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Development of a stable liquid formulation of live attenuated influenza vaccine.

White JA, Estrada M, Flood EA, Mahmood K, Dhere R, Chen D - Vaccine (2016)

Bottom Line: While live attenuated influenza vaccines are among the most efficacious and can be manufactured at low cost, they may require lyophilization to be stable enough for developing-country use, which adds a significant cost burden.In this study, potential stabilizing excipients were screened and optimized using the least stable influenza vaccine strain presently known, H1N1 (A/California/07/2009), as a model.Through this process, we identified a liquid formulation consisting of sucrose phosphate glutamate buffer with 1% arginine and 0.5% recombinant human serum albumin that provided storage stability of one year at 2-8°C for the influenza A and B strains tested.

View Article: PubMed Central - PubMed

Affiliation: PATH, Seattle, Washington, United States. Electronic address: jawhite@path.org.

No MeSH data available.


Related in: MedlinePlus

Formulation optimization. Formulations of LAIV H1N1 (A/California/07/2009) in SPG buffer and additional excipients were prepared at a titer of 2 × 106 log10 TCID50/mL. The formulations were stored at at 2 °C–8 °C (A), 25 °C (B), and 33 °C (C), and their titer was measured by TCID50. Formulations were tested for up to 20 weeks or until a titer loss greater than 1 log was observed. N = 1 for each formulation tested by TCID50 in triplicate. Error bars represent the standard deviation of three TCID50 replicates. Abbreviations: SPG, sucrose phosphate glutamate; BSA, bovine serum albumin; HPMC, hydroxypropyl methylcellulose; PVP, polyvinylpyrrolidone.
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fig0010: Formulation optimization. Formulations of LAIV H1N1 (A/California/07/2009) in SPG buffer and additional excipients were prepared at a titer of 2 × 106 log10 TCID50/mL. The formulations were stored at at 2 °C–8 °C (A), 25 °C (B), and 33 °C (C), and their titer was measured by TCID50. Formulations were tested for up to 20 weeks or until a titer loss greater than 1 log was observed. N = 1 for each formulation tested by TCID50 in triplicate. Error bars represent the standard deviation of three TCID50 replicates. Abbreviations: SPG, sucrose phosphate glutamate; BSA, bovine serum albumin; HPMC, hydroxypropyl methylcellulose; PVP, polyvinylpyrrolidone.

Mentions: In the second stage, lead formulations were optimized by combining excipients to further improve stability (Fig. 2). In addition, we tested wider concentration ranges for excipients to find the upper and lower limits of stability improvement. We also evaluated additional excipients: lactalbumin, HPMC, and PVP. As in the screening phase, arginine (Formulation-09) increased the stability of LAIV compared to SPG buffer alone (Formulation-01). Formulations containing arginine alone (Formulation-09 at 1% and Formulation-12 at 3%), 1% arginine with BSA (Formulation-17 at 0.5% BSA and Formulation-18 at 9% BSA), and 1% arginine with 0.5% gelatin (Formulation-16) showed stability for the length of the experiment (20 weeks) at 2–8 °C (Fig. 2A). Formulations containing 1% arginine held at 25 °C and 33 °C showed improved stability compared to those using SPG buffer alone. Formulations containing 3% arginine held at 25 °C and 33 °C showed an improvement in stability similar to formulations containing 1% arginine when compared to SPG buffer alone. The formulation containing 1% arginine and 0.5% BSA showed the largest stability improvement at 25 °C and 33 °C (Fig. 2B and C). A formulation containing 0.5% gelatin and 1% arginine showed stability similar to formulations of 1% arginine alone at 25 °C and 33 °C (Fig. 2B and C). HPMC and PVP appeared to destabilize LAIV and were not included in future formulations.


Development of a stable liquid formulation of live attenuated influenza vaccine.

White JA, Estrada M, Flood EA, Mahmood K, Dhere R, Chen D - Vaccine (2016)

Formulation optimization. Formulations of LAIV H1N1 (A/California/07/2009) in SPG buffer and additional excipients were prepared at a titer of 2 × 106 log10 TCID50/mL. The formulations were stored at at 2 °C–8 °C (A), 25 °C (B), and 33 °C (C), and their titer was measured by TCID50. Formulations were tested for up to 20 weeks or until a titer loss greater than 1 log was observed. N = 1 for each formulation tested by TCID50 in triplicate. Error bars represent the standard deviation of three TCID50 replicates. Abbreviations: SPG, sucrose phosphate glutamate; BSA, bovine serum albumin; HPMC, hydroxypropyl methylcellulose; PVP, polyvinylpyrrolidone.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940209&req=5

fig0010: Formulation optimization. Formulations of LAIV H1N1 (A/California/07/2009) in SPG buffer and additional excipients were prepared at a titer of 2 × 106 log10 TCID50/mL. The formulations were stored at at 2 °C–8 °C (A), 25 °C (B), and 33 °C (C), and their titer was measured by TCID50. Formulations were tested for up to 20 weeks or until a titer loss greater than 1 log was observed. N = 1 for each formulation tested by TCID50 in triplicate. Error bars represent the standard deviation of three TCID50 replicates. Abbreviations: SPG, sucrose phosphate glutamate; BSA, bovine serum albumin; HPMC, hydroxypropyl methylcellulose; PVP, polyvinylpyrrolidone.
Mentions: In the second stage, lead formulations were optimized by combining excipients to further improve stability (Fig. 2). In addition, we tested wider concentration ranges for excipients to find the upper and lower limits of stability improvement. We also evaluated additional excipients: lactalbumin, HPMC, and PVP. As in the screening phase, arginine (Formulation-09) increased the stability of LAIV compared to SPG buffer alone (Formulation-01). Formulations containing arginine alone (Formulation-09 at 1% and Formulation-12 at 3%), 1% arginine with BSA (Formulation-17 at 0.5% BSA and Formulation-18 at 9% BSA), and 1% arginine with 0.5% gelatin (Formulation-16) showed stability for the length of the experiment (20 weeks) at 2–8 °C (Fig. 2A). Formulations containing 1% arginine held at 25 °C and 33 °C showed improved stability compared to those using SPG buffer alone. Formulations containing 3% arginine held at 25 °C and 33 °C showed an improvement in stability similar to formulations containing 1% arginine when compared to SPG buffer alone. The formulation containing 1% arginine and 0.5% BSA showed the largest stability improvement at 25 °C and 33 °C (Fig. 2B and C). A formulation containing 0.5% gelatin and 1% arginine showed stability similar to formulations of 1% arginine alone at 25 °C and 33 °C (Fig. 2B and C). HPMC and PVP appeared to destabilize LAIV and were not included in future formulations.

Bottom Line: While live attenuated influenza vaccines are among the most efficacious and can be manufactured at low cost, they may require lyophilization to be stable enough for developing-country use, which adds a significant cost burden.In this study, potential stabilizing excipients were screened and optimized using the least stable influenza vaccine strain presently known, H1N1 (A/California/07/2009), as a model.Through this process, we identified a liquid formulation consisting of sucrose phosphate glutamate buffer with 1% arginine and 0.5% recombinant human serum albumin that provided storage stability of one year at 2-8°C for the influenza A and B strains tested.

View Article: PubMed Central - PubMed

Affiliation: PATH, Seattle, Washington, United States. Electronic address: jawhite@path.org.

No MeSH data available.


Related in: MedlinePlus