Novel formulations enhance the thermal stability of live-attenuated flavivirus vaccines

Inviragen Inc., Fort Collins, Colorado 80525,United States.
Vaccine (Impact Factor: 3.62). 07/2011; 29(43):7456-62. DOI: 10.1016/j.vaccine.2011.07.054
Source: PubMed


Thermal stability is important for the manufacture, distribution and administration of vaccines, especially in tropical developing countries, where particularly adverse field conditions exist. Current live-attenuated flavivirus vaccines exhibit relatively poor liquid stability in clinical settings, and clinicians are instructed to discard the yellow fever vaccine 1h after reconstitution. We have identified novel combinations of excipients that greatly enhance the thermal stability of live-attenuated DEN-2 PDK-53-based flavivirus vaccine candidates. Liquid formulations comprising a sugar, albumin and a pluronic polymer minimized the loss of flavivirus infectious titer to less than 0.5 log(10)pfu after storage for at least 8h at 37°C, 7 days at room temperature or at least 11 weeks at 4°C. Additionally, these formulations prevented reduction of viral infectivity after two freeze-thaw cycles of virus. Formulated candidate vaccines were readily lyophilized and reconstituted with minimal loss of viral titers. In mice, the formulations were safe and did not hinder the ability of the vaccine virus to generate a potent, protective immune response. These formulations provided significantly greater liquid-phase stability than has been reported previously for other flavivirus vaccine formulations. The enhanced thermal stability provided by the formulations described here will facilitate the effective distribution of flavivirus vaccines worldwide.

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    • "Nonetheless, the vaccines require storage and shipment at 2–8 • C. Upon reconstitution, the vaccines rapidly lose potency even when stored at 2–8 • C. To improve the thermal stability of TDV-2-based chimeric attenuated vaccine viruses, we screened and identified combinations of excipients that significantly enhance the thermal stability of these vaccines. A combination of three excipients, F-127 (a polyoxyethylene–polyoxypropylene block copolymer) trehalose and albumin, synergistically improved the thermal stability of these vaccine viruses [37]. These excipients have been incorporated into all TDV formulations that have been preclinically and clinically tested as described below. "
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