent on the definition of clear and tangible goals. To date, such goals have not been made explicit with regard to a Canadian initiative. Is the aim of the vaccination program the eradication of high-risk HPV types from the population ? Or is it to reduce the number of deaths from cervical cancer ? These different goals require different strategies. For example, pathogen eradication would imply a herd-immunity goal, thus possibly necessitating the vaccination of boys and young men. In contrast, the reduction of deaths from cervical cancer would suggest the need for a vaccine directed against more than the 2 high-risk HPV types in Gardasil, which may account for only somewhat more than two-thirds of cervical cancer cases.

• Information about the efficacy of Gardasil remains uncertain.Its real-world effectiveness is even less clear. To date, only a handful of randomized controlled trials of sufficient quality to qualify for systematic review have been reported.

• What is the length of immunologic protection the vaccine confers against HPV types 16 and 18 ? Will boosters be needed to maintain this limited coverage, and if so, when ? Other questions with regard to effectiveness centre on concerns about the possibility of short-term immunity altering the natural history of viral infection, as seems to be the situation with chicken pox protection has been of shorter duration than expected, and viral infections in older people have been more severe than those in children.

• Relatively few girls ( about 1200 aged 9 –15 years ) were enrolled in the clinical trials of Gardasil, the youngest of whom were followed for only 18 months. Based on the assumption that they will not yet have been exposed to HPV viruses, girls in this age group represent the priority target population for mass vaccination.

• Gardasil is the most expensive childhood vaccine proposed for mass use; it currently costs $404 for the 3 required doses. Yet, the cost-effectiveness analyses of proposed vaccination programs needed to evaluate this expense are missing. The lack of effectiveness data makes it difficult to estimate what reduction in repeat testing or colposcopy can be anticipated to counter some of the vaccination costs and precludes determining whether vaccination will have any added value.
Girls and women, even if vaccinated, will still need to practise safer sex and have access to existing care programs for Pap testing as well as for other reproductive health care.

Source: Canadian Medical Association Journal, 2007