Formulation Studies During Preclinical Development of Influenza Hemagglutinin and Virus-Like Particle Vaccine Candidates
A critical element of vaccine formulation studies is the identification of chemical and physical degradation pathways that compromise structural integrity, and which may in turn affect the clinical safety and efficacy, of macromolecular antigens. Formulat
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rticles (VLPs) are oligomeric associations of viral protein(s) that rely on the principles of self-assembly to create “bio-containers” with core-shell morphologies [1, 2]. VLPs present viral protein antigens on their surface in an array-like manner, similar to the assembly of virus capsids in nature [3]. Due to their repetitive antigen array display system, VLPs have been implicated in increased immune responses when used as vaccine platforms compared to monomeric versions of the same antigen protein [4, 5]. VLPs do not contain a genome, eliminating the possibility of infection through the replication of pathogenic viral components. Modern VLP production technology has taken advantage of advances in molecular cloning and expression systems, leading to a new class of safe and effective commercial and candidate vaccines [6, 7]. The production of VLPs as vaccine candidates brings challenges common to the manufacture of biological drugs, including requirements of formulation development to maintain long-term stability and efficacy in a pharmaceutical relevant form that can be conveniently administered to patients [7–9]. Maintaining the pharmaceutical stability of the oligomeric components in VLPs (e.g., proteins, lipid bilayers, etc.) is a key challenge in formulation development, since the particles may be prone to physicochemical degradation [10, 11]. VLP degradation can occur at any point during the manufacturing process ranging from expression, purification, and stresses during storage (e.g., photo-exposure, freezing, lyophilization, elevated temperatures, shipping, etc.), which can lead to a loss of vaccine potency and efficacy [12, 13]. Thus VLP formulation development aims to not
Sunil Thomas (ed.), Vaccine Design: Methods and Protocols, Volume 2: Vaccines for Veterinary Diseases, Methods in Molecular Biology, vol. 1404, DOI 10.1007/978-1-4939-3389-1_27, © Springer Science+Business Media New York 2016
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only elucidate the causes and mechanisms of vaccine instability, but to also increase storage stability by screening a library of potential excipients with various physicochemical and biological techniques to assess their ability to decrease the rate and extent of VLP degradation [7, 14]. Early stage formulation development of vaccine candidates mitigates against expenses and/or production delays, due to VLP instability, that can occur during a vaccine candidate’s clinical development [13]. 1.2 Physical and Chemical Degradation
VLP vaccines need to maintain immunogenicity and potency during long-term storage and subsequent distribution to clinical and/or vaccination sites. Therefore, formulation development strategies should be employed to ensure patients receive stable and efficacious vaccines [13]. One key aspect of successful formulation development of a vaccine is determining the chemical and physical degradation pathways that result in the loss of structural integrity and affects the potency and clinical efficacy [14]. Chemical degradation of protein antigens primarily occurs
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