Modern vaccines are based on highly purified recombinant antigens with excellent safety profiles. However, their immunogenicity is inferior compared to live attenuated or inactivated pathogen vaccines, which may inherently contain natural adjuvants in an unknown content. Therefore, the development of next generation vaccines relies on formulating antigens with defined adjuvants, which are capable of shaping adaptive immune responses resulting in strong and long-term protection. Furthermore, antigens based on virus-like particles (VLPs), which are formed by structural viral proteins and mimic the size and morphology of the pathogen, also present an increasingly popular strategy for vaccine development.<br/>In an approach of synergizing both of these strategies, we aim to engineer synthetic immunogenic constructs of virus-mimicking dimensions, which display and present antigens in a multimeric form and concurrently provide danger signals for pattern recognition receptors (PRRs). These virus-mimicking polymer assemblies (VMPAs) are designed around a series of synthetic water-soluble polymers capable of controlled hydrolytic breakdown under physiological conditions, which is enabled by inorganic phosphazene backbone, and bearing carboxylic acid functionalities for non-covalent interactions with biological targets.<br/>Applying asymmetric flow field flow fractionation (AF4) and dynamic light scattering (DLS) methods, we demonstrated that water-soluble polyphosphazenes spontaneously self-assembled with vaccine antigens, such as Hepatitis C Virus (HCV) envelope glycoprotein antigens or Respiratory Syncytial Virus (RSV) antigen, to form stable supramolecular assemblies of 60-100 nm in diameter. VMPA bound antigen was displayed in multiple copies and was freely accessible by neutralizing antibodies. To augment inherent immunostimulating and intracellular delivery capacity of polyphosphazenes, VMPAs were also decorated with R848, resiquimod - Toll-Like Receptor (TLR) 7/8 agonist, which was attached to the polymer through physiologically stable ionic links. In vivo, the resulting nano-constructs induced superior serum neutralization titers and shifted the response towards desirable cellular immunity.

Supramolecular assemblies of synthetic water-soluble polymers with immunogens as virus-mimicking nano-constructs for vaccine development

ACS Spring Meeting 2021

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