Towards a cross-protective influenza vaccine

PhD ceremony: Ms. N. van Braeckel Budimir, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Towards a cross-protective influenza vaccine

Promotor(s): prof. J.C. Wilschut, prof. A.L.W. Huckriede

Faculty: Medical Sciences

Although vaccination is the cornerstone of influenza prevention, and current inactivated influenza vaccines are safe, there is an increasing demand for further improvement of these vaccines. Indeed, influenza vaccine efficacy is suboptimal in a number of important target groups for vaccination, particularly the elderly and young children.

Current influenza vaccines induce a narrow and strain-specific immune response and fail to protect against different antigenic variants and subtypes. Therefore, development of vaccines capable of inducing a broadly protective immune response is required. One possible approach, addressed in this thesis, is to aim for induction of cross-protective Cytotoxic T-Lymphocytes (CTLs) specific for antigenic determinants that are conserved among different influenza variants and subtypes. This study demonstrates that Whole Inactivated Influenza (WIV) vaccine has the capacity to induce heterosubtypic cross-protection, mainly mediated by CTLs. CTL-inducing capacity of WIV is highly influenced by the virus inactivation method, as some treatments, such as Formalin-inactivation, severely compromise membrane fusion activity of WIV, required for successful delivery of antigen into the cytosol of antigen-presenting cell. Furthermore, we showed that heterosubtypic cross-protection induced by WIV vaccination critically depends on activation of Toll-like receptor 7 (TLR7) in dendritic cells, which is required for successful antigen cross-presentation. Finally, our results show that parenteral routes of WIV administration are superior in comparison to mucosal vaccination in terms of induction of cross-protective CTL responses. Taken together, our findings appear to support reconsideration of WIV as a “novel” vaccine formulation for induction of broadly protective immunity against influenza.