Stagnation or safety? Reassessment of the human papillomavirus vaccination dosing regimen in Japan

In Japan, the review of the Human Papillomavirus (HPV) vaccination system is recently progressing, and the vaccination rate of girls, which had once dropped to <1%, has now exceeded 30%, according to the latest statistics. ¹ The 9-valent HPV vaccine, recently authorized by the Japanese Ministry of Health, Labor and Welfare (MHLW), has shifted its dosing recommendations based on the recipient’s age in February 2023. In this protocol, for children first vaccinated under the age of 15, two doses are deemed adequate; whereas the conventional three-dose regimen continues to be recommended for individuals aged 15 and above when first vaccinated. This decision can be attributed not only to the lack of sufficient international evidence regarding the efficacy of the two-dose regimen in individuals aged 15 and above, but also to the pervasive traditionalist principles within Japanese organizations that inherently resist change, grounded in a commitment to infallibility. ² In fact, even for the previously disseminated bivalent Cervarix and quadrivalent Gardasil vaccine, approved in 2007 and 2010 in Japan respectively, three doses continue to be recommended for all ages. However, it is debatable as to the appropriateness of the continuation of the three-dose recommendation.

Indeed, it was previously reported that even with a regimen of two doses, seroconversion observed 4 weeks post-final vaccination approximated or exceeded 99%. ³ Moreover, a single dose regimen demonstrated the effectiveness of 97.5% against high-risk HPV types (types 16 and 18) 18 months post-vaccination, a statistic consistent across both bivalent and 9-valent vaccines. ⁴ In this context, the World Health Organization (WHO) has revised their recommendation from ‘two doses for individuals first vaccinated under the age of 15, and three doses for individuals aged 15 and above when first vaccinated’, announced in May 2017, to ‘one or two doses for 9–20-year-olds, and two doses for ages 21 and above’ in December 2022. ⁵ Within 3 months of this revision, Cambodia, for instance, decided to start mass vaccination for mainly 9-year-old girls from mid-2023 with a protocol of a single dose. In other countries around the world, as seen by the fact that Australia, the United Kingdom, and Mexico, have also indicated their intention to switch their protocol to a single vaccination, more discussion is in progress worldwide. Contrarily, in the case of Japan, the MHLW’s expert panel conference, held in February 2023, after the revision of the WHO’s recommendations, did not incorporate these changes, which raises legitimate concerns.

Revising the number of vaccine doses will be beneficial in multiple ways. Currently, Japan provides publicly funded routine HPV vaccination for girls aged 12–16, and offers a limited-time catch-up program for those born between fiscal years 1997 and 2006 until March 2025. While this protocol typically involves three doses of HPV vaccination, with a revision of the necessary number of vaccine doses, it is possible to cover multiple age cohorts within the same budget. ⁶ Moreover, while vaccination for males is currently excluded from Japan’s routine program, with high costs borne by the individual, approximately 24% of the global population across 47 countries includes male vaccination within their routine immunization programs. ⁵ The HPV vaccine has been proven effective in preventing male-associated cancers, including those of the oropharynx, penis, and anus. ⁷ Consequently, reassessing the dosing regimen of the HPV vaccination may promote the optimal allocation of medical resources by facilitating vaccination expansion to other age groups and males. Furthermore, this could contribute to reducing vaccination disparities, a topic highlighted during the Hiroshima G7 summit in May 2023. ⁸

In conclusion, as public awareness of and confidence in the vaccine are slowly regaining in Japan, ¹ policy-decision making based on updated evidence is essential to eliminate cervical cancer. Since global vaccine shortages are hindering the introduction of HPV vaccines, especially in low- and middle-income countries, ⁹ failure to reassess the current HPV vaccination regimen may also impede international cooperation and expose a potentially protectable population to risk. A study also indicates that higher vaccine doses can lead to fatigue for vaccination and a subsequent decrease in the population’s willingness to get vaccinated. ¹⁰ Thus, maintaining the three-dose HPV vaccination protocol is questionable, particularly when considering strategies to expand coverage among the target age group. A protocol revision could facilitate the extension of vaccination to additional age groups and males by achieving cost-effective vaccination strategies. Therefore, in the context of Japan and international cooperation, the future challenge is to promote discussion on achieving optimal distribution of HPV vaccine while accumulating evidence jointly through tie-ups between experts and the government.