HPV Immunization of Quebec Pre-Adolescents: Two or Three Doses?

In 2007, the Comité sur l’immunisation du Québec (CIQ) recommended an extended schedule exclusively for immunization against the human papilloma virus (HPV) starting in grade 4 (0, 6, 60 months); the committee also stated that the third dose should be administered “if judged necessary.” Since the introduction of the Québec HPV immunization program in 2008, similar programs (two doses administered six months apart and a possible third dose if necessary) have been introduced in Mexico and British Columbia. In 2012, the committee of immunization experts in Switzerland recommended for pre-adolescents a schedule comprising two doses administered six months apart. In recent years, a number of studies have been published on the immunogenicity of HPV vaccines administered according to alternative schedules and other studies are presently underway to document the efficacy of one, two, or three doses administered at different intervals.

The present advisory report, which is based on the theoretical framework put forward by Ericksonet al., summarizes the key data currently available regarding the pertinence of the administration of the third dose of HPV vaccine 60 months after the first dose.

To our knowledge, there are no good quality efficacy data for the schedules recommended by manufacturers (0, 1, 6 or 0, 2, 6 months) when vaccinating pre-adolescents. Nor efficacy data emerged yet from studies that have used a two-dose schedule with a six-month interval (0, 6 months) or an extended schedule (0, 6, 60 months).

However, some of the results presented at the International Papillomavirus Conference held in San Juan, Puerto Rico in December 2012 are summarized in this advisory report; these include efficacy data (observational studies) that show that there are no vaccine failures (breakthrough) for up to almost 10 years in young women who received the vaccine.

Immunogenicity data on available HPV vaccines show that the immune response measured in pre-adolescents (9-13 years) who received two doses six months apart is not inferior (in fact it is generally superior) to that obtained in vaccinated individuals aged 16 years or more, a group for which excellent efficacy data are observed for at least 10 years.

In girls aged 9-13 years, antibody levels one month after the administration of two doses (0, 6 months) or three doses (0, 2, 6 months) are comparable for all four types of HPV. Thirty-six months later, levels are still comparable for types 16 and 11. For types 18 and 6, however, observed antibody levels are lower in girls who received two doses than in girls in the same age group (9-13 years) who received three doses according to a 0-2-6 month schedule (however their antibody levels remain higher than those of women aged 16-23 who received 3 doses).

Preliminary Québec data on girls aged 9-10 years indicate that the first dose of quadrivalent vaccine produces detectable antibodies in 93-100% of girls, depending on the HPV type. These results indicate that a primary immune response occurs after the first dose when administered at this age. These data also indicate that the second dose increases antibody levels considerably. Indeed, a 56-109-fold increase of geometric mean titers (GMTs) was observed one month post-second dose when compared to pre-second dose GMTs. Such an increase indicates on an anamnestic response. The data also indicate that GMTs are slightly higher one month post-third dose than one month post second dose (from 1.1 to 1.8 fold).

HPV vaccines administered to girls aged 9-11 are well tolerated. However, a two-dose schedule would likely generate fewer adverse events following immunization (AEFI)than a three-dose schedule.

At the current cost of vaccines obtained for the public program, it would cost approximately three million dollars more each year to administer a booster dose to Québec grade 9 girls.

An analysis of the effectiveness and cost-effectiveness of different two- and three-dose immunization strategies, including the immunization of boys, was performed.

According to mathematical modeling predictions produced by the HPV-ADVISE Québec model, immunizing girls with a two-dose schedule is a highly cost-effective strategy and of all the strategies examined in this analysis, it is the one that produces the best cost-effectiveness ratio. The model also predictis that the addition of a third dose of vaccine could be a cost-effective strategy if one of the following conditions is met: (1) the period of protection conferred by two doses of vaccine is less than 30 years, or (2) the third dose extends the period of protection when the period of protection conferred by two doses is 30 years or more. According to the model predictions, immunizing both girls and boys using two or three doses is unlikely to be a cost-effective alternative (at the threshold of $40,000 per Quality-Adjusted Life-Year(QALY)) to vaccinating girls only, if the cost of the vaccine is greater than $40 per dose (including administration costs) for boys.

Given that close to 80% of girls are immunized against HPV and that this has an indirect impact on protection for boys, the current immunization program for girls appears to be very efficient (< $15,000 per QALY). At the current cost of the vaccine, extending immunization to all pre-adolescent boys would produce health benefits but, according to economic analyses conducted in Québec and elsewhere, these benefits would not be commensurate with the additional costs incurred at the population level, even with a two-dose schedule. At the vaccine’s current cost, introducing a publicly-funded program to immunize all boys could be justified on the basis of political considerations or the principle of ensuring equity, particularly for men who have sex with men (MSM). The feasibility, effectiveness and efficiency of a “targeted” approach that would allow to immunize young men who have or will have sex with men at a point in time when the vaccine is most effective (before they become sexually active) remain to be demonstrated. In terms of protecting men who have sex with men (MSM), the most feasible approach would be to extend vaccination to all pre-adolescent boys.

Schedules comprising fewer doses appear to be generally well accepted by the public and health professionals. However, no Québec study has assessed the acceptability of the two HPV immunization schedules analysed in this advisory report.

In the present immunization context (administration of a Tdap booster and introduction in 2013-2014 of a booster dose of a conjugate meningococcal vaccine in grade 9), negative impacts on acceptability and immunization coverage rates would likely occur if a third injection (HPV) were to be administered in one vaccination session to 14-year-old girls (Tdap + meningococcus + HPV).

Three-dose HPV vaccine schedules have been introduced in most countries and in other Canadian provinces. Switzerland has retained a two-dose schedule; Québec, if it were to arrive at a similar decision, would not be the first jurisdiction to adopt this scientifically defensible strategy.

Moreover, Australian studies have shown that only a few years after the introduction of the HPV immunization program for girls and women (vaccine provided for free until age 26 during the first two years of the program and to age 18 thereafter), herd immunity had developed, gradually conferring protection to the vast majority of vaccinated and unvaccinated boys and girls. The high vaccination coverage achieved in Québec in routine and catch up programs where the vaccine is offered free of charge to girls up to the age of 18 since 2008 is also contributing to create a herd immunity. If a minority of vaccinated individuals were to lose their immunity over time, they would remain protected indirectly, owing to the lower probability of exposure to the virus. Cervical cancer screening activities also provide an additional safety net, at least in terms of preventing this health problem.

Recommendations

After evaluating the available scientific data and consulting with experts, the members of the Comité sur l’immunisation du Québec have recommended by consensus not to provide a booster dose to grade 9 girls who received two doses of vaccine in the grade 4.

This recommendation is conditional upon the implementation of effective mechanisms to monitor the epidemiology of HPV and to timely detect any sign that might make questionable the reasons for this decision. The key measures that will need to be put in place are as follows:

1. Maintain scientific vigilance with respect to the results of alternative HPV immunization schedules, particularly those that comprise two doses. At present, we cannot rule out the possibility that a later booster dose may be required in the future with either two-dose or three-dose initial schedules.
2. Monitor antibody levels among the first cohorts of girls who received two doses at age 9 and compare the antibody levels in girls who received a booster dose with those who did not.
3. Measure the comparative efficacy of the two schedules (0, 6 months and 0, 6, 60 months) by implementing and carrying out the ICI-VPH study, which will measure persistent HPV infections in women immunized according to one or the other of these schedules.
4. It will also be important to monitor the prevalence of HPV infection (through cross-sectional studies) in successive cohorts of young women (those not vaccinated; those who received three doses on a catch-up basis; those who received three doses in grade 9; and those who received two doses in grade 4). Initial measures could be made in the context of a start-up study and then repeated over time.
5. Monitoring the types of HPV detected in precursors and cervical cancers constitutes another important aspect to be evaluated. This could be achieved using the demonstration zones put in place in 2008 in the Estrie and Capitale-Nationale regions. The types of HPV identified in cancers that occurred in these regions in 2006-2009 constitute a pre-immunization baseline. Repeating these measures over time would make it possible to monitor the evolution of the different types of HPV detected in cancers as the cohorts of vaccinated girls advance in age.
6. The future inclusion of cervical cancer precursors in the cancer registry will also make it possible to monitor the frequency of these lesions over time.
7. Measuring and monitoring the trends in incidence of lesions detected in the context of screening tests, diagnostic and follow-up examinations is another important component. However, the implementation of the Québec demonstration zones revealed how complex and difficult (manual collection, imprecise denominators, impossibility of knowing how many women in demonstration zones venture outside their region to access services, problems following the care trajectory when different facilities use different identifiers) it can be, in the absence of a provincial registry, to gather reliable information on screening, diagnosis and follow up activities and to measure the incidence of cancer precursors.

Immunization data gathered in schools are entered into the local systems (I-CLSC) of health and social service centres (CSSS) or in regional databases (VAXIN and LOGIVAC) that identify vaccinated individuals and the number of doses they received. The legislation governing the implementation of the provincial immunization registry provides the opportunity for the recovery of all historical immunization data housed in the various local and regional systems. For example, the data pertaining to girls vaccinated since the program was implemented in 2008 will be entered into the registry, which will facilitate monitoring.

It will also be important to pursue efforts to achieve and maintain levels of vaccine coverage that meet provincial objectives (90% in grade 4). Particular attention should be paid to verifying immunization status in grade 9 and offering the HPV vaccine (ideally in a school setting) to all girls who have no proof of immunization.

In the short term, a communication plan will be needed so that the various stakeholder groups for the Québec HPV immunization program can be informed about the reasons behind the recommendation not to administer the third dose of the extended schedule, as initially planned. It will also be important to emphasize that this recommendation applies only to the immunization of pre-adolescents and that the three-dose schedule (0, 2, 6 months) should be offered to all other age groups.

The CIQ also wishes to reiterate that HPV vaccines do not confer protection against all types of HPV and recommends that cervical cancer screening continue for all women, whether vaccinated or not. Furthermore, since HPV vaccines do not confer protection against all sexually transmitted infections, safe sex practices are recommended for everyone, regardless of their HPV immunization status.