A Fourth SARS-CoV-2 MRNA Vaccine in Strictly Seronegative Kidney Transplant Recipients

To the editor: Solid organ transplant recipients have demonstrated a lower humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination, leading transplant physicians to perform a third vaccine injection.1 However, despite this early booster, about 35% of patients remained seronegative and, thus, inadequately protected against coronavirus disease 2019 (COVID-19).2 Recently, a fourth mRNA injection has become available in France, as well as the possibility of monthly preventive preexposure monoclonal antibody therapy in low-responder or nonresponder patients.3,4 On the basis of physicians' expertise and patients' choice, kidney transplant recipients from 2 French university hospitals with a strictly negative serologic assessment (i.e., binding antibody unit [BAU] <1/ml) 1 month after the third injection were proposed to receive a fourth mRNA vaccine as an alternative to preexposure monoclonal antibody prophylaxis.

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We retrospectively evaluated 49 nonresponder kidney transplant recipients with a serologic assessment following a fourth mRNA vaccine (Table 1). The mean age was 63 years, and 47% were men. None of them had a history of COVID-19 infection nor anti-nucleocapsid IgG. Maintenance therapy consisted of calcineurin inhibitors in 77%, antiproliferative drugs in 83%, and steroids in 57%. They all had a strictly negative serology after the third injection (BAU, <1/ml, evaluated in different laboratories by ECLIA Roche, Architect Abbott, or Diasorin). The serologic screening was assessed in a median of 35 days following the fourth injection, and anti-spike IgG titers were expressed in BAU/ml after conversion, depending on the laboratory test.

 A total of 21 of 49 patients (42.8%) seroconverted (i.e., positive serology considered by laboratory thresholds) following the fourth injection, with a mean BAU titer of 82/ml (Figure 1). Of note, 4 of them had a high BAU titer (>264/ml), which can be considered as neutralizing,5 and 3 patients without seroconversion had a slight increase in anti-spike IgG. SARS-CoV-2 infection occurred in 1 patient, who previously developed a low humoral response following 4 injections (BAU, 14.2/ml), presenting with mild symptoms and not requiring oxygen-supportive care. Although no statistical differences were found between responders and nonresponders because of the small analyzed cohort, we noted lower steroid use (47% vs. 64%), less lymphopenia (62% vs. 75%), longer time between the third and fourth dose (93 vs. 82 days), and a larger utilization of the BNT162b vaccine (86% vs. 68%) in patients who developed a humoral response after the fourth injection. History of biopsy-proven acute rejection seemed more frequent in seronegative patients. Still, the clinical significance of these data may be hard to assess as most cases in this group (4 of 6) occurred >5 years ago.

Our report highlights the results of a fourth mRNA vaccine in strictly nonresponder kidney transplant recipients, resulting in seroconversion in 43% of them. Only 4 patients developed a strong humoral response that can be considered as protective from SARS-CoV-2 infection; other patients may benefit from another booster dose to improve their antibody titer.6 Further studies are required to clearly determine risk factors of nonresponse after a fourth mRNA vaccine in this selected population. A fourth mRNA vaccine in strictly nonresponder kidney transplant recipients induced a humoral response in 43%; however, this response remained globally weak and was probably not protective enough against COVID-19. Monoclonal antibody provides quicker and higher protection for these patients and thus may be considered, especially during a high-incidence SARS-CoV-2 infection period when the risk of contamination is higher.

1. Hall VG, Ferreira VH, Ku T, et al. Randomized trial of a third dose of mRNA-1273 vaccine in transplant recipients. N Engl J Med. 2021;385: 1244–1246. 

2. Qin CX, Moore LW, Anjan S, et al. Risk of breakthrough SARS-CoV-2 infections in adult transplant recipients. Transplantation. 2021;105:e265–e266. 

3. O'BrienMP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV antibody combination to prevent Covid-19. N Engl J Med. 2021;385:1184–1195. 

4. Caillard S, Thaunat O. COVID-19 vaccination in kidney transplant recipients. Nat Rev Nephrol. 2021;17:785–787. 

5. Feng S, Phillips DJ, White T, et al. Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection. Nat Med. 2021;27: 2032–2040. 

6. Caillard S, Thaunat O, Benotmane I, et al. Antibody response to a fourth messenger RNA COVID-19 vaccine dose in kidney transplant recipients: a case series. Ann Intern Med. Published online January 11, 2022 https://doi. org/10.7326/L21-0598