Composition of the neutralising antibody response predicts risk of BK virus DNAaemia in recipients of kidney transplants

Background: BK polyomavirus (BKV) DNAaemia occurs in 10% of recipients of kidney transplants, contributing to premature allograft failure. Evidence suggests disease is donor derived. Hypothetically, recipient infection with a different BKV serotype increases risk due to poorer immunological control. Thus, understanding the composition and activity of the humoral anti-BKV responses in donor/recipient (D/R) pairs is critical. Methods: Using 224 paired pre-transplant D/R samples, BKV VP1 genotype-specific pseudoviruses were employed to define the breadth of the antibody response against different serotypes (ELISA) and, to characterise specific neutralising activity (nAb) using the 50% inhibitory concentration (LogIC50). Mismatch (MM) ratios were calculated using the ratio of recipient ELISA or nAb reactive BKV serotypes relative to the number of donor reactive serotypes. Findings: BKV DNAaemia was observed in 28/224 recipients of kidney transplants. These recipients had lower nAb titres against all the serotypes, with median logIC50 values of 1.19–2.91, compared to non-viraemic recipients’ median logIC50 values of 2.13–3.30. nAb D/R MM ratios >0.67 associated with significantly higher risk of BKV viraemia, with an adjusted odds ratio of 5.12 (95% CI 2.07 to 13.04; p < 0.001). Notably, a mismatch against donor serotype Ic and II associated with adjusted odds ratios of 8.12 (95% CI 2.10 to 35.61; p = 0.002) and 4.52 (95% CI 1.19 to 19.23; p = 0.03) respectively. 21 recipients demonstrated broadly neutralising responses against all the serotypes, none of whom developed BKV DNAaemia post-transplant. In contrast, there was poor concordance with PsV-specific ELISA data that quantified the total antibody response against different serotypes. Interpretation: BKV nAb mismatch predicts post-transplant BKV DNAaemia. Specific mismatches in nAb, rather than total seroreactivity, are key indicators of BKV risk post-transplant. This has the potential to risk-stratify individuals and improve clinical outcomes by influencing the frequency of monitoring and individualised tailoring of immunosuppression. Furthermore, detailed examination of individuals with broadly neutralising responses may provide future therapeutic strategies. Funding: The research was funded by St. Peters Trust, Royal Free Hospital Charity and Wellcome Trust (grant numbers RFCG1718/05, SPT97 and 204870/Z/WT_/Wellcome Trust/United Kingdom).