Vaccines that induce broadly protective antibodies against influenza

Current influenza vaccines are only moderately effective. A main challenge is that the egg-based production presently used is time consuming, which means that the selection of which viral strains should be included is based on an educated guess as to which strains are more likely to cause next years' epidemic. Since conventional vaccines owe their efficacy to the induction of strain-specific and neutralizing antibodies, even a slight deviation of emerging viral strains from this guess will reduce vaccine efficacy. There are two main strategies for answering the efficacy challenge of current vaccines. Firstly, vaccine formats that allow for rapid production could be developed. This would allow for a reduction in the time between selection of influenza vaccine strains, and vaccine deployment in the population. As such, it would be easier to predict which viruses could cause the next epidemic. Secondly, new vaccine formats that induce immune responses capable of mediating broad protection against different influenza viruses could be developed. Such vaccine formats should be able to contribute protection both against seasonal influenza and the potential emergence of new influenza strains with pandemic potential. A prerequisite for development of vaccines able to raise broadly protective immune responses is knowledge on how repeated exposures to different vaccines or viruses will influence formation of new antibodies. We have now performed a series of experiments where we have qualitatively evaluated the re-activation of memory B-celle upon sequential exposure to antigenic variation. From these mouse studies, we have selected BCR sequenses from single cell isolation of influenza specific B-cells, and produced the corresponding antibodies. We have then evaluated affinity of the produced antibodies. The last step is now to perform an evaluation of the effector potential of these antibodies.

Current influenza vaccines are only moderately effective. The production time is in best case scenarios between 6-8 months, which leads to frequent mismatches between circulating epidemic strains and vaccine contents. Since conventional vaccines can only protect against a particular strain, even minor antigenic changes will render the vaccine inefficient. Furthermore, antigenic shifts will with unpredictable intervals lead to reassortment of high-pathogenic viruses with pandemic potential. WHO has declared it a great need to develop novel vaccine strategies for induction of broader protection (WHO, August 2016). Here, the main aim is to develop a vaccine that can confer broad and lasting protection against influenza. This will be achieved by mixing of a large number of different HAs to "blind" immunodominant and strain-specific epitopes, with the aim of steering immunity towards conserved but less immunogenic epitopes. In order to secure sufficient levels of immune responses for protective efficacy, the HAs in the mixture will be linked to a targeting moiety that directs the vaccine proteins specifically to the most relevant receptors on antigen presenting cells (APC). The immunological mechanisms associated with broad protection against influenza, and other variable and complex pathogens, are poorly characterized. Thus, an important aim of the present proposal will also be to characterize the antibody repertoire induced by the APC-targeted vaccine mixture. More specifically, antibodies from single germinal center cells will be sequenced, and the resulting sequences used for generation of the corresponding antibodies to allow for characterizations of protective efficacy. Such results will be highly relevant also for vaccine development against other pathogens exhibiting high genetic variability.