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Casirivimab–imdevimab to Prevent SARS-CoV-2 Infections in Solid Organ Transplant Recipients

Dimeglio, Chloé PhD1,2,3; Del Bello, Arnaud MD, PhD2,4; Chapuy-Regaud, Sabine PharmD, PhD1,2,3; Esposito, Laure MD4; Danet, Chloé PharmD5; Couat, Chloé MSc4; Izopet, Jacques PharmD, PhD1,2,3; Kamar, Nassim MD, PhD2,3,4

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doi: 10.1097/TP.0000000000004087
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Abstract

To the Editor:

Anti–(severe acute respiratory syndrome coronavirus 2) SARS-CoV-2 neutralizing monoclonal antibodies (mAbs), casirivimab and imdevimab (Ronapreve, Roche), reduce symptomatic and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons.1 Despite 3 doses of SARS-CoV-2 vaccine, a substantial number of solid organ transplant (SOT) recipients still have a weak or no humoral response.2,3 The French Authorities for Health recommended using preexposure neutralizing anti–SARS-CoV-2 mAbs to prevent coronavirus disease 2019 (COVID-19) in this setting.4

During the fourth wave of SARS-CoV-2 (August–September 2021), while Delta was the predominant variant and positivity of SARS-CoV-2 polymerase chain reaction (PCR) tests was at 6.8% in Southwest France, we gave our SOT patients who were nonresponder or weak responders the possibility to receive these mAbs. Weak responders were patients having anti-S concentration <141 binding antibody unit (BAU)/mL, a threshold that provides only 12.4% protection against SARS-CoV-2 in a cohort of healthcare workers.5 Patients were given 2 doses of casirivimab and imdevimab 1 mo apart (600:600 mg for the first dose and 300:300 mg for the second). Before each mAbs injection, patients had to provide a negative SARS-CoV-2 PCR in nasopharyngeal swab, and anti–SARS-CoV-2 antibodies had to be performed. A SARS-CoV-2 PCR was done in symptomatic patients, and antinucleocapsid antibodies were assessed in patients given mAbs before each injection to detect asymptomatic SARS-CoV-2 cases. Anti-N and anti-S antibodies were assessed using Alinity (SARS-CoV-2 antinucleocapsid immunoglobulin G and SARS-CoV-2 immunoglobulin G II Quant, Abbott Ireland, Diagnostic Division, Sligo, Ireland) before each injection. SARS-CoV-2 was detected with a nucleic acid amplification method (Aptima SARS-CoV-2 assay, Panther system, Hologic). According to French law (loi Jardé), anonymous retrospective studies do not require institutional review board approval. All patients gave their oral informed consent.

On September 20, 2021, 877 SOT patients had received 3 doses of mRNA BNT162b2 vaccine and had an available serology test at 1 mo after third dose. Of these, 399 (45.5%) had an anti-S concentration ≥141 BAU/mL. For the 478 remaining patients who were either nonresponders (n = 290; 60.7%) or weak responders (n = 188; 39.3%), we proposed the administration of mAbs monthly. We compared the outcome of the first 182 patients who were given mAbs during the fourth COVID-19 wave with the 296 other patients who did not get the mAbs during this period because of logistic issues (contacting the patients and organizing the administration of mAbs at the 1-d hospitalization unit), although they were listed to be treated. Patients were followed for 60 d.

Anti-S antibodies were detected in 20.5% of patients before the first injection of mAbs (median, 6.1; interquartile range, 1.9–9.1 BAU/mL) and 50.3% in the untreated group (median, 13.5; interquartile range, 5–56.7 BAU/mL; P = 0.08). Median anti-S antibody concentrations just before the second injection and 1 mo later were 8825 BAU/mL (range, 2988–19 096) and 8705 BAU/mL (range, 4266–18 485), respectively (P = 0.83). No serious adverse event was observed. Three patients experienced a transient malaise. One patient had a facial flushing only at first injection.

During follow-up of 60 d, no SARS-CoV-2 infection was observed in the treated group compared with 13 (4.4%; P < 0.01) in the untreated group (11 patients were infected by the Delta variant, 3 developed a severe disease, and 2 died; Table 1).

TABLE 1. - Characteristics of solid organ transplant patients who received or did not received monoclonal antibodies
Casirivimab–imdevimab (N = 182) Untreated group (N = 296) P
Median (IQR) Median (IQR)
Age (y) 63 (53–71) 61 (52–70) 0.49a
Time between transplantation and beginning of vaccination (mo) 71 (35–128) 75 (41–142) 0.23a
Time between last dose vaccine and first monoclonal antibodies  administration (d) 103 (93–115) NA
N (%) N (%)
Gender 0.82b
 Men 115 (63.8) 121 (62.2)
Transplanted organc 0.27b
 Kidney 134 (73.6) 215 (72.6)
 Liver 16 (8.8) 34 (11.5)
 Heart 25 (13.7) 26 (8.8)
 Simultaneous pancreas–kidney 5 (2.7) 10 (3.4)
History of cardiovascular disease 163 (89.6) 268 (90.5) 0.75b
Diabetes 43 (23.6) 73 (24.7) 0.8b
Immunosuppressive treatment
 Calcineurin inhibitors 143 (78.6) 253 (85.5) 0.08b
 Tacrolimus 137 (75.3) 233 (78.7) 0.43b
 Antimetabolites 127 (69.8) 216 (69.2) 0.35b
 mTOR inhibitors 42 (23.1) 57 (19.3) 0.32b
 Steroids 167 (91.2) 248 (83.8) 0.19b
 Belatacept 38 (20.9) 21 (7.1) <0.01b
SARS-CoV-2 infection during follow-up
 Positive SARS-CoV-2 RNA on a nasopharyngeal sample or positive  anti-N IgG antibody 0 (0) 13 (4.4)d <0.01e
aWilcoxon rank test.
bChi-square test.
cFor more legibility of the statistical analysis, we have reported only the 4 major types of grafts.
dJust before COVID-19, anti–SARS-CoV-2 antibodies were <141 BAU/mL in all patients but 1 (965 BAU/mL). Eleven patients were infected by the Delta variant, 1 by the Alpha variant, and 1 was untypoligible because of low viral load.
eFisher exact test.
BAU, binding antibody unit; COVID-19, coronavirus disease 2019; IgG, immunoglobulin G; IQR, interquartile range; mTOR, mammalian target of rapamycin; NA, not applicable; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Our data show that using preexposure neutralizing anti–SARS-CoV-2 mAbs is efficient for preventing COVID-19 and suggest that a similar strategy might work using neutralizing mAbs with activity against a variety of virus variants, such as Omicron.

REFERENCES

1. O’Brien MP, Forleo-Neto E, Musser BJ, et al.; Covid-19 Phase 3 Prevention Trial Team. Subcutaneous REGEN-COV antibody combination to prevent Covid-19. N Engl J Med. 2021;385:1184–1195.
2. Kamar N, Abravanel F, Marion O, et al. Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients. N Engl J Med. 2021;385:661–662.
3. 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.
4. National French Health Authority. RONAPREVE (casirivimab-imdevimab) (prophylaxie pré-exposition de l’infection à SARS-CoV-2). Available at https://www.has-sante.fr/jcms/p_3281544/fr/ronapreve-casirivimab-imdevimab-prophylaxie-pre-exposition-de-l-infection-a-sars-cov-2. Accessed August 6, 2021.
5. Dimeglio C, Herin F, Martin-Blondel G, et al. Antibody titers and protection against a SARS-CoV-2 infection. J Infect. 2021;84:248–288.

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