Background: The immunogenicity of a two-dose mRNA COVID-19 vaccine regimen is low in kidney transplant (KT) recipients. We report the first complete assessment of safety and cross-variant immunogenicity of a three-dose vaccine regimen in KT recipients.

Methods: We performed a prospective longitudinal study in sixty-one KT recipients given three doses of the BNT162b2 COVID-19 vaccine. We performed semi-structured pharmacovigilance interviews and monitored donor-specific antibodies and kidney function. We compared geometric mean titers (GMT) of anti-spike IgG, pseudo-neutralization activity against vaccine homologous and heterologous variants, frequency of spike-specific interferon (IFN)-γ-secreting cells, and antigen-induced cytokine production 28 days after the second and third doses. The immunoassays were also performed in non-transplanted individuals 28 days after the second dose to obtain reference values.

Findings: Reactions to vaccine were mild. One patient developed donor-specific anti-HLA antibodies after the second dose which could be explained by non-adherence to immunosuppressive therapy. Spike-specific IgG seroconversion raised from 44·3% (n=27) after the second dose to 62·3% (n=38) after the third dose (p<0·05). GMT increased from 528·3 (95% CI 300·0-930·1) to 2395 AU/ml (95% CI 1214-4724, p<0·0001). Serum neutralizing activity increased from 4·7% to 17·2% (Wuhan strain), 4·0% to 17·4% (alpha variant), 2·3% to 7·3% (beta variant), and 1·3% to 9·1% (gamma variant) after the third dose (p<0·0001), which remained lower than reference values. The mean frequency of IFN-γ-secreting cells increased from 19·9 (SD 56·0) to 64·0 (SD 76·8) cells/million PBMCs after the third dose (p<0·0001). A significant increase in IFN-γ responses was also observed in patients who remained seronegative after three doses (p<0·0001).

Interpretation: A third dose of the BNT162b2 vaccine increases both SARS-CoV-2-specific humoral and cellular responses in KT recipients with an acceptable tolerability profile. However, neutralizing antibody titres remain low after three doses, especially against variants of concern, and barrier measures and vaccination of the relatives remain essential.

Funding Information: This work was supported by grants from the Nice University Hospital (AOI) and the University of Cote d’Azur (IDEX).