Antibody and T-cell response to a third dose of SARS-CoV-2 mRNA BNT162b2 vaccine in kidney transplant recipients

To the editor:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has become the standard of care for the prevention of severe coronavirus disease 2019 (COVID-19), with a strongly positive impact in countries in which vaccination has been effectively promoted.S1 In kidney transplant recipients (KTRs), SARS-CoV-2 vaccination has been recommended through international guidelines.S2 Unfortunately, the data reported in KTRs are disappointing, with a low rate of seroconversion after 2 doses,¹ whereas the occurrence of severe infection after vaccination² is of concern. In this context, as of April 6, 2021, the French Administration recommends that solid organ transplant recipients receive a third mRNA vaccine dose at least 4 weeks after the second dose. Herein, we report the evaluation of humoral and cellular responses induced after the second and third doses of BNT162b2 (Pfizer–BioNTech) in 80 KTRs (see Supplementary Methods).

Baseline characteristics of the 80 KTRs are described in Table 1 . After the second dose, 30 KTRs (37.5%) had anti–spike IgG antibodies; and 49 KTRs (61.2%) had these antibodies after the third injection (P < 0.0001) (Figure 1 a). In patients already seropositive after the second dose (Figure 1b), median antibody titers increased from 217.1 arbitrary units (AU)/ml (interquartile range [IQR], 120.2–443.8 AU/ml) to 2238.3 AU/ml (IQR, 1934.4–7220.6 AU/ml; P < 0.0001). Forty-one KTRs (51.2%) displayed a significant number of IFN-γ–producing spike-reactive T cells after the second injection, and 56 (70%) displayed these cells after the third injection (P < 0.0001 compared with the second dose). No response to N, M, ORF3A, and ORF7A was evidenced, excluding a potential SARS-CoV-2 infection between the second and up to 1 month after the third dose. In these 41 patients, the median number of spike-reactive T cells increased from 225 spot-forming cells (SFCs)/10⁶ CD3+ T cells (IQR, 90–355 SFCs/10⁶ CD3⁺ T cells) to 330 SFCs/10⁶ CD3+ T cells (IQR, 187–610 SFCs/10⁶ CD3⁺ T cells; P < 0.0001) after the third dose (Figure 2 b). Vaccination status after the third dose is summarized in Supplementary Figure S1.

Table 1.

Baseline characteristics of patients and according to the immune response after the third dose of mRNA BNT162b2 vaccine (Pfizer–BioNTech)

Variable	Entire cohort (n = 80)	S+/E+ (n = 43)	S+/E– (n = 6)	S–/E+ (n = 13)	S–/E– (n = 18)
Age, yr, mean ± SD	63.6 ± 15.7	60.3 ± 14.9	66.7 ± 15.6	64.3 ± 18.1	70.2 ± 14.6
Sex (M/F), n	48/32	24/19	5/1	8/5	11/7
Time from transplantation, yr, median (IQR)	7.3 (3.4–14.1)	10.3 (4.7–16)	6.8 (3.5–17.5)	6.6 (1.6–14.2)	4.4 (1.7–6.8)
eGFR, ml/min per 1.73 m2, mean ± SD	44.8 ± 17.2	50.2 ± 14.2	46.6 ± 17.3	44.0 ± 21.6	32.0 ± 14.8
IS regimen, n (%)
Tacrolimus	46 (57.5)	22 (51.2)	6 (100)	10 (76.9)	8 (44.4)
Cyclosporine	14 (17.5)	13 (30.2)	0 (0)	1 (7.7)	0 (0)
MMF	61 (76.2)	32 (74.4)	4 (66.7)	13 (100)	12 (66.7)
AZA	9 (11.2)	6 (13.9)	0 (0)	0 (0)	3 (16.7)
mTOR inhibitors	10 (12.5)	7 (16.3)	1 (16.7)	1 (7.7)	1 (5.6)
Belatacept	12 (15)	1 (2.3)	0 (0)	1 (7.7)	10 (55.6)
Steroids	32 (40)	16 (37.2)	3 (50)	4 (30.8)	9 (50)

AZA, azathioprine; E, enzyme-linked immunosorbent spot; eGFR, estimated glomerular filtration rate; F, female; IQR, interquartile range; IS, immunosuppressive; M, male; MMF, mycophenolate mofetil; mTOR, mammalian target of rapamycin; S, serology.

Figure 1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike (S) antibody response in kidney transplant recipients (KTRs) following a second and third injection of SARS-CoV-2 mRNA BNT162b2 vaccine (Pfizer–BioNTech). Median and interquartile range for anti–S IgG antibody titers are shown. The threshold for antibody positivity is 50 arbitrary units (AUs)/ml. (a) S IgG antibody titers in all 80 KTRs. (b) S IgG titers in the 30 KTRs who were seropositive after the second dose. (c) S IgG titers in the 50 KTRs who were seronegative after the second dose.

Figure 2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–reactive interferon-γ–producing T cells in kidney transplant recipients (KTRs) following the second and third injection of the SARS-CoV-2 mRNA BNT162b2 vaccine (Pfizer–BioNTech). (a) Total numbers of T cells (expressed as spot-forming cells [SFCs]/10⁶ CD3⁺ T cells) reactive to overlapping peptide pools spanning the SARS-CoV-2 structural spike protein S (pools S1 and S2) in all 80 KTRs. Median and interquartile range are shown. (b) T-cell response in the 40 KTRs showing significant anti-spike T-cell numbers after the second dose. (c) T-cell response in the 40 KTRs without a significant T-cell response after the second dose (cutoffs for significant T-cell numbers were 25 and 40 SFCs/10⁶ CD3⁺ T cells for pools S1 and S2, respectively).

Baseline characteristics and immune response after the third dose, according to baseline immunosuppressive regimen, are described in Supplementary Tables S1 and S2 and Supplementary Figure S2.

Two KTRs presented with symptomatic COVID-19 67 and 72 days, respectively, after the third vaccine injection. One KTR was hospitalized but did not require intensive care. Both KTRs had a low number of spike-reactive T cells after the third dose (65 and 50 SFCs/10⁶ CD3⁺ T cells), and only the second KTR had a low titer of anti-spike antibodies (145 AU/ml).

We did not report any severe adverse events after the third vaccine dose. None of the patients presented an acute rejection after vaccination. We did not report any de novo donor-specific antibodies until 1 month after the third dose.

We provide herein the largest cohort of KTRs explored for both humoral and T-cell responses after a third dose of BNT162b2 vaccine. The seropositivity rate increased, with an important increase in median antibody titers in responders, reaching levels that have been found associated with the presence of neutralizing antibodies.S3 ^, S4 Our results are in line with other reports in solid-organ transplant recipients.^{3 ,} S5 ^, S6 Hall et al.,⁴ in a double-blind, randomized, placebo-controlled trial of a third dose of mRNA-1273 vaccine (Moderna), found that seroconversion, virus neutralization, and specific T-cell counts were statistically higher in the mRNA-1273 group. In our study, the rate of positive T-cell response increased from 51.2% to 70% after the third dose, with a median spike-reactive T-cell number comparable to that observed in the general population after 2 doses.S7

Our results suggest that the immune response to a third BNT262b2 dose is highly influenced by the intensity of the immunosuppressive regimen. As already reported,S8 belatacept-treated patients were the worst responders, developing no antibodies and no or only few specific T cells. Mycophenolic acid by itself appears associated with a lower seroconversion rate.S5 However, in our study, KTRs on cyclosporine were more likely to develop humoral and cellular responses than KTRs on tacrolimus (Supplementary Table S2), regardless of mycophenolate mofetil coadministration.

In addition, the BNT262b2 vaccine appears safe with regard to acute rejection and de novo donor-specific antibodies, a potent risk factors for antibody-mediated rejection and graft loss,S9 up to 1 month after the third dose.

In conclusion, a third dose of the SARS-CoV-2 mRNA BNT162b2 vaccine in KTRs increases the rate of positive antibody and T-cell responses in nonresponsive patients after the second dose and improves the magnitude of these responses in already seropositive patients. In patients without significant response after a third dose, anti–SARS-CoV-2 monoclonal antibodies could be proposed in prophylaxis,S10 as recommended by the French Administration since August 6, 2021.

Data Statement

All relevant data are within the article.