A WHO International Standard for neutralising antibodies to Chikungunya virus: development and evaluation

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BACKGROUND: Chikungunya fever is a mosquito-borne disease characterised by severe arthralgia and is caused by chikungunya virus (CHIKV), an alphavirus. The aim of this study was to establish a WHO International Standard for CHIKV-specific neutralising antibodies-a potential correlate of protection. METHODS: Two candidate International Standards (code numbers 1502/19 and 1504/19) were prepared: 1502/19 using plasma from a CHIKV-convalescent individual and 1504/19 using plasma from blood donors from a CHIKV-endemic region. Potencies of the two candidate International Standards were evaluated alongside samples from recovered individuals and donors previously infected with CHIKV, in an international study (2019-20), using a range of virus-neutralisation assays and immunoassays. Statistical analysis was used to estimate mean and relative potencies of the candidate International Standards. Participants included vaccine developers, arbovirus reference laboratories, and diagnostics manufacturers. FINDINGS: ). Intra-assay variation was considerably lower than inter-assay variation for the candidate International Standards, which varied by more than 100-fold; this variability was seen for all other anti-CHIKV-positive samples. Assay variability was substantially reduced when antibody titres from the panel of samples were expressed relative to 1502/19 or 1504/19. An agreement was reached to establish 1502/19 as the first WHO International Standard for anti-CHIKV neutralising antibodies, with an assigned unitage of 1000 International Unitage/mL. INTERPRETATION: The use of the candidate International Standards resulted in harmonisation of anti-CHIKV neutralisation titres, allowing for better comparison of results of neutralisation assays for anti-CHIKV antibodies, either as a consequence of natural infection or produced in response to different vaccines, and will be essential in estimating antibody titres associated with protection against CHIKV. FUNDING: German Ministry of Health (Bundesministerium für Gesundheit).