Intervals of 12 Months and 36-96 Months Are Non-Inferior to 6 Months in hpv16/18 Antibody Response: Findings of a Systematic Review and Meta-Analysis of Two-Dose HPV Vaccine Schedules With Intervals of Six Months or Longer

Human Papillomaviruses can cause cancer of multiple human anatomical sites, with essentially all cervical cancer cases worldwide being attributable to persistent HPV infections. HPV vaccination provides effective protection against HPV infections. An estimated 90% of cervical cancer cases occur in low and middle incomes, but only 20% of these countries have implemented HPV vaccination. In contrast, 82% of high income countries have included HPVV in their national vaccination programs. Current HPV vaccination schedules which recommend administering multiple doses within six months can be logistically challenging for both low- and middle-income as well as high-income countries. The ongoing global shortage of HPV vaccines that is expected to last until 2024 is an additional challenge. There are suggestions to extend the two dose 0,6 months schedule for the primary target population (females 9-14 years) to longer intervals, even up to 3-5 years, to ease logistics and relieve demand in the short-term. Interval extension however, requires evidence to support whether it will be beneficial. This paper reports findings of a systematic review of available studies, that compares the immunogenicity, efficacy and effectiveness of two-dose schedules of 7 or more months between doses with schedules of 6 months between doses. We found, similar to a previous systematic review, that increasing the two-dose interval from 6 months to 12 months resulted in non-inferior immunogenicity. Also an increase of the dose-interval from 6 months to 36-96 months, results in non-inferior antibody response to HPV6 and high risk HPV types 16 and 18, but not HPV11, based on data from an observational study. The effect of an interval of 8 or more months compared to an interval of 4-7 months on AGW incidence was inconclusive and no studies were available to assess efficacy or effectiveness against HPV infections or cancers. This highlights the acute scarcity of evidence necessary to evaluate two-dose schedules with intervals longer than 6 months. Nevertheless, our Page 4 of 64 non-inferiority findings indicate that a schedule with a 12 month interval can be adopted in lieu of one with a 6 month interval. However, even though the 36-96 month interval is indicated to be no worse than a 6 month interval in antibody response to HPV 16 and 18, the low certainty of the estimates derived from it, requires that it be studied further to confirm its effect on immunogenicity.