Cutting edge approaches toward novel and cross-protective influenza vaccines

Every year, recurrent influenza virus infections lead to excess hospitalizations and deaths. The very young, the elderly, pregnant women, and immunocompromised persons are at particular risk of influenza-related complications. Influenza places a heavy burden on health care systems worldwide and has a large economical impact. Currently licensed influenza vaccines provide antibody-mediated sterilizing protection when the requirement for antigenic match is fulfilled. This protection is limited in time because the ever-drifting main antigenic determinants of the virus, hemagglutinin (HA) and neuraminidase (NA), allow the virus to escape humoral immunity. For this reason, it is necessary to update seasonal vaccines continuously based on predictions of the strains that will likely circulate in the next season. If the virus strains included in the vaccine do not match the circulating strains, e.g. due to poor prediction accuracy or to complete antigenic shift of the viral HA and NA, the vaccine could be ineffective, leaving the vaccinated population susceptible for the circulating virus. Therefore, researchers all over the world are involved in the development of novel vaccines that protect against multiple influenza strains or even subtypes. A common theme among the variety of approaches that are explored, raising immunity against conserved features of the virus, is the underlying strategy. In this chapter, we highlight the principles of cross-protective immunity against influenza and discuss how effectively new vaccine candidates might provide cross-protective immunity. We explain how the design of broadly protective universal vaccines can exploit evolutionarily conserved structural features in the HA. The extracellular domain of matrix protein 2 (M2e) is highly conserved, and vaccines based on M2e are clinically most advanced. The concept and mechanism of protection provided by M2e vaccines are highlighted in this chapter. Vaccines based on internal influenza viral proteins such as matrix protein 1 and nucleoprotein are discussed. These viral antigens are conserved and naturally immunogenic, mainly as potent inducers of T-cell responses. In the last part of this book chapter, we discuss advantages and disadvantages of sterilizing immunity versus infection-permissive protection.