HPV vaccines: alternative dosage schedules

ABSTRACT

Introduction: The randomized control trials (RCTs) that resulted in licensure of HPV VLP vaccines used a traditional prime, prime-boost schedule for a subunit protein vaccine. These vaccines delivered predominantly to 9–14-year-old females with this schedule have been shown to be highly effective against vaccine HPV-type disease (CIN and genital warts) and infection. A two-dose prime-boost schedule is immunologically non-inferior to 3 doses in 9–14-year-olds and is currently widely adopted. However, even with a reduced dosage schedule, these vaccines are expensive to buy and expensive and logistically complex to deliver especially in low resource countries that bear the major burden of cervical cancer the most prevalent of HPV caused cancers.

Areas covered: Observational studies and post hoc analysis of RCTs show that 1 dose, although immunologically inferior to 2 and 3 doses, is as effective at preventing persistent infection with vaccine HPV types at least for 7–10 years. To address the issue of alternative dosage schedules that include 1 dose either as a single dose or extended 1 + 1 with the second dose 3–5 years post-first dose are under investigation in RCTs.

Expert opinion: Since, in the short term, vaccine supplies are constrained and will impact on the ability of countries to implement HPV vaccine programs: the challenges and opportunities of the alternative approaches in this scenario are discussed.

KEYWORDS:

• HPV vaccine
• antibody
• virus-like particle
• geometric mean titer
• avidity
• dosage schedule

Article Highlights

• HPV associated benign and malignant disease is a major global public health problem. HPV caused cancers (mainly cervical cancer) represent 5.2% of all cancers.

• There are three commercially available prophylactic vaccines:Cervarix® a bivalent HPV16/18 product (2vHPV) licensed 2007,Gardasil® a quadrivalent HPV6/11/16/18 product (4vHPV) licensed 2006,Gardasil9® HPV 6,11,16,18,31,33,45,52,58 a ninevalent product (9vHPV)licensed 2014.

• Real-world experience over 10 years shows high impact and effectiveness on vaccine HPV-type CIN of all grades and genital warts when these vaccines are delivered at high coverage to female adolescents.

• However, the major burden (86%) of cervical cancer is in low- and middle-income countries but <30% of these countries have introduced the vaccine. Major impediments are cost, both costs of the vaccine and also costs of delivery to adolescents in countries that have no infrastructure for adolescent immunization. The situation is exacerbated by constraints in vaccine supply likely to persist until 2022/25

• Alternative scheduling and/or reduction of doses are under discussion. The initial recommended 3-dose schedule of priming doses at 0 and 1/2 months followed by a boost at 6 months was changed in 2014 by WHO SAGE for adolescents at <15 years of age to 2 doses at 0 and 6 or 12 months.

• This change was based on immunobridging studies showing that GMTs in adolescents after 2 doses were non-inferior to those after 3 doses in 16–23-year-old women in whom efficacy had been demonstrated in the RCTs.

• Prior to this, extended interval schedules of 0–6 and 60 months had been introduced as off label programs in Mexico and Quebec province as a stepwise approach. This strategy in Mexico was a policy aimed at increasing coverage in a time of financial constraint.

• Evidence is accumulating from National immunization programs, posthoc analyses of the RCTs and a large observational cohort study that 1 dose may be enough to provide protection for at least 7-10 years against persistent HPV infection and high-grade cervical disease.

• However, there are no data from RCTs for immunogenicity and efficacy of 1 dose versus 2 or 3 doses.

• GMTs after 1 dose are inferior to 2 or 3 doses but seroconversion rates, antibody kinetics, and avidity indices are comparable and antibody after 1 dose persists for at least 7–10 years.

• In the absence of data from RCTs 1 dose schedules represent a risk for policymakers. One possible scenario is a 1+1 extended schedule for 9–14-year-old adolescents with an interval of 3–5 years between doses. Limited evidence suggests that a strong memory pool is established after the priming dose and a strong anamnestic response elicited with a boost after 3-, 6- and 8-year intervals.

• Irrespective of the arguments around alternative dosages, high vaccine coverage in the HPV naïve cohort and the ensuing herd protection remains the most important objective of any NIP.

Declaration of interest

M Stanley is a member of the Global Advisory Board HPV Vaccines MSD Merck. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.