Refocusing the immune response from structural to conserved non-structural proteins as a novel vaccination approach for inducing broad anti-enterovirus protection

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Multiple enteroviruses are associated with life-threatening and economically important diseases, yet the licensed vaccines are only available against poliovirus and enterovirus 71. The antigenic diversity of enterovirus capsids restricts the protective efficacy of vaccines only to antigenically very similar viruses. Even for closely related polioviruses, the three serotypes must be covered by separate vaccine products. In most cases such targeted vaccine development approach cannot even be implemented, either because of the biological constraints, such as antigenic diversity of rhinoviruses, or economic unattractiveness of developing vaccines against viruses only sporadically associated with severe pathologies, such as Coxsackie viruses linked to the development of diabetes, myocarditis and dilated cardiomyopathy. Thus, in spite of a pressing need for an effective vaccine coverage of existing and emerging enterovirus threats, the current vaccine development strategies focused on inducing neutralizing antibodies against capsid antigens are intrinsically incapable of delivering products meeting this demand. Yet, unlike the antigenically diverse capsids, the non-structural proteins of these viruses feature a significant degree of conservation, so that the elements of the replication machinery are essentially interchangeable among diverse enteroviruses, resulting in the phenomenon of extensive recombination of enterovirus genomes. In this application we present data to support, and propose to explore the hypothesis that posits the following: Antigenically diverse enteroviral capsids are immuno-dominant antigens which divert the development of immune response away from the conserved non-structural proteins. Consequently, by removing the input of the capsid proteins, the development of the immune response to enterovirus infection can be rerouted towards the conserved membrane-associated proteins of the replication machinery. likely resulting in: 1. Refocusing the protection mechanism from that based mostly on neutralizing antibodies to the one mediated by T-cell cytotoxicity, and 2. Providing protection against broad spectrum of enteroviruses.