Cell Biology & Molecular Genetics Research Works
Permanent URI for this collectionhttp://hdl.handle.net/1903/14
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Item Prospects for developing an Hepatitis C virus E1E2-based nanoparticle vaccine(Wiley, 2023-08-11) Toth, Eric A.; Andrianov, Alexander K.; Fuerst, Thomas R.Globally, more than 58 million people are chronically infected with Hepatitis C virus (HCV) with 1.5 million new infections occurring each year. An effective vaccine for HCV is therefore a major unmet medical and public health need. Since HCV rapidly accumulates mutations, vaccines must elicit the production of broadly neutralising antibodies (bnAbs) in a reproducible fashion. Decades of research have generated a number of HCV vaccine candidates. Based on the available data and research through clinical development, a vaccine antigen based on the E1E2 glycoprotein complex appears to be the best choice, but robust induction of humoral and cellular responses leading to virus neutralisation has not yet been achieved. One issue that has arisen in developing an HCV vaccine (and many other vaccines as well) is the platform used for antigen delivery. The majority of viral vaccine trials have employed subunit vaccines. However, subunit vaccines often have limited immunogenicity, as seen for HCV, and thus multiple formats must be examined in order to elicit a robust anti-HCV immune response. Nanoparticle vaccines are gaining prominence in the field due to their ability to facilitate a controlled multivalent presentation and trafficking to lymph nodes, where they can interact with both arms of the immune system. This review discusses the potential for development of a nanoparticle-based HCV E1E2 vaccine, with an emphasis on the potential benefits of such an approach along with the major challenges facing the incorporation of E1E2 into nanoparticulate delivery systems and how those challenges can be addressed.Item Structural and Biophysical Characterization of the HCV E1E2 Heterodimer for Vaccine Development(MDPI, 2021-05-29) Toth, Eric A.; Chagas, Andrezza; Pierce, Brian G.; Fuerst, Thomas R.An effective vaccine for the hepatitis C virus (HCV) is a major unmet medical and public health need, and it requires an antigen that elicits immune responses to multiple key conserved epitopes. Decades of research have generated a number of vaccine candidates; based on these data and research through clinical development, a vaccine antigen based on the E1E2 glycoprotein complex appears to be the best choice. One bottleneck in the development of an E1E2-based vaccine is that the antigen is challenging to produce in large quantities and at high levels of purity and antigenic/functional integrity. This review describes the production and characterization of E1E2-based vaccine antigens, both membrane-associated and a novel secreted form of E1E2, with a particular emphasis on the major challenges facing the field and how those challenges can be addressed.Item Immunopotentiating and Delivery Systems for HCV Vaccines(MDPI, 2021-05-25) Andrianov, Alexander K.; Fuerst, Thomas R.Development of preventive vaccines against hepatitis C virus (HCV) remains one of the main strategies in achieving global elimination of the disease. The effort is focused on the quest for vaccines capable of inducing protective cross-neutralizing humoral and cellular immune responses, which in turn dictate the need for rationally designed cross-genotype vaccine antigens and potent immunoadjuvants systems. This review provides an assessment of the current state of knowledge on immunopotentiating compounds and vaccine delivery systems capable of enhancing HCV antigen-specific immune responses, while focusing on the synergy and interplay of two modalities. Structural, physico-chemical, and biophysical features of these systems are discussed in conjunction with the analysis of their in vivo performance. Extreme genetic diversity of HCV-a well-known hurdle in the development of an HCV vaccine, may also present a challenge in a search for an effective immunoadjuvant, as the effort necessitates systematic and comparative screening of rationally designed antigenic constructs. The progress may be accelerated if the preference is given to well-defined molecular immunoadjuvants with greater formulation flexibility and adaptability, including those capable of spontaneous self-assembly behavior, while maintaining their robust immunopotentiating and delivery capabilities.Item Skin Vaccination with Ebola Virus Glycoprotein Using a Polyphosphazene-Based Microneedle Patch Protects Mice against Lethal Challenge(MDPI, 2022-12-27) Romanyuk, Andrey; Wang, Ruixue; Marin, Alexander; Janus, Benjamin M.; Felner, Eric I.; Xia, Dengning; Goez-Gazi, Yenny; Alfson, Kendra J.; Yunus, Abdul S.; Toth, Eric A.; Ofek, Gilad; Carrion, Ricardo Jr.; Prausnitz, Mark R.; Fuerst, Thomas R.; Andrianov, Alexander K.Ebolavirus (EBOV) infection in humans is a severe and often fatal disease, which demands effective interventional strategies for its prevention and treatment. The available vaccines, which are authorized under exceptional circumstances, use viral vector platforms and have serious disadvantages, such as difficulties in adapting to new virus variants, reliance on cold chain supply networks, and administration by hypodermic injection. Microneedle (MN) patches, which are made of an array of micron-scale, solid needles that painlessly penetrate into the upper layers of the skin and dissolve to deliver vaccines intradermally, simplify vaccination and can thereby increase vaccine access, especially in resource-constrained or emergency settings. The present study describes a novel MN technology, which combines EBOV glycoprotein (GP) antigen with a polyphosphazene-based immunoadjuvant and vaccine delivery system (poly[di(carboxylatophenoxy)phosphazene], PCPP). The protein-stabilizing effect of PCPP in the microfabrication process enabled preparation of a dissolvable EBOV GP MN patch vaccine with superior antigenicity compared to a non-polyphosphazene polymer-based analog. Intradermal immunization of mice with polyphosphazene-based MN patches induced strong, long-lasting antibody responses against EBOV GP, which was comparable to intramuscular injection. Moreover, mice vaccinated with the MN patches were completely protected against a lethal challenge using mouse-adapted EBOV and had no histologic lesions associated with ebolavirus disease.