Biotinylated peptide nanofibers for modulating the immune response

Abstract

Despite the fact that vaccination eradicates many diseases, a broad variety of disorders cannot be treated using current vaccine development methods. In addition, it is difficult to rapidly develop new vaccines following the sudden onset of a new pandemic, as the production and transport of vaccines to impoverished areas is still a major issue. The lack of sufficient vaccine production, for example, enabled the spread of swine flu in 2009, while HIV, Zika and malaria viruses currently lack effective vaccinations. In addition, while cancer vaccines represent a promising area of research, their clinical implementation is also limited by the absence of rapid and effective vaccine development methods. The development of new and effective vaccines is therefore quite vital. Moreover, recently used vaccines promote either humoral or cellular immune responses, while effective treatment requires the induction of both systems. Consequently, there is an urgent need for effective and easy-to-prepare vaccines that are capable of eliciting immune action through multiple channels. Peptide amphiphiles are small molecules that are able to self-assemble into nanoscale fibrous networks. These nanofibers are biodegradable, biocompatible and do not generate toxic byproducts, making them ideal for designing biomaterials. As such, nanofibers are a promising class of materials for inducing an effective immune response and overcoming some of the problems faced by current vaccine development methods. In this thesis, I detail the use of biotinylated peptide nanofiber systems as immunomodulatory materials that are capable of incorporating a broad variety of antigens in a modular manner. Briefly, biotinylated and non-biotinylated peptide amphiphiles (PA) were first synthesized, purified and characterized to determine their material properties. PAs were then induced to self-assemble in the presence of CpG oligonucleotide (ODN) adjuvants, and ovalbumin was conjugated to self-assembled biotinylated-PA (B-PA) nanofibers by streptavidin linkers. Splenocytes were isolated from the mouse spleen and treated with bioactive nanofibers to investigate the effect of bioactive nanofibers on the immune response. Following the confirmation of an effective combined immune response, live mice were exposed to the nanofiber adjuvants as a proof-of-concept demonstration of in vivo PA-vaccine efficiency. Both in vivo and in vitro studies demonstrated that B-PA nanofibers are able to effectively modulate the immune response. Given these observations, I suggest that the B-PA nanofiber can be used as an immunomodulatory material for promoting effective immune response against extracellular and intracellular pathogens, and especially for the vaccine-based treatment of cancer. As the antigen presented by the PA system can be changed in a modular manner, B-PA nanofibers can also be employed to rapidly develop new vaccines against sudden outbreaks of new viral strains.