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Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells

Shimizu et al., Scientific Reports, doi:10.1038/s41598-022-19993-w
Sep 2022  
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In Vitro study showing that casirivimab/imdevimab may induce antibody-dependent enhancement (ADE) within a specific concentration range. No ADE was observed for sotrovimab.
This study includes sotrovimab and casirivimab/imdevimab.
Shimizu et al., 16 Sep 2022, Japan, peer-reviewed, 12 authors.
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Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells
Jun Shimizu, Tadahiro Sasaki, Ritsuko Koketsu, Ryo Morita, Yuka Yoshimura, Ami Murakami, Yua Saito, Toshie Kusunoki, Yoshihiro Samune, Emi E Nakayama, Kazuo Miyazaki, Tatsuo Shioda
Scientific Reports, doi:10.1038/s41598-022-19993-w
Many therapeutic antibodies (Abs) and mRNA vaccines, both targeting SARS-CoV-2 spike protein (S-protein), have been developed and approved in order to combat the ongoing COVID-19 pandemic. In consideration of these developments, a common concern has been the potential for Ab-dependent enhancement (ADE) of infection caused by inoculated or induced Abs. Although the preventive and therapeutic effects of these Abs are obvious, little attention has been paid to the influence of the remaining and dwindling anti-S-protein Abs in vivo. Here, we demonstrate that certain monoclonal Abs (mAbs) approved as therapeutic neutralizing anti-S-protein mAbs for human usage have the potential to cause ADE in a narrow range of Ab concentrations. Although sera collected from mRNAvaccinated individuals exhibited neutralizing activity, some sera gradually exhibited dominance of ADE activity in a time-dependent manner. None of the sera examined exhibited neutralizing activity against infection with the Omicron strain. Rather, some ADE of Omicron infection was observed in some sera. These results suggest the possible emergence of adverse effects caused by these Abs in addition to the therapeutic or preventive effect. Therapeutic Ab drugs targeting SARS-CoV-2 S-protein have shown high preventive efficacy against disease development 1-3 . In addition, current SARS-CoV-2 mRNA vaccines for humans also target the S-protein on viruses as a critical antigen 4 . These mRNA vaccines generate robust neutralizing Abs 5-7 , but for both Ab drugs and vaccines targeting the S-protein, the possible induction of Ab-dependent enhancement (ADE) of infection is a concern [8] [9] [10] [11] . Recent reports have demonstrated that neutralizing mAbs against S-protein can exhibit ADE activity in a limited window of Ab concentrations [12] [13] [14] . An important issue requiring reconsideration is that the cells used to evaluate ADE potential are different in each report. In many cases, Fc-receptor (FcR)-positive and angiotensin-converting enzyme 2 (ACE2, the major receptor for SARS-CoV-2 15-17 )-negative cells lines (Raji, THP-1, and K562) are used as host cells for infection of SARS-CoV-2 pseudo-viruses expressing S-protein or authentic SARS-CoV-2 [12] [13] [14] 18, 19 . These reports have demonstrated that some anti-S protein mAbs have the potential to induce ADE of infection. The observed ADE can be blocked in the presence of FcR-blocker, demonstrating FcR dependence. Likewise, the Ab drugs casirivimab and imdevimab 1, 20, 21 , which target the SARS-CoV-2 S-protein, have also been evaluated by using FcR-positive and ACE2-negative cell lines (U937, THP-1,
Methods Mylc cell lines for SARS-CoV-2 infection. The procedure used to generate Mylc lines was previously reported 38, 39 . Briefly, immortalized myeloid cell lines were established by the lentivirus-mediated transduction of cMYC, BMI-1, GM-CSF, and M-CSF into human iPS cell-derived myeloid cells. These cell lines were further induced to express ACE2 and TMPRSS2 using lentiviral vectors. The established cell lines (K-ML2(AT), D05, and PhF lines) were derived from different human iPS cells and maintained as bulk cell lines. In some experiments, cloned cells (clone 35) were established from bulk lines by limiting dilution. Each cell line was cultured in MEM alpha (Gibco) supplemented with 10% (vol/vol) fetal bovine serum under 37 °C, 5% CO 2 , and watersaturated humidity conditions. Viruses. SARS-CoV-2/Hu/DP/Kng/19-020 (original strain, GenBank accession number: LC528232.1) was provided by the Kanagawa Prefectural Institute of Public Health, Kanagawa, Japan, and the Omicron strain (hCoV-19/Japan/TY38-873/2021) by the National Institute of Infectious Diseases, Japan. SARS-CoV-2 Delta strain (hCoV-19/USA/PHC658/2021, NR-55611) was obtained from BEI Resources. SARS-CoV-2 viruses were passaged in VeroE6-TMPRSS2 cells (obtained from the National Institutes of Biomedical Innovation, Health, and Nutrition, JCRB cell bank, Japan) two times. Viral stocks were aliquoted, examined for the presence of viral RNA by quantitative RT-PCR, and tested for mycoplasma (they were..
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