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1.
Eur J Pharm Biopharm ; 94: 220-8, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25998700

ABSTRACT

A major impediment to economical, worldwide vaccine distribution is the requirement for a "cold chain" to preserve antigenicity. We addressed this problem using a model human papillomavirus (HPV) vaccine stabilized by immobilizing HPV16 L1 capsomeres, i.e., pentameric subunits of the virus capsid, within organic glasses formed by lyophilization. Lyophilized glass and liquid vaccine formulations were incubated at 50°C for 12weeks, and then analyzed for retention of capsomere conformational integrity and the ability to elicit neutralizing antibody responses after immunization of BALB/c mice. Capsomeres in glassy-state vaccines retained tertiary and quaternary structure, and critical conformational epitopes. Moreover, glassy formulations adjuvanted with aluminum hydroxide or aluminum hydroxide and glycopyranoside lipid A were not only as immunogenic as the commercially available HPV vaccine Cervarix®, but also retained complete neutralizing immunogenicity after high-temperature storage. The thermal stability of such adjuvanted vaccine powder preparations may thus eliminate the need for the cold chain.


Subject(s)
Adjuvants, Immunologic/chemistry , Capsid Proteins/immunology , Oncogene Proteins, Viral/immunology , Papillomavirus Vaccines/chemistry , Papillomavirus Vaccines/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Calorimetry, Differential Scanning , Capsid Proteins/biosynthesis , Capsid Proteins/genetics , Dose-Response Relationship, Drug , Drug Stability , Drug Storage , Electrophoresis, Polyacrylamide Gel , Enzyme-Linked Immunosorbent Assay , Epitopes/chemistry , Female , Freeze Drying , Mice, Inbred BALB C , Microscopy, Electron, Transmission , Neutralization Tests , Oncogene Proteins, Viral/genetics , Protein Conformation , Spectrometry, Fluorescence , Temperature
2.
J Pharm Sci ; 104(2): 627-39, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25581103

ABSTRACT

During transport and storage, vaccines may be exposed to temperatures outside of the range recommended for storage, potentially causing efficacy losses. To better understand and prevent such losses, dominant negative inhibitor (DNI), a recombinant protein antigen for a candidate vaccine against anthrax, was formulated as a liquid and as a glassy lyophilized powder with the adjuvants aluminum hydroxide and glycopyranoside lipid A (GLA). Freeze-thawing of the liquid vaccine caused the adjuvants to aggregate and decreased its immunogenicity in mice. Immunogenicity of liquid vaccines also decreased when stored at 40°C for 8 weeks, as measured by decreases in neutralizing antibody titers in vaccinated mice. Concomitant with efficacy losses at elevated temperatures, changes in DNI structure were detected by fluorescence spectroscopy and increased deamidation was observed by capillary isoelectric focusing (cIEF) after only 1 week of storage of the liquid formulation at 40°C. In contrast, upon lyophilization, no additional deamidation after 4 weeks at 40°C and no detectable changes in DNI structure or reduction in immunogenicity after 16 weeks at 40°C were observed. Vaccines containing aluminum hydroxide and GLA elicited higher immune responses than vaccines adjuvanted with only aluminum hydroxide, with more mice responding to a single dose.


Subject(s)
Adjuvants, Pharmaceutic/chemistry , Aluminum Hydroxide/chemistry , Anthrax Vaccines/chemistry , Lipid A/chemistry , Adjuvants, Pharmaceutic/metabolism , Aluminum Hydroxide/metabolism , Animals , Anthrax Vaccines/metabolism , Drug Stability , Female , Freeze Drying/methods , Freezing , Glass , Lipid A/metabolism , Mice , Mice, Inbred BALB C
3.
Eur J Pharm Biopharm ; 85(2): 279-86, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23583494

ABSTRACT

Lyophilization was used to prepare dry, glassy solid vaccine formulations of recombinant ricin toxin A-chain containing suspensions of colloidal aluminum hydroxide adjuvant. Four lyophilized formulations were prepared by using combinations of rapid or slow cooling during lyophilization and one of two buffers, histidine or ammonium acetate. Trehalose was used as the stabilizing excipient. Aggregation of the colloidal aluminum hydroxide suspension was reduced in formulations processed with a rapid cooling rate. Aluminum hydroxide particle size distributions, glass transition temperatures, water contents, and immunogenicities of lyophilized vaccines were independent of incubation time at 40 °C for up to 15 weeks. Mice immunized with reconstituted ricin toxin subunit A (RTA) vaccines produced RTA-specific antibodies and toxin-neutralizing antibodies (TNAs) regardless of the length of high temperature vaccine storage or the degree of aluminum adjuvant aggregation that occurred during lyophilization. In murine studies, lyophilized formulations of vaccines conferred protection against exposure to lethal doses of ricin, even after the lyophilized formulations had been stored at 40 °C for 4 weeks. A corresponding liquid formulation of vaccine stored at 40 °C elicited RTA-specific antibody titers but failed to confer immunity during a ricin challenge.


Subject(s)
Drug Stability , Recombinant Proteins/chemistry , Ricin/chemistry , Vaccines, Subunit/chemistry , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Adjuvants, Pharmaceutic/chemistry , Adjuvants, Pharmaceutic/pharmacology , Aluminum Hydroxide/chemistry , Animals , Antibodies, Neutralizing/immunology , Antibody Formation/immunology , Buffers , Chemistry, Pharmaceutical/methods , Drug Storage , Excipients/chemistry , Female , Freeze Drying/methods , Hot Temperature , Mice , Particle Size , Recombinant Proteins/immunology , Ricin/immunology , Transition Temperature , Trehalose/chemistry , Vaccines, Subunit/immunology , Water/chemistry
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