Structural and immunogenic characterisation of ChAdOx1 Chik-derived Chikungunya VLPs supports a mechanistic rationale for vaccine-induced protection

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes severe chronic arthritis in humans and constitutes an expanding global threat. We previously reported that a single unadjuvanted dose of ChAdOx1 Chik vaccine was safe and elicited cross-protective functional antibodies against four distinctive CHIKV lineages in a Phase 1 trial. Here, we show that the CHIKV structural polyprotein encoded by ChAdOx1 Chik can assemble into CHIKV virus-like particles (VLPs) in mammalian cells. Cryo-EM derived reconstruction confirms that these CHIKV VLPs closely resemble the structure of the native virion and LC-MS demonstrates authentic E1/E2 glycosylation. In C57BL/6 mice, unadjuvanted CHIKV VLPs conferred significant protection against viremia and CHIKV-induced foot swelling. A head-to-head comparison of three adjuvant-free platforms encoding structural antigens derived from ChAdOx1 Chik showed that viral-vectors and VLPs induced similar CHIKV-neutralising antibody titres, both surpassing immunisation with soluble E2. Together, these structural and immunogenicity data support a mechanistic rationale that VLP assembly mediated by the clinically relevant ChAdOx1 Chik vaccine contributes to its vaccine-induced protection demonstrated in pre-clinical and clinical studies.