Omicron breakthrough infection in a kidney-transplant patient given pre-exposition casirivimab and imdevimab monoclonal antibodies.

coronavirus disease‐19

messenger RNA

Severe Acute Respiratory Syndrome coronavirus 2

Despite three doses of Severe Acute Respiratory Syndrome coronavirus 2 (SARS‐CoV‐2) vaccine, the humoral response and consequently the clinical protection remain low in immunosuppressed patients, particularly in solid‐organ‐transplant patients. , Approximately two‐third of patients develop anti‐SARS‐CoV‐2 antibodies at 1 month after three doses vaccine. However, 30% of patients of them have an anti‐S concentration <141 BAU/mL. In a cohort of healthcare workers, it has been shown that this threshold provides only 12.4% protection against SARS‐CoV‐2. In France, the French authorities for Health recommended to offer pre‐exposition neutralizing casirivimab and imdevimab monoclonal antibodies in immunosuppressed patients with no or weak response to three doses of SARS‐CoV‐2 vaccine. Patients having anti‐S concentration <30 BAU/mL after three doses vaccine were considered as weak responders by the health authorities. Casirivimab and imdevimab monoclonal antibodies had to be given monthly independently of the anti‐S concentration, although it was mandatory to be measured just before each infusion.

Hence, between August and December 2021, 436 solid‐organ‐transplant patients followed in our department were given pre‐exposition casirivimab and imdevimab 1 month apart (600:600 mg for the first dose and 300:300 mg thereafter). Before each injection, patients had to provide a negative SARS‐CoV‐2 PCR in nasopharyngeal swab, and anti‐N and anti‐S antibodies were performed just before the infusion. The measurement of anti‐S concentration was performed to assess the pharmacokinetic of antibodies and to determine whether the infusions can be spaced. Anti‐N was assessed to determine whether patients were infected by SARS‐CoV‐2 despite the use of prophylactic monoclonal antibodies. Nevertheless, anti‐N and anti‐S concentrations did not affect treatment decision. A SARS‐CoV‐2 PCR and antinucleocapsid antibodies were also done in symptomatic patients. Anti‐N and anti‐S antibodies were assessed using Alinity (SARS‐CoV‐2 antinucleocapsid IgG and SARS‐CoV‐2 IgG II Quant, Abbott Ireland, Diagnostic Division, Sligo, Ireland) before each injection.

Through 10 January 2022, one of the 436 patients had a breakthrough coronavirus disease‐19 (COVID‐19) infection diagnosed. The latter is a 69‐year‐old kidney transplant patient who had received a kidney transplant in September 2020 for nephroangiosclerosis. His maintenance immunosuppressive regimen was based on tacrolimus‐everolimus and steroids. Despite three doses of BNT 162b2 messenger RNA (mRNA) COVID‐19 vaccine, he did not develop antispike protein antibodies. Consequently, we initiated pre‐exposition casirivimab and imdevimab on August 30th (600:600 mg). A second injection was given on September 24th (300:300 mg). Due to the decrease of the incidence of SARS‐CoV‐2 in our area in October and November (<50/100 000 inhabitants), the third dose was postponed and was given on December 7th when the incidence increased again above 100/100 000 inhabitants. On December 21th, that is, 14 days after the last injection of casirivimab and imdevimab, he presented with fever, fatigue, and diarrhea. SARS‐CoV‐2 PCR was positive. Viral sequencing revealed Omicron variant (No E484K, E484Q, L452R mutation and presence of 69/70 deletion and K417N mutation). At admission, anti‐S antibodies concentration was at 5623 BAU/mL. It was nil before the first monoclonal antibodies injection, 7613 BAU/mL just before the second injection, and 2156 BAU/mL before the third injection. The patient required nasal oxygen. Chest CT scan revealed mild COVID‐related lesions. Everolimus was transiently stopped and dexamethasone was given. The patient discharged 6 days after the diagnosis.

Our report shows the utility of the concept of pre‐exposure prophylaxis. No patient who was given prophylaxis was infected by the delta variant. Conversely, to our knowledge, this is the first case of SARS‐CoV‐2 breakthrough in patients given pre‐exposition casirivimab and imdevimab. It occurred despite a high concentration of anti‐S antibodies. In healthcare workers, an anti‐S concentration above 1700 BAU/mL conferred a 100% protection against non‐Omicron variants. This observation confirms that very high levels of anti‐S antibodies are required to prevent Omicron infection.

It was recently shown in vitro that the Inhibitory Concentrations (IC50) of casirivimab, imdevimab, or their combination against Omicron variants were >9000 ng/mL. Hoffmann et al. confirmed that entry driven by the Omicron spike was fully resistant against imdevimab and casirivimab. Currently, Evushled, a combination of two monoclonal antibodies cilgavimab and tixagevimab, is authorized in several countries, including the United States, to be used prophylactically. In vitro, the IC50 of cilgavimab, tixagevimab, or their combination against Omicron variants were 1079, >9000, and 1355 ng/mL, respectively. Clinical reports are mandatory to assure that Evushled is efficient to prevent Omicron infection. Finally, it was shown that sotrovimab is efficient for early treatment of COVID‐19 and is remains active against Omicron. The IC50 of sotrovimab is 1114 ng/mL. However, there is no data to support the use of sotrovimab prophylactically and it is not approved in this setting. Further studies are required to identify the best strategy to prevent SARS‐CoV‐2 infection in immunosuppressed patients without humoral response to full vaccination.

CONFLICT OF INTEREST

The authors declare no conflict of interest.