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Istvan Toth

Istvan Toth

ARC Australia Professorial Fellow Chair in Biological Chemistry Editor-in-Chief, Current Drug Delivery Editor-in-Chief, Drug Delivery Letters University of Queensland Australia

Title: Dendritic Vaccine Delivery Systems

Biography

Biography: Istvan Toth

Abstract

Subunit vaccines that contain the minimal microbial components necessary to stimulate appropriate immune responses have the potential to overcome allergic response or autoimmunity that can result from using classical vaccines. We developed new delivery systems by combining the adjuvant and antigenic peptide epitopes into one chemically bonded dendritic entity. The presentation of epitopes on the nanoparticles surface was optimized to elicit a strong immune response in mouse models. rn Infection with group A streptococci (GAS), one of the most common and widespread human pathogens, can result in a broad range of diseases, with the potential to develop acute and post-infectious rheumatic fever and rheumatic heart disease. Immunity to GAS relies on the production of opsonic antibodies specific to the hypervariable N-terminal and conserved C-terminal regions of the coiled-coil α-helical M protein, a GAS major virulence factor. To improve vaccine delivery we developed a self-adjuvanting lipid core peptide (LCP) dendrimer system that included the antigen, a T helper epitope, a carrier, and the adjuvant within the same molecular entity. The system allowed the attachment of multiple copies of antigens. We investigated the structural requirements to elicit production of different antibodies (IgA, IgG) and assessed the influence of complex size on the level of antibody production1.rn Recent developments in nanomedicine/vaccinology have identified that size and morphological characteristics of nanoparticle vaccines affect their efficacy. Preliminary investigations have demonstrated that polymer-based nanoparticles that displayed peptide epitopes on their surface induced very strong immune responses against those epitopes. We have also shown that this response was dependent on the size of the total construct. We explored the efficacy of nanoparticle vaccines using a human papillomavirus (HPV) model. HPV infection, most commonly HPV-16, is responsible for the vast majority of cases of cervical cancer, which is the second most common cancer in women worldwide. The development of therapeutic vaccines that eliminate HPV infected cells and eradicate established HPV-associated tumors would therefore be beneficial and desirable. We established a synthetic pathway to conjugate human papillomavirus peptide antigens to the polymeric core to create macromolecular vaccine candidates to treat HPV-related cancers. These conjugates reduced tumor growth and eradicated established E7-expressing TC-1 tumors in mice after a single immunization, without the addition of an external adjuvant2.rn We extended our vaccine delivery platform investigations by using lutenizing hormone-releasing hormone (LHRH) as antigen. An anti-LHRH vaccine aims to control the level of sex hormones FSH and LH by generating antibodies against LHRH in murine and ovine models.rnWe have observed significant IgG antibody response after primary immunization without the use of additional adjuvant. The antibody response was enhanced and longer lasting when we co-administered commercial adjuvant AdjuVacTM [Lab Anim (NY) 2007, 36 (9) 51-58] with our LCP-LHRH vaccine formulation3.rn1) Zaman M, Chandrudu S, Giddam AK, Reiman J, Skwarczynski M, McPhun V, Moyle PM, Batzloff MR, Good MF, Toth I. Group A Streptococcal vaccine candidate: contribution of epitope to size, antigen presenting cell interaction and immunogenicity. Nanomedicine (London). 2014;9(17):2613-26242) rn2) Liu TY, Hussein WM, Giddam AK, Jia Z, Reiman FM, Zaman M, McMillan NAJ, Good MF, Monteiro MJ, Toth I, Skwarczynski M. Polyacrylate-based delivery system for self-adjuvanting anticancer peptide vaccine. Journal of Medicinal Chemistry. 2015;58:888-8963) rn3) Goodwin D, Varamini P, Simerska P, D’Occhio MJ, Toth I. Design, synthesis and evaluation of a gonadotroping releasing hormone-based subunit vaccine in rams (Ovis aries). Vaccine. 2015 Available online 09 Feb 2015rn