title: Vaccine instability in the cold chain: mechanisms, analysis and formulation strategies.
abstract: Instability of vaccines often emerges as a key challenge during clinical development (lab to clinic) as well as commercial distribution (factory to patient). To yield stable, efficacious vaccine dosage forms for human use, successful formulation strategies must address a combination of interrelated topics including stabilization of antigens, selection of appropriate adjuvants, and development of stability-indicating analytical methods. This review covers key concepts in understanding the causes and mechanisms of vaccine instability including (1) the complex and delicate nature of antigen structures (e.g., viruses, proteins, carbohydrates, protein-carbohydrate conjugates, etc.), (2) use of adjuvants to further enhance immune responses, (3) development of physicochemical and biological assays to assess vaccine integrity and potency, and (4) stabilization strategies to protect vaccine antigens and adjuvants (and their interactions) during storage. Despite these challenges, vaccines can usually be sufficiently stabilized for use as medicines through a combination of formulation approaches combined with maintenance of an efficient cold chain (manufacturing, distribution, storage and administration). Several illustrative case studies are described regarding mechanisms of vaccine instability along with formulation approaches for stabilization within the vaccine cold chain. These include live, attenuated (measles, polio) and inactivated (influenza, polio) viral vaccines as well as recombinant protein (hepatitis B) vaccines.
authors.affiliation: Macromolecule and Vaccine Stabilization Center, Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Ozan S
authors.initials: OS
authors.lastname: Kumru
authors.affiliation: Macromolecule and Vaccine Stabilization Center, Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Sangeeta B
authors.initials: SB
authors.lastname: Joshi
authors.affiliation: Temptime Corporation, Morris Plains, NJ 07950, USA.
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Smith
authors.affiliation: Macromolecule and Vaccine Stabilization Center, Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: C Russell
authors.initials: CR
authors.lastname: Middaugh
authors.affiliation: Temptime Corporation, Morris Plains, NJ 07950, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Prusik
authors.affiliation: Macromolecule and Vaccine Stabilization Center, Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047, USA. Electronic address: volkin@ku.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Volkin
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry; D000818:Animals; D000941:Antigens / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods* / Q000639:trends; D003080:Cold Temperature; D004355:Drug Stability; D004356:Drug Storage / Q000379:methods; D017325:Hepatitis B Vaccines / Q000737:chemistry; D006801:Humans; D007252:Influenza Vaccines / Q000737:chemistry; D008458:Measles Vaccine / Q000737:chemistry; D023321:Poliovirus Vaccines / Q000737:chemistry; D014612:Vaccines / Q000737:chemistry* / Q000276:immunology / Q000592:standards
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D017325:Hepatitis B Vaccines; D007252:Influenza Vaccines; D008458:Measles Vaccine; D023321:Poliovirus Vaccines; D014612:Vaccines
keywords: Adjuvant; Cold chain; Formulation; Lyophilization; Stability; Vaccine