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Yang, Hyeon, Baek, Kang, Lee, Lee, Huh, Cho, Kang, Chung, Peck, Won, Lee, Kim, Hwang, Lee, Kim, Lee, and Ko: Loss of Neutralizing Activity of Tixagevimab/Cilgavimab (Evusheld™) Against Omicron BN.1, a Dominant Circulating Strain Following BA.5 During the Seventh Domestic Outbreak in Korea in Early 2023
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Infectious Diseases, Microbiology & Parasitology

Journal of Korean Medical Science 2023; 38(27): e205.

Published online: 30 May 2023

DOI: https://doi.org/10.3346/jkms.2023.38.e205

Loss of Neutralizing Activity of Tixagevimab/Cilgavimab (Evusheld™) Against Omicron BN.1, a Dominant Circulating Strain Following BA.5 During the Seventh Domestic Outbreak in Korea in Early 2023

Jinyoung Yang1, *, Seokhwan Hyeon2, *, Jin Yang Baek1, 3, Min Seo Kang1, Keon Young Lee1, Young Ho Lee1, Kyungmin Huh1, Sun Young Cho1, Cheol-In Kang1, Doo Ryeon Chung1, Kyong Ran Peck1, Gunho Won2, Hye Won Lee2, Kwangwook Kim2, Insu Hwang2, So Yeon Lee2, Byung Chul Kim2, Yoo-kyoung Lee2, Jae-Hoon Ko1

1Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

2Division of Vaccine Development Coordination, Center for Vaccine Research, National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju, Korea.

3Asia Pacific Foundation for Infectious Diseases (APFID), Seoul, Korea.

Address for Correspondence: Yoo-kyoung Lee, DVM. Division of Vaccine Development Coordination, Center for Vaccine Research, National Institute of Infectious Diseases, National Institute of Health, Korea Disease Control and Prevention Agency, 212 Osongsaengmyeong 2-ro, Osong-eup, Heungdeok-gu, Cheongju 28160, Republic of Korea. leeykyoung@korea.kr

Address for Correspondence: Jae-Hoon Ko, MD, PhD. Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea. jaehoon.ko@gmail.com

Equal contributor:

*Jinyoung Yang and Seokhwan Hyeon contributed equally to this article.

Received 17 April 2023       Accepted 16 May 2023

© 2023 The Korean Academy of Medical Sciences.

The Korean Academy of Medical Sciences

https://creativecommons.org/licenses/by-nc/4.0/
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Tixagevimab/cilgavimab is a monoclonal antibody used to prevent coronavirus disease 2019 among immunocompromised hosts and maintained neutralizing activity against early omicron variants. Omicron BN.1 became a dominant circulating strain in Korea early 2023, but its susceptibility to tixagevimab/cilgavimab is unclear. We conducted plaque reduction neutralization test (PRNT) against BN.1 in a prospective cohort (14 patients and 30 specimens). BN.1 PRNT was conducted for one- and three-months after tixagevimab/cilgavimab administration and the average PRNT ND50 of each point was lower than the positive cut-off value of 20 (12.9 ± 4.5 and 13.2 ± 4.2, respectively, P = 0.825). In the paired analyses, tixagevimab/cilgavimab-administered sera could not actively neutralize BN.1 (PRNT ND50 11.5 ± 2.9, P = 0.001), compared with the reserved activity against BA.5 (ND50 310.5 ± 180.4). Unlike virus-like particle assay, tixagevimab/cilgavimab was not active against BN.1 in neutralizing assay, and would not be effective in the present predominance of BA.2.75 sublineages.

Graphical Abstract

jkms-38-e205-abf001.jpg

Keywords: COVID-19, SARS-CoV-2, Evusheld, Neutralizing Antibody, BN.1 Variant

Since omicron variant (B.1.1.529) became the fifth variant of concern (VOC) on November 26, 2021, omicron sublineages have led the coronavirus disease 2019 (COVID-19) outbreaks to date.123 The diversity of circulating omicron sublineages, so called ‘variant soup,’ makes it more difficult to expect outbreak situation and potential effect of monoclonal antibody agents than before.4 Unlike previous outbreak waves that were dominated by one or two dominant circulating variants,15 the seventh domestic outbreak wave of Korea, which began on late October 2022 and ended on February 2023, showed a transition of dominant circulating variant from BA.5 to BN.1 with a mixture of other omicron sublineages. BA.5, BA.2.75, and XBB variants were derived from BA.2, and CH.1, CJ.1, and BN.1 were included in the sublineage of BA.2.75. Fig. 1A presents the distribution of omicron sublineages in Korea from early 2022 to March 2023, along with sampling points of the study population. Tixagevimab/cilgavimab (Evusheld™; AstraZeneca, London, UK), a monoclonal antibody agent used to prevent COVID-19 among immunocompromised (IC) patients, was introduced in Korea on August, 2022, during the sixth domestic outbreak wave dominated by BA.5.1 In previous publication, we demonstrated neutralizing activity of tixagevimab/cilgavimab against BA.5 comparable with healthy vaccinated individuals who experienced BA.1/BA.2 breakthrough infections, providing background evidence of tixagevimab/cilgavimab use during BA.5 dominance.1 However, further experimental data about tixagevimab/cilgavimab activity against newly circulating strains, especially against BN.1, is required for its continuous use. Although the U.S. Food and Drug Administration-approved fact sheet of tixagevimab/cilgavimab suggested a moderately reduced activity against BN.1 (68-fold reduction), similar to that against BA.5 (33- to 65-fold reduction), but these data were based on the experiment of antibody-dependent viral entry into FcγRII-expressing Raji cells using recombinant virus-like particles (VLPs) pseudotyped with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins.6 To provide essential data whether to continue tixagevimab/cilgavimab use in Korea during BN.1 predominating period, we conducted the plaque reduction neutralization test (PRNT) against BN.1 and reviewed currently circulating strains and published data.
A prospective cohort study was conducted in a tertiary care hospital in Korea. Current indications for tixagevimab/cilgavimab administration in Korea were those who have not been diagnosed to be SARS-CoV-2 positive within seven days, who are ≥ 12 years of age, weigh ≥ 40kg, and meet one of the following conditions: 1) those receiving immunosuppressive therapy or high-intensity chemotherapy, 2) those who have received hematopoietic stem cell transplant or chimeric antigen receptor T cell therapy within six months, 3) those who have received a solid organ transplant within one year, 4) those who have human immunodeficiency virus infection and are not expected to have CD4 T cell ≥ 200/mm2 with sufficient treatment, and 5) those who have primary immunodeficiency. A total of 19 IC patients who met the above criteria were prospectively recruited, and received either 300 mg (n = 5) or 600 mg (n = 14) of tixagevimab/cilgavimab, based on the patient’s discretion (the same cohort participated in the previous publication1). Blood sampling was conducted before and one, three, six months after tixagevimab/cilgavimab administration. During the follow-up period, specimens collected after administration of additional dose of tixagevimab/cilgavimab, intravenous immune globulin (IVIG), COVID-19 vaccination, or diagnosis of breakthrough infections were excluded from the present analysis.
The laboratory procedures were provided in the previous publication.1 In brief, an electrochemiluminescence immunoassay kit (Elecsys Anti-SARS-CoV-2 S; Roche diagnostics, Basel, Switzerland) was used for the semi-quantitative measurement of anti-SARS-CoV-2 spike protein antibody (Sab). BN.1 sublineage (NCCP No. 43439) was utilized for BN.1 PRNT. To compare laboratory test results, Student’s t-test was used. A linear regression model was utilized to assess the correlations between antibody titers and timeline. For the interpretation of the correlation coefficient, R2 ≥ 0.7 was considered a strong correlation, R2 ≥ 0.4 a moderate correlation, and R2 < 0.4 a weak Correlation.7 All P values were two-sided tests, and those < 0.05 were considered statistically significant. GraphPad Prism version 9.4.1 (GraphPad Software, San Diego, CA, USA) was used for all statistical analyses.
Baseline characteristics of 19 IC patients were previously presented.1 In brief, average age was 53.9 ± 13.8 years old and 13 (68.4%) were male. Nine (47.4%) patients had B-cell malignancy, nine (47.4%) received solid organ transplantation, and one (5.3%) had Good’s syndrome. Thirteen (68.4%) patients received at least two doses of vaccination and 10 (52.6%) patients had a previous history of SARS-CoV-2 infection. The Sab level at baseline sampling (624.8 ± 975.8 BAU/mL) was lower than the range of the 3rd vaccine response of a healthy adult cohort (range, 3,719.0–38,544.0 BAU/mL), and six patients (31.6%) showed negative result.1
Fig. 1B shows a waning kinetics of 14 IC patients who received 600 mg of tixagevimab/cilgavimab. A total of 30 specimens were evaluated and log10 Sab BAU/mL linearly decreases over time after tixagevimab/cilgavimab with a strong correlation (R2 = 0.921, P < 0.001). Based on a correlation equation deduced from the linear regression analysis (Log10 Sab BAU/mL = −0.1742*[months] + 4.145), the peak Sab (10,136 ± 1,513 BAU/mL) measured one month after administration decreased to a half level approximately 3.5 months after administration. When the total 19 IC patients including five patients receiving 300 mg of tixagevimab/cilgavimab, the Sab level measured one month after administration (8,953 ± 2,715 BAU/mL) was decreased to less than half two months later (three months after administration, 3,602 ± 1,360 BAU/mL, P < 0.001; Fig. 1C). The same specimens were tested for BN.1 PRNT, and the average ND50 were lower than the positive cut-off value at both one- and three-months after tixagevimab/cilgavimab administration (12.9 ± 4.5 and 13.2 ± 4.2, respectively, P = 0.825; Fig. 1D). When the specimens collected one month after administration were compared with BA.5 PRNT in pair (14 specimens), it was apparently noticed that the specimens could actively neutralize BA.5 (ND50 310.5 ± 180.4), but not BN.1 (ND50 11.5 ± 2.9, P = 0.001; Fig. 1E).
Since the beginning of COVID-19 pandemic, many anti-SARS-CoV-2 monoclonal antibody agents have been developed.8910 Despite their clinical effectiveness, most of them were withdrawn from the market due to rapidly emerging SARS-CoV-2 variants. Also, short half-life of monoclonal antibody limited its usage only to the prevention of disease progression at the early phase of infection. Tixagevimab/cilgavimab was developed with two successful strategies to overcome these limitations. To overcome spike protein mutations of emerging variants, it was designed as a cocktail of two difference monoclonal antibodies that simultaneously bind to distinct non-overlapping epitopes of the viral spike protein.11 An extended half-life was obtained by reengineering Fc variant amino acids, and therefore it could be used for pre-exposure prophylaxis in addition to early outpatient treatment, especially for poor vaccine responders such as organ transplant recipients or patients with hematologic malignancies.111213141516 Despite mild to moderate decrease of antiviral activity against early omicron sublineages, including BA.1, BA.2, BA.4, and BA.5, it could be used during the omicron dominated outbreak period of 2022, by increasing dosage from 300 to 600 mg.18 As it would not be feasible to perform neutralizing tests against all the newly emerging strains of live viruses, the manufacturer utilized VLP assay to reflect mutations of spike proteins.6 However, unlike VLP assay result that exhibited moderately decreased activity to BN.1, similar with BA.5, tixagevimab/cilgavimab was not active against BN.1 in the present analysis. Such discrepancy was also noticed for BA.2.75 in the other publication.17 Although BA.2.75 was reported to have moderately reduced susceptibility in the pseudotyped VLP assay, BA.2.75 was not susceptible in neutralizing assay.17
To interpret the present investigation in the context of domestic outbreak situation, we summarized detection rates of SARS-CoV-2 variants in Korea during the first quarter of 2023 and published data (Table 1). Among the major circulating variants, BA.5 was the only strain known to be susceptible against tixagevimab/cilgavimab but the proportions rapidly decreased to 4.0% in March 2023. Sublineages of BA.2.75 are in increasing trend. BA.2.75 was reported to have moderately reduced susceptibility in the pseudotyped VLP assay, but was not susceptible in neutralizing assay in another report.17 Likewise, BN.1 reported to have moderately reduced susceptibility in the pseudotyped VLP assay but was not susceptible in the present analysis. Taken together, the outbreak situation of the first quarter of 2023 is characterized with increasing trend of BA.2.75 sublineages, most of which show loss of susceptibility to tixagevimab/cilgavimab.
The present study has several limitations. First, the number of enrolled patients was small and most of them were kidney transplant recipients and lymphoma patients. Nevertheless, we conducted a serial sampling up to six months after administration and exhibited a linear waning of Sab titers. The BN.1 PRNT was conducted for two time points and also compared with BA.5 PRNT. These results clearly presented loss of susceptibility of BN.1 to tixagevimab/cilgavimab and provides essential information on the practical decision whether to continue use of tixagevimab/cilgavimab. Second, PRNT against other circulating BA.2.75 sublineages, including CJ.1 and CH.1.1 was not conducted. Considering the same discrepant pattern between VLP assay and neutralizing test was noticed in BA.2.75 and BN.1, it would be less likely that these BA.2.75 sublineages would be susceptible to tixagevimab/cilgavimab. Tixagevimab/cilgavimab is no longer authorized in the United States as of January 26, 2023. Since it would not be effective against currently circulating SARS-CoV-2 variants, tixagevimab/cilgavimab should not be prescribed in current outbreak situation of Korea as well.
In conclusion, unlike VLP assay, this study using neutralizing test did not show activity of tixagevimab/cilgavimab against BN.1, the dominant circulating strain in Korea during the first quarter of 2023. Tixagevimab/cilgavimab would be less likely to be effective in the present predominance of BA.2.75 sublineages.

Ethics Statement

Informed consent was obtained from all the participants and this study was approved by Samsung Medical Center Institutional Review Board (SMC 2020-03-113 and 2021-11-050).

ACKNOWLEDGMENTS

The authors would like to express their gratitude to all participants who participated voluntarily in this study.

Notes

Funding: This study was supported by a research program fund (#2021-ER2303-00) from the Korea Disease Control and Prevention Agency and a Samsung Medical Center Grant (#SMO1230121).

Disclosure: The authors have no potential conflicts of interest to disclose.

Author Contributions:

  • Conceptualization: Yang J, Won G, Kim BC, Lee YK, Ko JH.

  • Data curation: Yang J, Kang MS, Lee KY, Lee YH, Huh K, Cho SY, Kang CI, Chung DR, Peck KR, Ko JH.

  • Formal analysis: Yang J, Won G, Lee HW, Kim K, Hwang I, Lee SY, Ko JH.

  • Investigation: Yang J, Hyeon S, Baek JY, Won G, Lee HW, Kim K, Hwang I, Lee SY.

  • Methodology: Yang J, Hyeon S, Baek JY, Won G, Lee HW, Kim K, Hwang I, Lee SY.

  • Writing - original draft: Yang J, Won G, Lee YK, Ko JH.

  • Writing - review & editing: Ko JH.

References

1. Yang J, Won G, Baek JY, Lee YH, Kim H, Huh K, et al. Neutralizing activity against omicron BA.5 after tixagevimab/cilgavimab administration comparable to those after omicron BA.1/BA.2 breakthrough infections. Front Immunol. 2023; 14:1139980. PMID: 36936968.
2. World Health Organization. Classification of omicron (B.1.1.529): SARS-CoV-2 variant of concern. Updated 2021. Accessed on April 10, 2023. https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern .
3. Lee JJ, Choe YJ, Jeong H, Kim M, Kim S, Yoo H, et al. Importation and transmission of SARS-CoV-2 B.1.1.529 (omicron) variant of concern in Korea, November 2021. J Korean Med Sci. 2021; 36(50):e346. PMID: 34962117.
4. Callaway E. COVID ‘variant soup’ is making winter surges hard to predict. Updated 2022. Accessed on April 10, 2023. https://www.nature.com/articles/d41586-022-03445-6 .
5. Ahn S, Jang J, Park SY, Yang S, Ryu B, Shin E, et al. Outbreak report of COVID-19 during designation of class 1 infectious disease in the Republic of Korea (January 20, 2020–April 24, 2022). Public Health Wkly Rep. 2022; 15(30):2126–2136.
6. U.S. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Evusheld™ (tixagevimab co-packaged with cilgavimab). Updated 2023. Accessed April 28, 2023. https://www.fda.gov/media/154701/download .
7. Schober P, Boer C, Schwarte LA. Correlation coefficients: appropriate use and interpretation. Anesth Analg. 2018; 126(5):1763–1768. PMID: 29481436.
8. National Institutes of Health. Anti-SARS-CoV-2 monoclonal antibodies, COVID-19 treatment guidelines. Updated 2023. Accessed on April 10, 2023. https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/anti-sars-cov-2-monoclonal-antibodies/ .
9. Lee JY, Lee JY, Ko JH, Hyun M, Kim HA, Cho S, et al. Effectiveness of regdanvimab treatment in high-risk COVID-19 patients to prevent progression to severe disease. Front Immunol. 2021; 12:772320. PMID: 34899724.
10. Park S, Je NK, Kim DW, Park M, Heo J. Effectiveness and safety of regdanvimab in patients with mild-to-moderate COVID-19: a retrospective cohort study. J Korean Med Sci. 2022; 37(13):e102. PMID: 35380027.
11. Loo YM, McTamney PM, Arends RH, Abram ME, Aksyuk AA, Diallo S, et al. The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans. Sci Transl Med. 2022; 14(635):eabl8124. PMID: 35076282.
12. Levin MJ, Ustianowski A, De Wit S, Launay O, Avila M, Templeton A, et al. Intramuscular AZD7442 (tixagevimab-cilgavimab) for prevention of Covid-19. N Engl J Med. 2022; 386(23):2188–2200. PMID: 35443106.
13. Montgomery H, Hobbs FDR, Padilla F, Arbetter D, Templeton A, Seegobin S, et al. Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2022; 10(10):985–996. PMID: 35688164.
14. Oh YJ, Kim J, Kang ES, Rhu J, Choi GS, Joh JW. Analysis of antibody responses after COVID-19 vaccination in liver transplant recipients: a single-center study. J Korean Med Sci. 2023; 38(16):e121. PMID: 37096307.
15. Yang J, Lee KW, Baek JY, Bae S, Lee YH, Kim H, et al. Augmented humoral and cellular immunity against severe acute respiratory syndrome coronavirus 2 after breakthrough infection in kidney transplant recipients who received 3 doses of coronavirus disease 2019 vaccine. Am J Transplant. 2023; 23(4):565–572. PMID: 36739177.
16. Song SH, Chung KY, Jee Y, Chung HS, Kim K, Minn D, et al. Immunogenicity of SARS-CoV-2 vaccine in kidney transplant recipients: a cross-sectional study in Korea. J Korean Med Sci. 2023; 38(5):e22. PMID: 36747360.
17. Planas D, Bruel T, Staropoli I, Guivel-Benhassine F, Porrot F, Maes P, et al. Resistance of omicron subvariants BA.2.75.2, BA.4.6, and BQ.1.1 to neutralizing antibodies. Nat Commun. 2023; 14(1):824. PMID: 36788246.
Fig. 1

Schematic view of the study and antibody kinetics after administration of tixagevimab/cilgavimab 600 mg. (A) Schematic view of the study, presented along with SARS-CoV-2 variant distribution in Korea from January 2022 to March 2023. We revised and extended the period of the Fig. 1 in the previously published article.1 After administration of tixagevimab/cilgavimab 600 mg, log10 Sab BAU/mL values exhibited a linearly waning kinetics (B). Compared to the peak point measured one month after admininistartion, a significant reduction of Sab titers was noticed after three months (C). PRNT ND50 titers against BN.1 were low at both points without significant difference, most of which were under the positive cut-off value of 20 (D). When the values of the peak point were compared, PRNT ND50 against BN.1 were significantly lower than that against BA.5 (E) unlike previously reported pseudotyped VLPs assay.6

IC = immunocompromised, Sab = anti-spike protein antibody, BAU = binding antibody unit, PRNT = plaque reduction neutralization test, ND50 = 50% neutralizing dose, VLP = virus-like particles, ns = not significant.
aExcept for BN.1, the proportion of which is presented separately.
***P < 0.001.
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Table 1

Tixagevimab/cilgavimab susceptibility of SARS-CoV-2 variants circulating during the first quarter of 2023 in the Republic of Korea

jkms-38-e205-i001
Pango lineage and WHO classification (as of 30 March 2023) Average detection rate in Republic of Koreaa Effect of tixagevimab/cilgavimab
U.S. FDA factsheet6 NIH treatment guideline8
Category December 2022 January 2023 February 2023 March 2023 Susceptibility (VLPsb) Susceptibility (Authentic virus) In vitro susceptibility Anticipated clinical activity
BA.5 sublineages
BA.5 Total 49.2 25.7 9.8 4.0 33- to 65-fold reduction 2.8- to 16-fold reduction Moderate reduction Active
Dom/Imp 52.1/33.0 24.3/14.6 9.8/10.9 4.0/4.9
BQ.1 (VUM) Total 6.4 8.3 7.8 9.9 > 2,000-fold reduction ND Marked reduction Unlikely to be active
Dom/Imp 5.6/10.8 8.7/5.7 7.9/5.4 11.8/5.1
BQ.1.1 Total 5.2 8.3 3.4 NR > 2,000-fold reduction ND Marked reduction Unlikely to be active
Dom/Imp 3.9/11.8 3.8/8.6 2.9/5.4
BF.7 Total 3.7 4.9 2.2 NR > 5,000-fold reduction ND Marked reduction Unlikely to be active
Dom/Imp 3.4/5.2 3.1/13.9 2.0/6.3
BA.2.75 sublineages
BA.2.75 (VUM) Total 6.6 10.0 7.2 3.7 2.4- to 15-fold reduction ND Loss of activity against BA.2.75.2 was previously reported.17
Dom/Imp 6.6/6.6 10.8/5.8 7.3/5.1 3.7/2.4
CJ.1 Total NR NR NR 4.8 ND ND NR NR
Dom/Imp 5.0/1.0
CH.1.1 (VUM) Total NR NR 5.7 5.5 ND ND NR NR
Dom/Imp 5.9/3.0 5.6/3.1
BN.1 Total 23.9 41.7 58.0 53.1 68-fold reduction ND Not susceptible in the present analysis
Dom/Imp 24.2/23.1 44.9/24.0 59.4/32.1 54.7/20.3
XBB sublineages
XBB.1.5 (VOI) Total NR 0.6 2.1 10.1 > 5,000-fold reduction ND Marked reduction Unlikely to be active
Dom/Imp 0.3/2.8 1.5/12.4 8.8/39.8
XBB.1.9.1 Total NR NR NR 2.8 ND ND NR NR
Dom/Imp 2.6/7.6
The data of FDA factsheet and NIH treatment guideline are accessible online via the webpage provided in the references.6 , 8
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, WHO = World Health Organization, FDA = Food and Drug Administration, NIH = National Institutes of Health, VLP = virus-like particles, Dom = domestic, Imp = imported, VUM = variants under monitoring, VOI = variants of interest, NR = not reported, ND = not determined.
aAccording to the weekly report from the Korea Disease Control and Prevention Agency.
bThe manufacturer assessed the potential of tixagevimab/cilgavimab to mediate antibody-dependent viral entry in FcγRII-expressing Raji cells co-incubated with recombinant VLPs pseudotyped with SARS-CoV-2 spike protein, with antibody concentrations at a range of 6.6 nM (1 µg/mL) to 824 pM (125 ng/mL).6
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