Anthrax vaccine powder formulations for nasal mucosal delivery

Ge, Jingping; Joshi, Sangeeta B.; Peek, Laura J.; Brandau, D; Huang, Juan; Ferriter, Matthew; Woodley, Wendy D.; Ford, Brandi M.; Mar, Kevin D.; Mikszta, John A.; Hwang, C. Robin; Ulrich, Robert G.; Harvey, Noel G.; Middaugh, C. Russell; Sullivan, Vincent J.

doi:10.1002/jps.20484

Cited by 88 publications

(84 citation statements)

References 36 publications

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“…This was most prominent at the highest temperatures. When the r 2 method was used to evaluate parallelism, significant decreases in immunogenicity were detected only at 70°C and 100°C ( The data presented herein, along with results obtained by other authors (4,8,10), support the concept that TNA can quantify differences among anthrax vaccine batches that have been altered by exposure to high temperature during storage. However, these experiments represent only a first step toward The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.…”

supporting

confidence: 78%

“…The stability of protective antigen (PA), a major antigen included in anthrax vaccines, is critical to establish the suitability of a formulation for long-term storage. PA is denatured at temperatures as low as 40°C (4,7,9), which can jeopardize vaccine potency if the product is heated at any time prior to its administration, even during manufacturing. The current potency assay for anthrax vaccines is an active protection test that consumes many animals and requires security and biosafety measures because of the use of virulent Bacillus anthracis.…”

mentioning

confidence: 99%

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Reduction of Immunogenicity of Anthrax Vaccines Subjected to Thermal Stress, as Measured by a Toxin Neutralization Assay

Castelán-Vega

Corvette

Sirota

et al. 2011

Clin Vaccine Immunol

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We report that a toxin neutralization assay (TNA) can detect a decrease in the immunogenicity of anthrax vaccines as a consequence of brief exposure to elevated temperature. This attribute of TNA may help in adopting immunogenicity as a replacement of the current potency test, which involves protection from lethal challenge.All anthrax vaccine that enters the Strategic National Stockpile must maintain its potency through protracted storage periods. Thus, robust, practical, and meaningful potency tests are essential to evaluate vaccine manufacturing consistency and stability. The stability of protective antigen (PA), a major antigen included in anthrax vaccines, is critical to establish the suitability of a formulation for long-term storage. PA is denatured at temperatures as low as 40°C (4, 7, 9), which can jeopardize vaccine potency if the product is heated at any time prior to its administration, even during manufacturing. The current potency assay for anthrax vaccines is an active protection test that consumes many animals and requires security and biosafety measures because of the use of virulent Bacillus anthracis. To circumvent these drawbacks, immunogenicity assays have been developed in which lethal challenge is replaced with the measurement of differential antibody induction using in vitro tests.We assessed whether a toxin neutralization assay (TNA) can detect changes in antibody response as a consequence of the exposure of an experimental recombinant PA vaccine (rPAV) and BioThrax, a commercial vaccine, to high temperatures for brief periods. The number of possible time/temperature combinations to which a vaccine can be exposed before use is very high. Therefore, we selected a few combinations to model the possibility of using murine immunogenicity to detect anthrax vaccine exposure to nonideal storage conditions.We used a published method (3), slightly modified, to measure neutralizing activity in mouse sera. The reference serum and samples were prediluted with Dulbecco's modified Eagle medium (DMEM) and serially diluted (1:2) in a 96-well microtiter plate. Predilution was made to achieve full neutralization curves, i.e., to obtain upper and lower asymptotes. Lethal toxin (LT; 100 ng/ml of PA plus 80 ng/ml of lethal factor in DMEM) was added, and mixtures were incubated (37°C and 5% CO 2 ) for 30 min. One well in each column contained only the sample at the lowest dilution tested (sample control [SC]). One column contained normal mouse serum diluted 1:25 in DMEM. Toxin activity was confirmed by the addition of LT to four wells (LT control), while four wells were used to verify cell viability (reagent control). Toxin-serum mixtures were added to J774A.1 cells seeded in a second 96-well plate (40% to 60% confluence) and incubated (37°C and 5% CO 2 ) for 4 h. Cell viability was estimated with a vital dye, MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] (2). The absorbance per well (determined as the change in optical density [⌬OD] at 570 and 690 nm) was transformed to the percentag...

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supporting

confidence: 78%

mentioning

confidence: 99%

Reduction of Immunogenicity of Anthrax Vaccines Subjected to Thermal Stress, as Measured by a Toxin Neutralization Assay

Castelán-Vega

Corvette

Sirota

et al. 2011

Clin Vaccine Immunol

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“…A similar approach has been successfully applied to the formulation of anthrax and malaria vaccine candidates. 27,34 In the present studies, a number of sugars, polyols, aminoacids and polyanions displayed significant inhibition to the rate of aggregation of RSV at 56˚C. Thermal treatment of RSV presumably produces non-native conformational states in the envelope glycoproteins that lead to irreversible intermolecular interaction and subsequently virus aggregation.…”

Section: High Throughput Screening For Inhibitors Of Rsv Aggregationmentioning

confidence: 55%

High-throughput screening of stabilizers for Respiratory Syncytial Virus: Identification of stabilizers and their effects on the conformational thermostability of viral particles

Ausar

Espina²,

Brock³

et al. 2007

Human Vaccines

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Respiratory syncytial virus (RSV) is the leading cause of severe respiratory infection in children worldwide. Recombinant live attenuated viral preparations are one of the most promising strategies for vaccination but they typically possess poor thermostability. In this work, a library of compounds was screened and stabilizers were selected based on their ability to inhibit the aggregation of RSV perturbed at 56˚C. After screening and selection of excipients, the conformational stability of the RSV proteins was evaluated in the presence of potential stabilizers. The secondary and tertiary structures as well as aggregation/dissociation of RSV were monitored using circular dichroism and second derivative UV absorption spectroscopies and light scattering, respectively, as a function of temperature (10-90˚C). RSV membrane fluidity was also evaluated by generalized polarization of Laurdan fluorescence. Screening experiments showed that a variety of sugars, amino acids, polyols and polyanions inhibited the aggregation of viral particles. Conformational stability studies demonstrated that the addition of sugars and polyols stabilized RSV as indicated by a significant increase in the transition melting temperature (Tm) of both the secondary and tertiary structures as well as the gel to liquid crystalline membrane transition. These results should provide the basis for rational development of more physically stable formulations of live attenuated RSV vaccines.

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“…This, in turn, can be used to determine the optimal conditions for trial formulations and high throughput excipient screening assays. 13,[18][19][20][21][31][32][33] The present research expands the application of EPDs to a more complex and heterogeneous system than those that have been previously studied. The EPD of Ty21a cells clearly indicates that the cells are most stable at pH 6 to 7 and at temperatures below 30°C.…”

Section: Methodsmentioning

confidence: 90%

Towards development of stable formulations of a live attenuated bacterial vaccine: A preformulation study facilitated by a biophysical approach

Zeng¹,

Fan²,

Chiueh³

et al. 2009

Human Vaccines

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Anthrax vaccine powder formulations for nasal mucosal delivery

Cited by 88 publications

References 36 publications

Reduction of Immunogenicity of Anthrax Vaccines Subjected to Thermal Stress, as Measured by a Toxin Neutralization Assay

Reduction of Immunogenicity of Anthrax Vaccines Subjected to Thermal Stress, as Measured by a Toxin Neutralization Assay

High-throughput screening of stabilizers for Respiratory Syncytial Virus: Identification of stabilizers and their effects on the conformational thermostability of viral particles

Towards development of stable formulations of a live attenuated bacterial vaccine: A preformulation study facilitated by a biophysical approach

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