A fourth dose of the mRNA-1273 SARS-CoV-2 vaccine improves serum neutralization against the Delta variant in kidney transplant recipients

Abstract

Research has suggested that even 3 doses of severe acute respiratory syndrome coronavirus 2 mRNA-based vaccines might be unable to elicit a sufficient immune response in immunocompromised kidney transplant recipients.1Benotmane I. Gautier G. Perrin P. et al.Antibody response after a third dose of the mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients with minimal serologic response to 2 doses.JAMA. 2021; 326: 1063-1065Google Scholar,2Hall V.G. Ferreira V.H. Ku T. et al.Randomized trial of a third dose of mRNA-1273 vaccine in transplant recipients.N Engl J Med. 2021; 385: 1244-1246Google Scholar Although the antibody response mounted by the Pfizer and AstraZeneca vaccines in immunocompetent subjects seems sufficient to neutralize the Delta variant,3Subbaraman N. How do vaccinated people spread Delta? What the science says.https://www.nature.com/articles/d41586-021-02187-1Date accessed: September 14, 2021Google Scholar the effectiveness appears 3- to 5-fold lower than that observed against the Alpha variant.4Planas D. Veyer D. Baidaliuk A. et al.Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization.Nature. 2021; 596: 276-280Google Scholar,5Lopez Bernal J. Andrews N. Gower C. et al.Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) variant.N Engl J Med. 2021; 385: 585-594Google Scholar In addition, standard vaccination schemes are beset by low immunogenicity in immunocompromised subjects, who remain prone to develop severe coronavirus disease 2019 (COVID-19).3Subbaraman N. How do vaccinated people spread Delta? What the science says.https://www.nature.com/articles/d41586-021-02187-1Date accessed: September 14, 2021Google Scholar The purpose of this study is to describe the kinetics of the neutralizing antibody response against the Delta strain before and after a fourth dose of the mRNA-1273 (Moderna) vaccine in kidney transplant recipients who had experienced a weak antibody response after 3 previous doses. We also assessed the correlation between this neutralizing activity and levels of IgG against the receptor-binding domain (RBD) of the spike protein. Sixty-seven kidney transplant recipients (median age 56.6 years; interquartile range [IQR] 47–64.6 years; n = 41 [61.2%] men) showed a weak humoral response after 3 doses of the mRNA-1273 vaccine and received a fourth dose (Supplementary Methods). None of these patients had a history of COVID-19 and displayed anti–nucleocapsid antibodies. The median interval from transplantation to the fourth dose was 6.1 years (IQR 2.2–11.4 years). As for immunosuppressive therapy, 97% of the study patients were being treated with calcineurin inhibitors, 82% with mycophenolate mofetil, 76% with steroids, and 18% with mammalian target of rapamycin inhibitors (Table 1). The median interval between the third and fourth doses was 68 days (IQR 63–82 days). After the fourth dose, the median anti-RBD titer increased significantly (P < 0.0001) from 13 binding antibody units (BAUs)/ml (IQR 2.6–66.3 BAUs/ml) to 112.5 BAUs/ml (IQR 13.5–260 BAUs/ml) (Figure 1a). In parallel, median inhibitory dilution 50 (ID50) titers increased significantly (P = 0.0001) from <7.5 (IQR <7.5–15.1) to 47.1 (IQR <7.5–284.2). Although only 16% of patients (n = 11) harbored neutralizing antibodies against the Delta strain before the fourth injection, this percentage raised to 66% (n = 44) afterward (Figure 1b). Patients with undetectable neutralizing antibodies after the third dose were less likely to have their neutralizing capacity increased after the fourth dose (median fold change 1.1 [IQR 1–7.5] vs. 6.3 [IQR 2–15.9]; P = 0.01). Of the 9 patients who were seronegative after the third dose, only 1 displayed a strong anti-RBD IgG response (>143 BAUs/ml) and 2 were able to neutralize the Delta variant after the fourth dose. Additionally, 81% of patients with a weak immune response after the third dose displayed a strong anti-RBD IgG response after the fourth injection. Notably, 63.8% of them were able to neutralize the Delta variant after the fourth dose. Interestingly, patients under combined therapy with tacrolimus, mycophenolate mofetil, and steroids displayed lower neutralizing ID50 titers (median ID50 titers 25.6 vs. 140.6; P = 0.01). Neutralizing ID50 titers against the Delta variant were positively correlated with anti-RBD titers (Pearson r2 = 0.54; P < 0.0001; Figure 1c). Once the anti-RBD titer exceeded 143 BAUs/ml after the fourth dose, the specificity, sensitivity, positive predictive value, and negative predictive value for detecting neutralizing activity were 92.9%, 74.3%, 93.6%, and 72.2%, respectively. Neither major adverse events nor graft rejections were observed after the fourth dose. One patient, who lacked neutralizing activity after the fourth injection (ID50 titer <7.5), developed symptomatic COVID-19 caused by the Delta variant 19 days after receiving the fourth dose.Table 1General characteristics of the study patients according to the neutralizing ID50 titers after the fourth doseCharacteristicEntire cohort (N = 67)Neutralizing ID50 below 30 (n = 28)Neutralizing ID50 above 30 (n = 39)PAge, yr56.6 (47–64.6)53.1 (45–64.6)57.6 (50.6–64.6)0.29Male sex41 (61.2)12 (42.9)29 (74.4)0.01BMI, kg/m225.6 (22.3–29.6)24.3 (22.2–28.9)26.6 (22.7–29)0.48Comorbidities Cardiovascular disease19 (28.4)8 (28.5)11 (28.2)0.59 Diabetes27 (39.3)10 (35.7)17 (43.6)0.61 Hypertension53 (79.1)21 (75)32 (82)0.56Time from kidney transplantation, yr6.1 (2.2–11.4)5.1 (1.8–11.1)7.5 (2.5–11.3)0.32First transplantation54 (80.6)23 (82.1)31 (79.5)1Deceased donor55 (82.1)22 (78.6)33 (84.6)0.54CNI0.2 Tacrolimus51 (76.1)24 (85.7)27 (69.2) Cyclosporine14 (20.9)3 (10.7)11 (28.2) No CNI2 (3)1 (3.6)1 (2.6)MMF/MPA55 (82)24 (85.7)31 (79.5)0.74mTOR inhibitors12 (17.9)4 (14.3)8 (20.5)0.74Steroids51 (76.1)24 (85.7)27 (69.2)0.15Tacrolimus + MMF/MPA + steroids35 (52.2)19 (67.9)16 (41)0.05Serum creatinine (μmol/l)132 (106.2–162.5)131.3 (100.2–157.8)132 (115.3–162.6)0.61History of graft rejection15 (22.4)12 (42.8)3 (7.7)0.002BMI, body mass index; CNI, calcineurin inhibitor; ID50, inhibitory dilution 50; MMF, mycophenolate mofetil; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin.Data are expressed as median (interquartile range) or n (%). Open table in a new tab BMI, body mass index; CNI, calcineurin inhibitor; ID50, inhibitory dilution 50; MMF, mycophenolate mofetil; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin. Data are expressed as median (interquartile range) or n (%). In this cohort of 67 kidney transplant recipients who showed a low immune response after 3 doses of the mRNA-1273 (Moderna) vaccine, a fourth dose significantly increased the neutralizing response against the Delta variant. Specifically, the proportion of patients harboring neutralizing antibodies against the Delta strain rose significantly from 16% to 66%. In our study, men displayed higher neutralizing ID50 titers than did women. Although this observation has no obvious pathophysiological explanations, it is in accordance with the results published by Masset et al.6Masset C. Kerleau C. Garandeau C. et al.A third injection of the BNT162b2 mRNA COVID-19 vaccine in kidney transplant recipients improves the humoral immune response.Kidney Int. 2021; 100: 1132-1135Google Scholar after the third dose. Patients with a history of cellular or antibody-mediated rejection were less likely to display a neutralizing antibody response. This may be attributed to a higher burden of immunosuppression implemented in response to the rejection episodes. Only 2 published studies have focused on the effect of a fourth vaccine dose in patients who had undergone solid organ transplantation. In a small cohort of 18 solid organ transplant recipients, Alejo et al.7Alejo J.L. Mitchell J. Chiang T.P.Y. et al.Antibody response to a fourth dose of a SARS-CoV-2 vaccine in solid organ transplant recipients: a case series.Transplantation. 2021; 105: e280-e281Google Scholar found that 8 patients with a negative or low response after the third dose developed high antibody titers after the fourth injection, a result in line with our current data.7Alejo J.L. Mitchell J. Chiang T.P.Y. et al.Antibody response to a fourth dose of a SARS-CoV-2 vaccine in solid organ transplant recipients: a case series.Transplantation. 2021; 105: e280-e281Google Scholar Moreover, 6 of the 10 patients who already had high positive titers after 3 doses showed additional boosting after the fourth injection. This report did not provide data on the neutralizing activity, which has been shown to be highly predictive of immune protection against symptomatic severe acute respiratory syndrome coronavirus 2 infection.8Khoury D.S. Cromer D. Reynaldi A. et al.Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.Nat Med. 2021; 27: 1205-1211Google Scholar In another cohort of 37 patients, Kamar et al.9Kamar N. Abravanel F. Marion O. et al.Assessment of 4 doses of SARS-CoV-2 messenger RNA–based vaccine in recipients of a solid organ transplant.JAMA Netw Open. 2021; 4e2136030Google Scholar assessed antibody response, neutralizing activity, and T-cell response; a slight improvement of humoral response was observed. In the work by Kamar et al.,9Kamar N. Abravanel F. Marion O. et al.Assessment of 4 doses of SARS-CoV-2 messenger RNA–based vaccine in recipients of a solid organ transplant.JAMA Netw Open. 2021; 4e2136030Google Scholar 86% of the study patients (32 of 37) had no immune response after 3 doses. Conversely, 87% of our study participants (58 of 67) showed a weak antibody response after 3 doses. This may at least in part explain the discrepancies between the 2 investigations. This is, to our knowledge, the first study to assess the effect of a fourth dose vaccine by taking into account the neutralizing activity against the Delta variant. Previous research has focused on the response of solid organ transplant recipients after a third vaccine dose.1Benotmane I. Gautier G. Perrin P. et al.Antibody response after a third dose of the mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients with minimal serologic response to 2 doses.JAMA. 2021; 326: 1063-1065Google Scholar,6Masset C. Kerleau C. Garandeau C. et al.A third injection of the BNT162b2 mRNA COVID-19 vaccine in kidney transplant recipients improves the humoral immune response.Kidney Int. 2021; 100: 1132-1135Google Scholar Although improvements have been observed for both B- and T-cell responses, a significant proportion of nonresponders (30%–50%) was reported. In a double-blind, randomized, placebo-controlled trial of a third dose of mRNA-1273 vaccine, Hall et al.2Hall V.G. Ferreira V.H. Ku T. et al.Randomized trial of a third dose of mRNA-1273 vaccine in transplant recipients.N Engl J Med. 2021; 385: 1244-1246Google Scholar found a higher neutralizing activity in the vaccine group versus the placebo group (median percent virus neutralization 71% vs. 25%, respectively). These observations suggest the existence of an “antigen dose effect,” indicating that stronger immune stimuli are required to improve vaccine immunogenicity. There have been previous reports of better immunogenicity after additional vaccine doses or higher vaccine dosing in immunocompromised patients.S1,S2 Although a consensus threshold for COVID-19 seroprotection has not been defined yet, higher antibody titers have been correlated with a reduced risk of symptomatic infections.S3,S4 These data, coupled with our findings, indicate that a fourth vaccine injection is beneficial in transplant recipients who show a weak response after 3 doses. It is nonetheless concerning that a fourth injection was still unable to elicit neutralizing antibodies against this variant in approximately one-third of our study sample. These patients should maintain strict sanitary protection measures and/or be considered as candidates for higher vaccine doses or prophylactic administration of monoclonal anti–severe acute respiratory syndrome coronavirus 2 antibodies. Although immunosuppressive modulation during vaccination could be another alternative to improve vaccine response, this approach should be weighed against the risk of developing acute rejection. No data are currently available on the cost-effectiveness of this strategy. In summary, our data indicate that a fourth mRNA-1273 vaccine injection in kidney transplant recipients with a weak antibody response after 3 previous doses improves serum neutralization against the Delta variant. All the authors declared no competing interests. Download .pdf (.08 MB) Help with pdf files Supplementary File (PDF)