On the adjuvanticity of hyaluronan: The case of a SARS-CoV-2 vaccine

Vaccines based on mRNA have been fundamental in facing the COVID-19 pandemic, however, they still raise concerns about stability and long-term efficacy. Thus, protein-based vaccines remain valid options and hence the study of effective adjuvants is crucial. Here, we developed a COVID-19 vaccine based on the receptor-binding domain (RBD) of SARS-CoV-2 Spike protein, which is covalently conjugated to the natural polymer hyaluronan (HA) that acts as an immunological adjuvant. Vaccination of K18-hACE2 mice with HA-RBD was well tolerated, and elicited high and sustained titres of RBD-binding antibodies and SARS-CoV-2-neutralizing antibodies, without the addition of other immunostimulatory compounds. Most importantly, HA-RBD vaccination conferred long-term protection to K18-hACE2 mice after challenge with SARS-CoV-2, also in the case of two consequent infections driven by different variants. These findings demonstrate the efficacy of HA-based vaccination against COVID-19 disease, and support the promising use of HA as an efficient and well tolerated adjuvant.