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Assessment of the biodistribution of aluminum-based vaccine adjuvants using ¹¹¹/¹¹⁵In-AlO(OH)

University of British Columbia

Aluminum-based adjuvants are found in a wide range of non-living vaccines to enhances antibody-mediated immune responses. Alhydrogel is one of the most common aluminum-based adjuvants and consists of 1-12 μm clusters of loosely aggregated aluminum oxyhydroxide (AlO(OH)) nanoparticles. Despite widespread use since in 1930s, the biodistribution of this adjuvant is poorly understood. The current assumption within the field is that AlO(OH) particles remain at the site of injection and slowly dissolve over time. However, rare neurological and muscle adverse effects, such as macrophagic myofasciitis, are thought to be due to the bio-persistence of the adjuvant at the site of injection and the distribution of AlO(OH) nanoparticles throughout the body. The objective of this thesis was to examine if component nanoparticles of Alhydrogel distribute following administration. In order the test this hypothesis, traceable forms of AlO(OH) were synthesized by doping the adjuvant’s crystal structure with different indium isotopes. Various physical, morphological and functional assessments showed that the doped adjuvant closely matched commercial Alhydrogel. Using a radioactive version of the tracer, ¹¹¹In-AlO(OH), the biodistribution of the adjuvant was assessed using serial SPECT/CT imaging. Approximately 20% of the tracer was released from the site of injection over 15 days and could be found in organs like the draining lymph nodes and liver. A novel application of mass cytometry was used to examine the kinetics and cellular distribution of ¹¹⁵In-AlO(OH) particles within the draining lymph nodes; the adjuvant appeared at this site within 1 day and reached peak levels 15 days post-injection. The adjuvant was sequestered into antigen presenting cells and induced the up-regulation of maturation markers in adjuvant-positive dendritic cells within the draining lymph node. Finally, electron microscopy coupled with atomic mapping confirmed the presence of Alhydrogel component nanoparticles in the draining lymph node and liver. This thesis presents the most detailed assessment to date of the biodistribution of aluminum-based adjuvants. Understanding Alhydrogel’s biodistribution can help shed light on the adjuvant’s immunostimulatory mechanisms and adverse events. Lessons learnt from one of the world oldest adjuvants can be applied to the design of next generation of immunopotentiators.

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2018-02-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/59042

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/