Differential serum neutralisation of omicron sublineages in patients receiving prophylaxis with tixagevimab-cilgavimab.

Monoclonal antibodies against SARS-CoV-2 have been useful prophylactic and therapeutic tools in patients at high risk of severe COVID-19. However, the use of this approach depends on the SARS-CoV-2 variant.1Levin MJ Ustianowski A De Wit S et al.Intramuscular AZD7442 (tixagevimab–cilgavimab) for prevention of COVID-19.N Engl J Med. 2022; 386: 2188-2200Crossref PubMed Scopus (266) Google Scholar Because of the rapidly changing variants, in-vitro neutralisation data using relative fold-changes in effective concentration (EC50) are frequently used to decide whether a given monoclonal antibody will be effective for a variant.2US Food and Drug AdministrationFDA announces Evusheld is not currently authorized for emergency use in the U.S.https://www.fda.gov/drugs/drug-safety-and-availability/fda-announces-evusheld-not-currently-authorized-emergency-use-usDate accessed: February 17, 2023Google Scholar However, these data are difficult to interpret if the serum concentration of the monoclonal antibody is not known. Therefore, a more clinically relevant way is to directly test variant-specific neutralisation from serum samples obtained from patients who have received the monoclonal antibody (in-vivo method). In-vitro data show a substantial reduction in tixagevimab–cilgavimab activity against omicron BA.4/5, BQ.1.1, and XBB.1.5.3Wang Q Iketani S Li Z et al.Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants.Cell. 2023; 186 (e8): 279-286Summary Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 4Tuekprakhon A Nutalai R Dijokaite-Guraliuc A et al.Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum.Cell. 2022; 185 (e13): 2422-2433Summary Full Text Full Text PDF PubMed Scopus (280) Google Scholar However, it has been noted that serum monoclonal antibody levels are between 10 and 1000-fold greater than required to achieve 90% of the maximal efficacy against ancestral (Wuhan-like) virus.5Stadler E Chai KL Schlub TE et al.Determinants of passive antibody effectiveness in SARS-CoV-2 infection.medRxiv. 2022; (published online Jan 1.) (preprint).https://www.medrxiv.org/content/10.1101/2022.03.21.22272672v1PubMed Google Scholar Therefore, clinical efficacy might not be completely lost even if there is in-vitro resistance. We did a prospective single-arm study to test the effect of a 300 mg dose of tixagevimab–cilgavimab on omicron neutralisation in recipients of organ transplantations who are immunosuppressed. A pseudovirus neutralisation assay was used to determine neutralising antibody activity against omicron sublineages (BA.4/5, BQ.1.1, XBB.1.5) in serum collected at day 0 and at week 3 after the administration of 300 mg of tixagevimab–cilgavimab (appendix pp 1–2). Results were expressed in log10 of the inhibitory dilution with 50% virus neutralisation (ID50). The primary outcome was the proportion of patients that had detectable neutralisation at 3 weeks after injection. Patients were followed for two months after administration for breakthrough COVID-19. We enrolled 79 recipients of organ transplantation and analysed 75 who had paired samples at baseline and week 3. The median age of the analysed population was 66 years (interquartile range [IQR], 55·2–68·8), and 70·7% were men. Organ types included 25 (33·3%) lung, 20 (26·7%) heart, 14 (18·7%) kidney, 8 (10·7%) liver, and 8 (10·7%) combined transplantations. The cohort was highly vaccinated against COVID-19, with all patients having previously received 3 or more doses of mRNA vaccine. 17 (22·7%) patients had a previous episode of COVID-19, with a median time from infection to tixagevimab–cilgavimab administration of 147 days (IQR 123–233). Before receiving tixagevimab–cilgavimab, 30 (40%) of 75 patients had detectable neutralisation against omicron BA.4/5, 25 (33·3%) had detectable neutralization against BQ.1.1, and 19 (25·3%) had detectable neutralisation against XBB.1.5. Since both BQ.1.1 and XBB.1.5 evade immunity conferred by vaccination, the presence of baseline neutralisation might have been driven by previous infection.6Uraki R Ito M Furusawa Y et al.Humoral immune evasion of the omicron subvariants BQ.1.1 and XBB.Lancet Infect Dis. 2023; (published online Dec 7.)https://doi.org/10.1016/S1473-3099(22)00816-7Summary Full Text Full Text PDF Scopus (36) Google Scholar Patients with documented previous COVID-19 infection were more likely at baseline to have BQ.1.1 neutralisation (odds ratio [OR] 4·1, 95% CI 1·3–12·7) and XBB.1.5 neutralisation (OR 5·4, 95% CI 1·7–17·4). 3 weeks after receiving tixagevimab–cilgavimab, 74 (98·7%) of the 75 patients had detectable BA.4/5 neutralisation, and median antibody titre increased from 0 log10 ID50 (IQR 0–2·2) to 2·8 (IQR 2·6–3·0), p<0·001 (figure A). However, neutralisation against BQ.1.1 and XBB.1.5 did not improve at week 3, with detectable neutralisation in only 24 (32·0%) of 75 patients against BQ.1.1 and 19 (25·3%) patients against XBB.1.5. Also, the antibody titre at week 3 did not significantly change compared with baseline for either BQ.1.1 or XBB.1.5 (figure B). Six (8%) of 75 patients had breakthrough COVID-19 during the 2-month follow-up period. Two (33%) of them required hospitalisation and supplementary oxygen. None were admitted to the ICU or died. Variant sequencing was available from two patients and showed the BA.4/5 sublineage in both. We show that serum from patients who received tixagevimab–cilgavimab was capable of neutralising BA.4/5 in almost all cases even though published in-vitro data have shown a 10–100-fold change in EC50 compared with the B.1 variant.7Arora P Kempf A Nehlmeier I et al.Omicron sublineage BQ.1.1 resistance to monoclonal antibodies.Lancet Infect Dis. 2023; 23: 22-23Summary Full Text Full Text PDF PubMed Scopus (41) Google Scholar However, no neutralisation was noted for BQ.1.1 and XBB.1.5, for which in-vitro data shows a change in EC50 of more than 3 log10-fold.7Arora P Kempf A Nehlmeier I et al.Omicron sublineage BQ.1.1 resistance to monoclonal antibodies.Lancet Infect Dis. 2023; 23: 22-23Summary Full Text Full Text PDF PubMed Scopus (41) Google Scholar Our results suggest that in-vitro data correlate with serum neutralisation at high levels of resistance. However, lower levels of in-vitro resistance should be corroborated by patient samples where possible. In summary, our findings suggest clinically relevant activity of tixagevimab–cilgavimab against BA.4/5 but minimal use against BQ.1.1 and XBB.1.5 in patients at risk of severe COVID-19. AH and DK contributed equally. The study was funded in part by the COVID-19 Immunity Task Force via the Public Health Agency of Canada (grant number 2122-HQ-000067 to DK). DK has received clinical trials grants from GSK and Roche and consultancy fees from GSK, Roche, Merck, Takeda, and Exevir. AH has received a clinical trials grant from Merck and consultancy fees from Merck and Takeda. A-CG has received research funds from a research contract with Providence Therapeutics Holdings for other projects. All other authors declare no competing interests. Download .pdf (.31 MB) Help with pdf files Supplementary appendix