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Summary of the National Advisory Committee on Immunization's updated recommendations on human papillomavirus (HPV) vaccines: Nine-valent human papillomavirus (HPV) of minimum intervals between doses in the HPV immunization schedule.

Background
Human papillomavirus (HPV) infections are the most common sexually transmitted infections, and in the absence of vaccination it is estimated that 75 percent of sexually active Canadians will have an HPV infection at some point in their lives. Quadrivalent (HPV4) and bivalent (HPV2) vaccines have been authorized for use in Canada since 2007 and 2010, respectively. Canada's National Advisory Committee on Immunization (NACI) has previously recommended HPV4 vaccination in males and females according to a three-dose (0, 2, 6 months) or a two-dose (0, 6 months) immunization schedule, or HPV2 vaccination for females according to a three-dose (0, 1, 6 months) or a two-dose (0, 6 months) immunization schedule, depending on the age and health status of the recipient. In February 2015, a nine-valent (HPV9) vaccine (Gardasil®9, Merck Canada Inc.) was authorized for use in Canada for the prevention of HPV types 6-, 11-, 16-, 18-, 31-, 33-, 45-, 52- and 58-related cancers and anogenital warts (AGW) in females aged 9 to 45 years and males aged 9 to 26 years.


Objectives
To summarize evidence on the new HPV9 vaccine and make recommendations for its use in Canada, to review epidemiological data on the relative contribution to disease outcomes of the 5 additional genotypes covered in the HPV9 vaccine, and to clarify acceptable minimum intervals between vaccine doses in either a 2-dose or 3-dose HPV immunization schedule.


Methods
The NACI HPV working group performed literature reviews on the topics of HPV vaccine minimum dose intervals, and the HPV9 vaccine. Vaccine manufacturers provided additional data for review. All evidence was reviewed, rated, and a representative dataset for each trial was reported in evidence tables. A knowledge synthesis was performed, and NACI approved specific evidence-based recommendations, elucidating the rationale and relevant considerations.


Results
At the time of the review, only one published peer-reviewed study of HPV9 vaccine was available for inclusion, but information from additional unpublished studies in the form of presentations, posters, and abstracts were shared by the vaccine manufacturer to be appraised.​: Based on the evidence available to date, the HPV9 vaccine is recommended on a three-dose schedule for females aged 9 to 26 years; females aged over 26 years who have not been vaccinated previously or who have not completed the vaccination series; and males aged 9 to 26 years. There is insufficient evidence at this time to recommend a two-dose immunization schedule with HPV9 vaccine, but a clinical trial to assess alternate dosing schedules for HPV9 vaccine is currently underway. The efficacy of HPV9 vaccine in preventing infection and disease related to HPV types 31, 33, 45, 52 and 58 in individuals previously immunized with HPV4 vaccine has not been assessed. In Canada, immunization against HPV types 16 and 18 with HPV2, HPV4 or HPV9 vaccine can prevent approximately 70% of anogenital cancers and 60% of high-risk precancerous cervical lesions. Immunization with either HPV4 or HPV9 vaccine can prevent approximately 90% of AGWs (HPV types 6 and 11). Immunization with HPV9 vaccine can prevent up to an additional 14% of anogenital cancers and up to 30% of high-risk precancerous cervical lesions caused by the additional five HPV types (31, 33, 45, 52 and 58) against which the vaccine protects. The disease burden associated with the five additional genotypes contained in HPV9 vaccine is not equally shared between the sexes, with the additional benefit primarily observed among females.​: In terms of the HPV immunization schedule, there is a paucity of published evidence supporting shortened or flexible minimum intervals for HPV vaccines, compared to ample evidence endorsing the recommended schedules as well as evidence supporting delays in the receipt of booster doses. Assumptions about the immunogenicity and efficacy of shortened 'flexibility range' minimum dose intervals rely heavily on the manufacturer's unpublished data on file and their Health Canada-approved recommendations included in the product monographs. The NACI recommendations and evidence grades based on these results are included below.


Conclusions
In addition to the HPV 6, 11, 16, and 18 strains that can be covered by other HPV vaccines, the HPV9 vaccine is expected to provide further protection by preventing infection and disease related to HPV types 31, 33, 45, 52 and 58. Protecting against these additional strains may prevent up to an additional 14% of anogenital cancers and up to 30% of high-risk precancerous cervical lesions in Canada. Efforts should be made to administer HPV vaccines at the recommended intervals. When an abbreviated schedule is required, minimum intervals between HPV vaccine doses should be met including a minimum interval of 24 weeks between the first and last dose in either a 2-dose or 3-dose schedule.