ReviewReduced dose human papillomavirus vaccination: An update of the current state-of-the-art
Introduction
Human papillomavirus (HPV) is the main causal agent of cervical cancers. This association was first reported by Harald zur Hausen and his team in the early 1980s [1]. HPV was then verified as the cause of cervical cancer, following a number of molecular epidemiological studies [2], [3]. Since then, research has focused on the prevention of cervical cancer, including the prevention of HPV infection through vaccination. The major breakthrough in vaccine development was the discovery of the self-assembly L1 capsid viral proteins into virus-like particles (VLPs), which induced the production of high-level neutralizing antibodies, forming the basis for the current HPV vaccines [4].
There are currently more than 170 HPV types identified, with at least 13 types classified as carcinogenic. With the exception of the newly licensed nonavalent HPV vaccine (Gardasil® 9), which requires more long term studies to evaluate its efficacy and impact on cervical cancers globally (particularly to the 5 new cancer causing types included in the vaccine), the two HPV vaccines (Cervarix® and Gardasil®) currently used in most developed countries only protects against two oncogenic HPV types (HPV 16 and 18; accounting for 70% of cervical cancers) [5]. Also, as HPV vaccines are only available to a minority of the world's women, and many of these countries do not have a comprehensive effective cervical screening program with treatment of precursor lesions, cervical cancer is the fourth most common cancer in women worldwide, according to recent data from the World Health Organization (WHO) [6]. Approximately 530,000 new cases of cervical cancer occur every year, with 85% of these cases occurring in developing countries [6]. Highly successful cervical cancer secondary prevention activities are often not available or accessible to the world's poorest women. Furthermore, the high cost of HPV vaccines is a major obstacle in low- and middle-income countries. The GAVI Alliance (formerly known as Global Alliance of Vaccines and Immunization) has subsidized and supported the introduction of HPV vaccine in low-income countries, but to date, Bhutan and Lao PDR are the only GAVI-eligible Asian countries to take up this offer. Although low-income countries are eligible for GAVI support, middle-income countries are ineligible and struggle to afford the vaccines. There are also logistical issues in administering the vaccine in a three-dose schedule over 6 months. These issues have led to the exploration of alternative schedules, which could potentially alleviate the issues of vaccine cost and delivery. Based on the increasing evidence of non-inferior antibody responses between girls receiving two doses of HPV vaccine and women receiving three doses, the WHO and European Medical Association (EMA) have revised their recommendation from giving three doses to two doses to girls below the age of 15, provided the second dose is administered 6 months apart. Several countries (i.e. Canada and United Kingdom) have already implemented a two-dose HPV schedule. However, long-term protection is yet to be determined and the immunology of reduced dose HPV schedules is still unclear. This review will focus on the immunology of evaluating reduced dose HPV vaccine schedules as compared with the standard three-dose schedule.
Section snippets
Immune response to HPV during natural infection
The immune response to natural infection with HPV is weak and very slow (up to 18 months), as important signals for the induction of immune responses are absent, due to the ability of the virus to evade the immune response. HPV's replication is exclusively intra-epithelial, and there is minimal or no exposure of viral proteins in infected cells, preventing the activation of the immune system [7]. Furthermore, HPV infection is not blood-borne, and does not induce cell death, resulting in very
Immune responses induced by HPV vaccination
There are currently three licensed HPV vaccines (Table 1); Gardasil® (Merck & Co., Inc.; 4vHPV) a quadrivalent vaccine with Alum adjuvant that protects against four genotypes (HPV 6, 11, 16 and 18) and Cervarix® (GlaxoSmithKline; 2vHPV), a bivalent vaccine with the novel adjuvant AS04 (made up of an aluminum salt and monophosphoryl lipid A) that activates innate immunity [16], and protects against infection with HPV 16 and 18. A new next-generation nonavalent HPV vaccine, Gardasil® 9 (Merck &
HPV vaccination immunobridging studies
Due to ethical issues of evaluating clinical outcomes in adolescents below the age of 15 years, safety and immunogenicity bridging studies of HPV vaccination are conducted instead, so that the licensing of the vaccines can be extended for use in early adolescent girls or boys before the onset of sexual activity.
In immunobridging studies for HPV vaccines, both 4vHPV and 2vHPV have demonstrated at least 1–2 fold higher levels of HPV vaccine genotype-specific antibodies in adolescent girls and
Evidence of non-inferior antibody responses in reduced dose HPV schedules
The use of reduced dose schedules in vaccinology is not unusual as other vaccines such as Pneumococcal, Hepatitis A and Meningococcal C dosing schedules have been revised from three to two doses, following clinical studies that have demonstrated non-inferiority in immunogenicity and safety [36], [37], [38]. High costs of HPV vaccines and logistical issues with delivery, together with higher antibody responses observed in young adolescents, has prompted the exploration of reduced dose HPV
Clinical outcomes following reduced dose HPV schedules
A number of studies have investigated the impact of reduced dose HPV schedules on clinical outcomes (Table 3). The study in Costa Rica reported no significant difference against newly acquired HPV 16/18 infection in women aged 18–25 years old, who received either one, two or three doses of 2vHPV when compared with the control group (received modified Hepatitis A vaccine) post-vaccination. However, the analysis for the group who received one dose should be interpreted with caution due to the
Gaps in the knowledge of reduced dose HPV schedules
Despite the recommendation of two-dose HPV schedules, further research is required to assess the clinical effectiveness of this schedule, particularly in low- and middle-income countries, where disease burden is greatest [52]. The evidence for non-inferior immunogenicity of two- vs three-dose HPV schedules in adolescents was inconclusive according to a recent systematic review and meta-analysis of the current literature [53]. It is also important to note that the vaccines are not licensed as a
Novel immunological markers of vaccine-induced protection
The major cell subsets involved in the immune response generated by HPV vaccination are depicted in Fig. 1. While antibody is the primary mechanism of protection against HPV infection, the role of T and B cell populations are also important, particularly for long-term protection. Identification of these markers of protection induced by HPV vaccines will be important in monitoring vaccine effectiveness. The current understanding for generation of robust antibodies from B cells requires ‘help’
Conclusion
Preliminary data from reduced dose HPV schedules are encouraging, and would be most beneficial to developing countries where logistics and cost of the vaccine are major issues. Despite the potential benefits of reduced dose HPV schedules, there are still important research questions to evaluate long-term protection, and the immunological correlates associated with clinical effectiveness. Future studies aimed at addressing these important concepts will be of greatest benefit.
Acknowledgements
The work was part of the New Vaccine Evaluation Project (NVEP), funded by the Fiji Health Sector Support Project and Australian Aid-JTA, the Department of Foreign Affairs and Trade, Australia. ZQT is supported by a Melbourne Research Scholarship from The University of Melbourne and a Murdoch Childrens Research Institute top-up scholarship. FMR is a recipient of an NHMRC Early Career Fellowship. This work was also supported in part by the Victorian Government's Operational Infrastructure Support
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These authors contributed equally to this work.