Immune responses following 3rd and 4th doses of heterologous and homologous COVID-19 vaccines in kidney transplant recipients

Abstract

Background: Solid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3rd- (V3) and 4th- (V4) doses of heterologous and homologous vaccines in a kidney transplant population.

Methods: We undertook a single centre cohort study of 724 kidney transplant recipients prospectively screened for serological responses following 3 primary doses of a SARS-CoV2 vaccine. 322 patients were sampled post-V4 for anti-spike (anti-S), with 69 undergoing assessment of SARS-CoV-2 T-cell responses. All vaccine doses were received post-transplant, only mRNA vaccines were used for V3 and V4 dosing. All participants had serological testing performed post-V2 and at least once prior to their first dose of vaccine.

Findings: 586/724 (80.9%) patients were infection-naïve post-V3; 141/2586 (24.1%) remained seronegative at 31 (21-51) days post-V3. Timing of vaccination in relation to transplantation, OR: 0.28 (0.15-0.54), p=0.0001; immunosuppression burden, OR: 0.22 (0.13-0.37), p<0.0001, and a diagnosis of diabetes, OR: 0.49 (0.32-0.75), p=0.001, remained independent risk factors for non-seroconversion. Seropositive patients post-V3 had greater anti-S if primed with BNT162b2 compared with ChAdOx1, p=0.001.Post-V4, 45/239 (18.8%) infection-naïve patients remained seronegative. De novo seroconversion post-V4 occurred in 15/60 (25.0%) patients. There was no difference in anti-S post-V4 by vaccine combination, p=0.50. T-cell responses were poor, with only 11/54 (20.4%) infection-naive patients having detectable T-cell responses post-V4, with no difference seen by vaccine type.

Interpretation: A significant proportion of transplant recipients remain seronegative following 3- and 4- doses of SARS-CoV-2 vaccines, with poor T-cell responses, and are likely to have inadequate protection against infection. As such alternative strategies are required to provide protection to this vulnerable group.

Funding: MW/PK received study support from Oxford Immunotec.

Keywords: COVID-19; Immunosuppression; Kidney transplant; Vaccination.

Figure 1

Serological responses to 3rd and 4th dose vaccination. (A) Anti-S concentrations post-V3 in infection-naïve patients receiving ChAdOx1²-mRNA1273, ChAdOx1²-BNT162b2, BNT162b2²-mRNA1273 and BNT162b2³, were 319 (125-3213), 518 (98-2049), 412 (106-841) and 1110 (246-2969) BAU/ml respectively. Significantly higher concentrations were seen with BNT162b2 as V3 following priming with BNT162b2 compared with ChAdOx1, p=0.0011 (B) Anti-S concentrations post-V4 in infection-naïve patients receiving ChAdOx1²-mRNA1273-BNT162b2, ChAdOx1²-BNT162b2², BNT162b2²-mRNA1273-BNT162b2 and BNT162b2⁴, were no different between groups. (C) Anti-S concentrations post-V4 by dose of vaccine seroconverted. +++, -++, and -+ denote seroconversion post V2, V3 and V4 respectively. The median anti-S in infection-naïve patients post-V4 in those seroconverting post V2-, V3- or V4- were 1561 (567-5211), (101-851) and 19 (9.7-48) BAU/ml respectively. (D) Anti-S concentrations post 2nd-, 3rd- and 4th vaccinations by infection exposure Anti-S concentrations were greater in patients with prior infection (568 (54-2237) post-V2, 3791 (1142-5680) post-V3 and 3993 (835-5680) BAU/ml post-V4) compared with infection-naïve patients (9.2 (7.1-173) post-V2, 295 (9.1-1611) post-V3 or 437 (26-2211) BAU/ml post-V4). There was no difference between post-V2 concentrations in patients with prior infection compared with infection naïve individuals post-V3, p=0.06 or post-V4, p=0.99.

Figure 2

Cellular responses to 4th dose vaccination. (A) T-cell responses were greater in infection-naïve individuals who were seropositive post-V4, 10 (2-34) SFU/106 PBMC, compared with those who were seronegative, 1 (0-8) SFU/106 PBMC. (B) There was no difference in the magnitude of cellular responses between those patients who were primed with ChAdOx1² compared with BNT162b2², with a median 9 (1-65) and 6 (2-19) SFU/10⁶ PBMC respectively, p=0.72. (C) T-cell responses were greater in infection exposed compared with infection-naïve individuals, with a median SFU/10⁶ PBMC of 92 (8-212) and 6 (2-26) respectively, p=0.0098. *For purposes of data representation, values of 0 were replaced by 1.