*3.4. The Need for Thorough Comparative Studies*

As described above, the immune response elicited by CLP-based vaccines is likely influenced by multiple factors. However, direct comparisons of many of these variables have so far been lacking in the field. Firstly, there are no conclusive comparisons between the different conjugation systems. A study by Leneghan et al. indicates that unidirectional antigen display obtained by split-protein conjugation is more favorable than the disordered display elicited by chemical conjugation [55]. However, these results may in part be due to a combination of additional confounding factors such as the particle size, epitope density and chemical modifications of the antigen, all of which varied between the tested vaccines. This study highlights the difficulty with conducting such comparative studies, as it is challenging to separate the many variables intrinsically associated with different CLP platforms. Likewise, the full immunological effect of capsid backbones from divergent origins, containing different intrinsic properties, remains to be defined. When considering the final vaccine formulation, it would moreover be important to compare the effect of extrinsic adjuvants, to ascertain which work best in synergy with the immune-activation obtained by the CLP platform. Improved consensus in these areas would greatly aid in refining and directing the rational design of CLP-based vaccines. This could provide a toolbox of components that can intentionally be combined to modulate or skew the response, to induce the most suitable immune activation against a given disease or antigen.
