**9. Second generation vaccines targeting L1**

Both current commercial vaccines show excellent safety and efficacy profiles and there seems to be little room for improvement in either aspect when addressing the HPV type-specific protection. Some countries are considering or are in the process of implementing a two dose regiment, driven by the intention to minimize costs [74, 75]. Such deliberations would benefit from higher immunogenicity of the VLP vaccine, which could possibly be achieved by using stronger adjuvant systems. But naturally, it seems unlikely that Merck or GSK would find a sufficient economical motivation to move along this road. What's more, there is only a limited repertoire of adjuvants that can be used in prophylaxis for a young target population.

Both Merck and GSK are probably not highly motivated in developing second generation HPV vaccines that would compete with their blockbusters. An exception is the nonavalent HPV VLP vaccine that is currently evaluated by Merck in clinical trials. A number of pre-clinical studies focused on the development of L1-based vaccines that overcome one or more of the limitations discussed above. These second generation approaches addressed delivery (e.g. oral), production systems (plant, E. coli), stability (e.g. capsomeres) and extension to thera‐ peutic applications (chimeric L1 proteins) [76-78]. In light of the fact that the current VLP vaccines are inducing a limited degree of cross-protection, for which the nature is not yet known, one could envision modifying the L1 protein so as to extend the breadth of protection, but to our knowledge, this strategy is currently not pursued.

As indicated above, the protective range of Cervarix® and Gardasil® is mainly limited to the vaccine type papillomaviruses. In their clinical trial GSK could show that immunization with Cervarix® induces cross-protection against additional types such as HPV 31, 33 and 45 and Gardasil® induces protection against HPV 31, albeit at lower efficacy. As a consequence, in 2010 the European Medicines Agency has approved the amendment of the license of Cervarix® in prevention of HPV 31, 33 and 45 induced lesions. The molecular mechanisms for the enhanced cross-protection of Cervarix® in comparison to Gardasil® is not fully understood. One explanation could be the fact that Cervarix® is inducing higher titers against HPV 16 and HPV 18, possibly due to the stronger adjuvants used in the formulation of Cervarix®. Another explanation could be structural differences of the VLPs contained in the two vaccines.

However, despite this extended cross-protection observed for Cervarix® about 20% of cervical cancer cases remain uncovered by the vaccine. To breach this gap, Merck MSD is currently evaluating a nonavalent HPV VLP vaccine in phase III clinical trials. In addition to the nononcogenic HPVs 6 and 11, this vaccine includes VLPs of HPV types 16, 18, 31, 33, 45, 52 and 58 and theoretically would reach close to 88% efficacy. It remains to be determined whether this cocktail of nine different VLPs is able to induce prolonged protective responses against the corresponding HPV types or if due to interference this may not be possible. Further, because of increasing vaccine complexity this strategy will be limited due to rising costs in production. Also, it will be difficult to prove vaccine efficacy in preventing cervical dysplasia induced by rather rare HPV types, such as HPV 52 and HPV 58, if neutralizing antibodies or at least prevention of infection by these types are not accepted as surrogate markers by the licensing agencies.
