Prevalence study of cellular capsid-specific immune responses to AAV1, 2, 4, 5, 8, 9 and rh10 reveals particular features for AAV9

Xicluna, R.; Avenel, A.; Vandamme, C.; Devaux, M.; Jaulin, N.; Couzinie, C.; Le Duff, J.; Charrier, A.; Guilbaud, M.; Adjali, O.; Gernoux, G.

doi:10.1101/2023.12.20.570598

bioRxiv · 10.1101/2023.12.20.570598

Prevalence study of cellular capsid-specific immune responses to AAV1, 2, 4, 5, 8, 9 and rh10 reveals particular features for AAV9

Xicluna, R.·Avenel, A.·Vandamme, C.·Devaux, M.·Jaulin, N.·Couzinie, C.·Le Duff, J.·Charrier, A.·Guilbaud, M.·Adjali, O.·Gernoux, G.

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Abstract

Recombinant adeno-associated virus (rAAV) vectors appear, more than ever, to be efficient viral vectors for in vivo gene transfer as illustrated by the approvals of 7 drugs across Europe and the USA. Nevertheless, pre-existing immunity to AAV capsid in humans remains one of the major limits for a successful clinical translation. Whereas pre-existing humoral response to AAV capsid is well documented, the prevalence of pre-existing capsid-specific T cell responses still needs to be studied and characterized. Here, we investigated the prevalence of AAV-specific circulating T cells towards AAV2, 4, 5, 8, 9 and rh10 in a large cohort of healthy donors using the standard IFN{gamma} ELISpot assay. We observed the highest prevalence of pre-existing cellular immunity to AAV9 serotype followed by AAV8, AAV4, AAV2, AAVrh10 and AAV5 independently of the donors serological status. An in-depth analysis of T cell responses towards the 2 most prevalent serotypes 8 and 9 shows that IFN{gamma} secretion is mainly mediated by CD8 T cells for both serotypes. A polyfunctional analysis reveals different cytokine profiles between AAV8 and AAV9. Surprisingly, no IL-2 secretion was mediated by anti-AAV9 immune cells suggesting that these cells may rather be exhausted or terminally differentiated than cytotoxic T cells. Altogether, these results suggest that pre-existing immunity to AAV may vary depending on the serotype and support the necessity of using multiparametric monitoring methods to better characterize anti-capsid cellular immunity and foresee its impact in rAAV-mediated clinical trials.

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Xicluna, R., Avenel, A., Vandamme, C., Devaux, M., Jaulin, N., Couzinie, C., Le Duff, J., Charrier, A., Guilbaud, M., Adjali, O., Gernoux, G.. 2023-12-21. Prevalence study of cellular capsid-specific immune responses to AAV1, 2, 4, 5, 8, 9 and rh10 reveals particular features for AAV9. https://doi.org/10.1101/2023.12.20.570598

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