Protective Non-neutralizing anti-N-terminal Domain mAb Maintains Fc-mediated Function against SARS-COV-2 Variants up to BA.2.86-JN.1 with Superfluous In Vivo Protection against JN.1 Due to Attenuated Virulence
(2024) In Journal of immunology 213(5). p.678-689- Abstract
Substantial evidence supports that Fc-mediated effector functions of anti-spike Abs contribute to anti-SARS-Cov-2 protection. We have previously shown that two non-neutralizing but opsonic mAbs targeting the receptor-binding domain and N-terminal domain (NTD), Ab81 and Ab94, respectively, are protective against lethal Wuhan SARS-CoV-2 infection in K18-hACE2 mice. In this article, we investigated whether these protective non-neutralizing Abs maintain Fc-mediated function and Ag binding against mutated SARS-CoV-2 variants. Ab81 and Ab94 retained their nanomolar affinity and Fc-mediated function toward Omicron and its subvariants, such as BA.2, BA.4, BA.5, XBB, XBB1.5, and BQ1.1. However, when encountering the more heavily mutated BA.2.86,... (More)
Substantial evidence supports that Fc-mediated effector functions of anti-spike Abs contribute to anti-SARS-Cov-2 protection. We have previously shown that two non-neutralizing but opsonic mAbs targeting the receptor-binding domain and N-terminal domain (NTD), Ab81 and Ab94, respectively, are protective against lethal Wuhan SARS-CoV-2 infection in K18-hACE2 mice. In this article, we investigated whether these protective non-neutralizing Abs maintain Fc-mediated function and Ag binding against mutated SARS-CoV-2 variants. Ab81 and Ab94 retained their nanomolar affinity and Fc-mediated function toward Omicron and its subvariants, such as BA.2, BA.4, BA.5, XBB, XBB1.5, and BQ1.1. However, when encountering the more heavily mutated BA.2.86, Ab81 lost its function, whereas the 10 new mutations in the NTD did not affect Ab94. In vivo experiments with Ab94 in K18-hACE2 mice inoculated with a stringent dose of 100,000 PFU of the JN.1 variant revealed unexpected results. Surprisingly, this variant exhibited low disease manifestation in this animal model with no weight loss or death in the control group. Still, assessment of mice using a clinical scoring system showed better protection for Ab94-treated mice, indicating that Fc-mediated functions are still beneficial. Our work shows that a protective anti-receptor-binding domain non-neutralizing mAb lost reactivity when BA.2.86 emerged, whereas the anti-NTD mAb was still functional. Finally, this work adds new insight into the evolution of the SARS-CoV-2 virus by reporting that JN.1 is substantially less virulent in vivo than previous strains.
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- author
- Izadi, Arman LU ; Godzwon, Magdalena LU ; Söderlund Strand, Anna LU ; Schmidt, Tobias LU ; Kumlien Georén, Susanna ; Drosten, Christian ; Ohlin, Mats LU and Nordenfelt, Pontus LU
- organization
-
- Quantitative immunobiology (research group)
- LTH Profile Area: Engineering Health
- Department of Immunotechnology
- Division of Medical Microbiology
- Center of Pediatric Rheumatology (research group)
- LU-ATMP: Lund University Advanced Therapy Medicinal Products
- LUCC: Lund University Cancer Centre
- LU Profile Area: Light and Materials
- LTH Profile Area: Nanoscience and Semiconductor Technology
- NanoLund: Centre for Nanoscience
- LTH Profile Area: Photon Science and Technology
- epIgG (research group)
- SEBRA Sepsis and Bacterial Resistance Alliance (research group)
- publishing date
- 2024-07-17
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of immunology
- volume
- 213
- issue
- 5
- pages
- 678 - 689
- publisher
- American Association of Immunologists
- external identifiers
-
- pmid:39018495
- ISSN
- 1550-6606
- DOI
- 10.4049/jimmunol.2300675
- language
- English
- LU publication?
- yes
- additional info
- Copyright © 2024 by The American Association of Immunologists, Inc.
- id
- 0ca50331-aa18-49d2-af86-e0ad06f1ffc4
- date added to LUP
- 2024-08-20 10:12:43
- date last changed
- 2024-08-20 12:03:19
@article{0ca50331-aa18-49d2-af86-e0ad06f1ffc4, abstract = {{<p>Substantial evidence supports that Fc-mediated effector functions of anti-spike Abs contribute to anti-SARS-Cov-2 protection. We have previously shown that two non-neutralizing but opsonic mAbs targeting the receptor-binding domain and N-terminal domain (NTD), Ab81 and Ab94, respectively, are protective against lethal Wuhan SARS-CoV-2 infection in K18-hACE2 mice. In this article, we investigated whether these protective non-neutralizing Abs maintain Fc-mediated function and Ag binding against mutated SARS-CoV-2 variants. Ab81 and Ab94 retained their nanomolar affinity and Fc-mediated function toward Omicron and its subvariants, such as BA.2, BA.4, BA.5, XBB, XBB1.5, and BQ1.1. However, when encountering the more heavily mutated BA.2.86, Ab81 lost its function, whereas the 10 new mutations in the NTD did not affect Ab94. In vivo experiments with Ab94 in K18-hACE2 mice inoculated with a stringent dose of 100,000 PFU of the JN.1 variant revealed unexpected results. Surprisingly, this variant exhibited low disease manifestation in this animal model with no weight loss or death in the control group. Still, assessment of mice using a clinical scoring system showed better protection for Ab94-treated mice, indicating that Fc-mediated functions are still beneficial. Our work shows that a protective anti-receptor-binding domain non-neutralizing mAb lost reactivity when BA.2.86 emerged, whereas the anti-NTD mAb was still functional. Finally, this work adds new insight into the evolution of the SARS-CoV-2 virus by reporting that JN.1 is substantially less virulent in vivo than previous strains.</p>}}, author = {{Izadi, Arman and Godzwon, Magdalena and Söderlund Strand, Anna and Schmidt, Tobias and Kumlien Georén, Susanna and Drosten, Christian and Ohlin, Mats and Nordenfelt, Pontus}}, issn = {{1550-6606}}, language = {{eng}}, month = {{07}}, number = {{5}}, pages = {{678--689}}, publisher = {{American Association of Immunologists}}, series = {{Journal of immunology}}, title = {{Protective Non-neutralizing anti-N-terminal Domain mAb Maintains Fc-mediated Function against SARS-COV-2 Variants up to BA.2.86-JN.1 with Superfluous In Vivo Protection against JN.1 Due to Attenuated Virulence}}, url = {{http://dx.doi.org/10.4049/jimmunol.2300675}}, doi = {{10.4049/jimmunol.2300675}}, volume = {{213}}, year = {{2024}}, }