ARCHIVED - Recommendations on a Human Papillomavirus Immunization Program

9. Research questions

Many questions raised at the National HPV Research Priorities Workshop in Quebec City in November 2005 remain pertinent and unanswered⁽⁷⁵⁾. While it is important to avoid delays in offering HPV vaccine on a routine basis, it is also important that research gaps are answered. Similar research priorities were identified by NACI in its HPV statement of February 2007⁽²⁾.

9.1 Fundamental research

Baseline data are needed on the transmission of HPV in subpopulations (e.g. Aboriginal, immunocompromised), the distribution of HPV types and the prevalence, duration, natural history and costs (in terms of screening, diagnosis and treatment) of HPV-associated diseases. It would be useful to know the impact of migration, ethnicity, underlying health status and geographic isolation on the effectiveness of primary and secondary prevention programs, and the psychosocial burden of identified precursors of disease on particular groups.

9.2 Intervention research

Alternative HPV immunization schedules need to be examined. Given the observation during clinical trials that younger girls produced a high antibody response to HPV vaccine after two doses, there are research studies under way to examine a two-dose immunization schedule. A clinical trial in which two doses of vaccine are being administered to girls aged 9-14 began in 2007 in four Canadian provinces. Data on the short- and long-term immunogenicity, efficacy and effectiveness associated with a two-dose as compared with a three-dose schedule will be available within the next few years.

The possibility of administering HPV vaccine through an extended schedule could also be examined. One option is as follows: first two doses administered 6 months apart in primary school and the third dose in high school, if needed. The arguments underlying this proposal may be grouped into two categories, immunologic and operational.

1. Immunologic arguments
   • It is well known that spacing out doses generally produces higher antibody levels. This has been well demonstrated by the recombinant hepatitis B vaccine⁽⁷⁷⁾. Further, there is no well-articulated justification for the schedules of 0, 1 and 6 or 0, 2 and 6 months proposed by the manufacturers.
   • The administration of a catch-up dose after 5 years produces very high GMTs, much higher than those produced after primary vaccination. This has been observed for hepatitis B vaccines (Quebec cohorts)^(78,79) and HPV vaccines⁽¹⁹⁾. In the context of HPV, with the goal of maximum protection before the onset of sexual activity, the administration of this dose in high school appears well justified on the basis of current knowledge. The lack of data on the duration of protection conferred by HPV vaccines adds further justification, as this schedule will produce the highest possible levels during the last in-school vaccination.
2. Operational arguments
   • Vaccination in primary school produces very high vaccination coverage at a relatively low administration cost. This is the best time to administer the vaccine, because of the quality of the immune response and the efficiency of administering the vaccine with other school-based programs. Some provinces already have a two-dose program for hepatitis B vaccination. The introduction in the near future of a two-dose schedule for hepatitis A and B using a combined vaccine is being considered by some jurisdictions. The combined hepatitis A and B vaccine and the HPV vaccine could be administered simultaneously, with no need to add a third vaccination session.
   • If a third dose is needed in high school, it could be co-administered with Tdap (tetanus, diphtheria and pertussis), which would decrease related costs and increase vaccination coverage.
   • The administration of two doses in primary school instead of three will probably increase acceptance by students, parents and health personnel while reducing costs and allowing for the vaccination of more young girls with the same resources.
   • This schedule follows the approved schedule and does not constitute a contravention of existing norms regarding vaccination schedules. The principle of not repeating a vaccination course or doses when there have been extended intervals between doses is accepted in vaccinology.

Additional research is required on the consequences for safety and immunogenicity of co-administration with other vaccines and on the safety and immunogenicity of the vaccine during pregnancy, among immunocompromised individuals and in Aboriginal populations. The herd immunity according to level of coverage and the effect of natural infection on the antibody level in vaccinated individuals should be documented. Comparison of the use and effectiveness of bivalent versus quadrivalent vaccines should be undertaken. Other areas of priority are the impact of HPV immunization programs on cervical screening, in terms not only of compliance and screening intervals but also the sensitivity, specificity and predictive value of different tests.

9.3 Program delivery research

The potential effect of an immunization program on sexual behaviour, cervical screening programs and health care services needs to be investigated. Periodic measurement of knowledge, attitudes and beliefs of health professionals and the public regarding HPV immunization is a research priority. Creative means for increasing the accessibility of HPV vaccine for women should be developed. Finally, because of the risks, the burden of disease and the impacts of HPV infection may be different in subpopulations, such as immigrant and Aboriginal population, research is required to ensure that routine HPV immunization programs adequately meet the needs of those subpopulations.