HPV vaccination trials have hithereto used clinical endpoints, such as condyloma, CIN, VIN or AIN, with transient or persistent detectability of HPV DNA being used for exploratory analyses. HPV serology has been used to determine eligibility for per-protocol analyses (which have typically been restricted to subjects who are both HPV DNA-negative and HPV seronegative at baseline).
However, with the large-scale and solid evidence on the efficacy of HPV vaccines for preventing clinical disease, it is debatable if it is ethical to use clinical endpoints for vaccination trials (1). Actually, also using infection (HPV DNA persistence) as endpoint is also debatable. It is clearly demonstrated that the infection causes cancer at multiple sites and that the infection can be prevented by vaccination.
The endpoint that still would be possible to use is immunogenicity (HPV Serology). Serology has already been used to establish immunogenicity also in age groups that have not been targeted by efficacy trials (so-called immunobridging studies) and in trials comparing different doses, target groups and vaccine batches (1). A wider use of the HPV serology endpoint for the future is anticipated, for example in trials of second generation vaccines or in basic research evaluating new vaccines or new administration strategies.
The major caveat is that there is only limited international standardization of HPV serology. International Standards (IS) that define an international unit (IU) of HPV antibodies have, for HPV16 and 18, been established by the WHO and can be ordered from the National Institute for Biological Standards and Controls (NIBSC)(2). Their use is described in the WHO HPV Laboratory Manual, resulting in that all laboratories doing HPV16 or 18 serology are able to report the results in IU.
Sourcing and establishment of IS also for antibodies to other HPV vaccine types would be important and will be pursued.
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References:
1. Primary endpoints for future prophylactic human papillomavirus vaccine trials: towards infection and immunobridging.
Lowy DR, Herrero R, Hildesheim A; Participants in the IARC/NCI workshop on Primary Endpoints for Prophylactic HPV Vaccine Trials.
Lancet Oncol. 2015 May;16(5):e226-33. doi: 10.1016/S1470-2045(15)70075-6.
2. The first international standard for antibodies to HPV16 .
Ferguson M, Wilkinson DE, Heath A, Matejtschuk P.
Vaccine. 2011 Sep 2;29(38):6520-6. doi: 10.1016/j.vaccine.2011.07.007.