<p>Most vaccines require refrigerated transport and storage, which is costly, challenging in low-resource settings, and results in the loss of up to 50% of vaccines globally due to “cold-chain” failures. Here, tetanus toxoid vaccine (TT) was thermostabilized by encapsulation within a metal-organic framework (MOF), zeolitic imidazolate framework-8 (TT@ZIF-8). Its physicochemical properties were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and confocal microscopy. Unencapsulated TT fell below the 80% activity threshold within 4 days at 40˚C and 60˚C according to immunoassay analysis. Aqueous suspensions of TT@ZIF-8 also declined below 80% activity within a week at both temperatures, likely due to MOF degradation in water. Dried TT@ZIF-8 performed better, retaining 80% stability for 33 days at 40˚C and 22 days at 60˚C. When TT@ZIF-8 was suspended in a non-aqueous mixture of propylene glycol and ethanol, it remained 80% stable for approximately 4 months at 40˚C and 2.5 months at 60˚C. Arrhenius modeling predicted this formulation may qualify for “controlled temperature chain” designation, allowing partial vaccine removal from the cold chain. These studies suggest that MOF encapsulation of vaccines like TT can enable dramatic improvements in vaccine stability during storage without refrigeration.</p> Graphical abstract <p></p>