All vaccines lose potency over time and the rate of potency loss is temperature-dependent. Therefore, cold-chain systems have been established to ensure that the potency of vaccines is maintained by storing them under refrigerated conditions (in most cases between 2 and 8 degrees C) until the point of use. This article aims to review the approaches being used to develop thermostable vaccine formulations that would be resistant to damage caused by freezing or excessive heat, and that could reduce dependence on the cold chain. The challenges associated with the implementation of these novel formulations are discussed, as well as the potential benefits and opportunities of taking vaccines out of the cold chain.

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HighlightsInterviews (158) conducted with immunization personnel in 6 countries.Respondents are interested in vaccines with improved heat and freeze stability.Most involved in vaccine purchases would pay a slight premium for those features.Most saw value in controlled temperature chain (CTC) use of vaccines.Many highlighted the need for careful consideration of CTC risks/benefits.

Recent studies have revealed that vaccines containing aluminum adjuvant are exposed to sub-zero temperatures while in the cold chain more frequently than was previously believed. This raises concerns that these freeze-sensitive vaccines may be damaged and offer inadequate protection. This study was undertaken to characterize the immediate qualitative changes of one such vaccine, hepatitis B, caused by freeze exposure. Hepatitis B vaccine was subjected to freezing temperatures ranging from 0 degrees C to -20 degrees C for up to three episodes with durations ranging from 1 hour to 7 days. The vaccine was analyzed for freezing point, particle size distribution, tertiary structure, and in vitro and in vivo potency. Whether or not hepatitis B vaccine freezes was shown to be dependent on an array of factors including temperature, rate of temperature change, duration of exposure, supercooling effects and vibration. Vaccine exposed to "mild" freezing (-4 degrees C or warmer) temperatures did not freeze and remained qualitatively unaltered. Single or repeated freezing events at temperatures of -10 degrees C or lower were associated with aggregation of the adjuvant-antigen particles, structural damage of the antigen, and reduction of immunogenicity in mice. Damage to the vaccine increased with duration of freezing, lower temperature, and the number of freezing episodes. With vibration, vaccine froze at -6 degrees C after 1 hour and damage occurred. Freezing and freeze damage to vaccines containing aluminum salt adjuvant represent real risks to the effectiveness of immunization and should be prevented by strengthening the cold chain system or, alternatively, development of freeze-stable vaccine formulations.

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