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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

Confirmation of lead formulations containing increased LAIV titer. Formulations of LAIV H1N1 (A/California/07/2009) or type B (B/Brisbane/60/2008) in SPG buffer and selected excipients were prepared at a titer of 1 × 107 log10 TCID50/mL. The formulations were stored at at 2–8 °C (A), 25 °C (B), and 33 °C (C), and their titer was measured by TCID50. Formulations were tested for up to 52 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. (D) Summary of time (in weeks) to 1 log loss for the lead formulations identified represents the lower 95% confidence interval from the average of all three experiments lead formulations were evaluated. NT = not tested.
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fig0020: Confirmation of lead formulations containing increased LAIV titer. Formulations of LAIV H1N1 (A/California/07/2009) or type B (B/Brisbane/60/2008) in SPG buffer and selected excipients were prepared at a titer of 1 × 107 log10 TCID50/mL. The formulations were stored at at 2–8 °C (A), 25 °C (B), and 33 °C (C), and their titer was measured by TCID50. Formulations were tested for up to 52 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. (D) Summary of time (in weeks) to 1 log loss for the lead formulations identified represents the lower 95% confidence interval from the average of all three experiments lead formulations were evaluated. NT = not tested.

Mentions: To confirm the formulations selected, we tested a higher concentration (1 × 107 log10 TCID50/mL) of LAIV strains (H1N1 and type B) (Fig. 4). The higher titer better mimics what would be present in a vaccine product. In addition, to avoid using animal-derived raw materials, we tested formulations that substituted HSA or rHSA for BSA. Formulations containing 1% arginine (Formulation-09) and 1% arginine with 0.5% rHSA (Formulation-20) with both H1N1 and type B were stable for the length of the experiment (42.6 weeks H1N1 and 42.2 weeks type B using the lower 95% confidence Interval) at 2–8 °C. H1N1 formulations with 1% arginine improved stability compared to formulations with SPG buffer alone (p-value <0.0001), but not as much as formulations containing 1% arginine with 0.5% rHSA (Formulation-20, p-value <0.0001) at 25 °C. However, at 33 °C, H1N1 formulations with 1% arginine or 1% arginine with 0.5% rHSA showed similar stability. Type B formulations with 1% arginine showed statistically significant improvements in stability compared to formulations with SPG buffer alone at 2–8 °C and 25 °C (p-values <0.0001). Type B formulations with 1% arginine and 0.5% rHSA showed slightly improved stability compared to 1% arginine alone at 25 °C and 33 °C. The addition of 0.5% rHSA appeared to slightly improve the stability of formulations for both LAIV H1N1 and type B strains compared to stability with 1% arginine alone, although these differences were not statistically significant.


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)

Confirmation of lead formulations containing increased LAIV titer. Formulations of LAIV H1N1 (A/California/07/2009) or type B (B/Brisbane/60/2008) in SPG buffer and selected excipients were prepared at a titer of 1 × 107 log10 TCID50/mL. The formulations were stored at at 2–8 °C (A), 25 °C (B), and 33 °C (C), and their titer was measured by TCID50. Formulations were tested for up to 52 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. (D) Summary of time (in weeks) to 1 log loss for the lead formulations identified represents the lower 95% confidence interval from the average of all three experiments lead formulations were evaluated. NT = not tested.
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fig0020: Confirmation of lead formulations containing increased LAIV titer. Formulations of LAIV H1N1 (A/California/07/2009) or type B (B/Brisbane/60/2008) in SPG buffer and selected excipients were prepared at a titer of 1 × 107 log10 TCID50/mL. The formulations were stored at at 2–8 °C (A), 25 °C (B), and 33 °C (C), and their titer was measured by TCID50. Formulations were tested for up to 52 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. (D) Summary of time (in weeks) to 1 log loss for the lead formulations identified represents the lower 95% confidence interval from the average of all three experiments lead formulations were evaluated. NT = not tested.
Mentions: To confirm the formulations selected, we tested a higher concentration (1 × 107 log10 TCID50/mL) of LAIV strains (H1N1 and type B) (Fig. 4). The higher titer better mimics what would be present in a vaccine product. In addition, to avoid using animal-derived raw materials, we tested formulations that substituted HSA or rHSA for BSA. Formulations containing 1% arginine (Formulation-09) and 1% arginine with 0.5% rHSA (Formulation-20) with both H1N1 and type B were stable for the length of the experiment (42.6 weeks H1N1 and 42.2 weeks type B using the lower 95% confidence Interval) at 2–8 °C. H1N1 formulations with 1% arginine improved stability compared to formulations with SPG buffer alone (p-value <0.0001), but not as much as formulations containing 1% arginine with 0.5% rHSA (Formulation-20, p-value <0.0001) at 25 °C. However, at 33 °C, H1N1 formulations with 1% arginine or 1% arginine with 0.5% rHSA showed similar stability. Type B formulations with 1% arginine showed statistically significant improvements in stability compared to formulations with SPG buffer alone at 2–8 °C and 25 °C (p-values <0.0001). Type B formulations with 1% arginine and 0.5% rHSA showed slightly improved stability compared to 1% arginine alone at 25 °C and 33 °C. The addition of 0.5% rHSA appeared to slightly improve the stability of formulations for both LAIV H1N1 and type B strains compared to stability with 1% arginine alone, although these differences were not statistically significant.

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