Life science
Medicine / Healthcare, Drug development

Development of therapeutic and preventive strategies for severe
COVID-19 by targeting the severe infection mechanism
Laboratory of Immunochemistry, WPI Immunology Frontier Research Center; Department of Immunochemistry,
Research Institute for Microbial Diseases; Center for Infectious Disease Education and Research
Professor Hisashi Arase

Researchmap https://researchmap.jp/read0187233

Life science

Abstract
Antibodies against the receptor-binding domain (RBD) of thespike protein of SARS-CoV-2 play an important role as neutralizing
antibodies by blocking binding to the host cell receptor, ACE2,thereby suppressing the infection of SARS-CoV-2. However, thisstudy revealed that when antibodies bind to a specific site on thespike protein of the SARS-CoV-2, the conformation of the spike
protein is changed and the binding of spike protein to ACE2 is enhanced, thereby increasing the infectivity of the SARS-CoV-2. Such
infectivity-enhancing antibodies were found in severe COVID-19
patients and also in some uninfected individuals. These findings
suggest that infectivity-enhancing antibodies could be involved inthe severity of SARS-CoV-2 infection.

predicting the severity of COVID-19. In addition, depending on thefuture appearance of SARS-CoV-2 variants, it may be required todevelop vaccines that do not induce the production of infectivity-enhancing antibodies by removing the epitopes of infectivity-enhancing antibodies from spike protein.

▍ Background & Results
SARS-CoV-2 infection causes severe pneumonia in some infected individuals, even though most of them have mild disease.
Therefore, some host factors may be involved in severe COVID-19,
but the factors that cause severe disease remain unclear. Neutralizing antibodies against SARS-CoV-2 play an important role ininfection protection. In addition to neutralizing antibodies, many antibodies against spike proteins are produced in COVID-19 patients.
In addition to neutralizing antibodies, COVID-19 patients produce
many antibodies against spike proteins, but the detailed functionsof these antibodies have not been clarified. On the other hand, antibodies to the viruses have been reported to be an exacerbating
factor in dengue virus and feline infectious peritonitis virus, one ofcoronaviruses, which is called antibody dependent enhancement(ADE) of infection. However, Fc receptors expressed on certain
types of immune cells are involved in the ADE, and thus such antibodies are not involved in the infection of lung cells, which do
not express Fc receptors. In this study, in order to elucidate thefunction of antibodies produced in COVID-19 patients, we analyzed in detail the function of 76 monoclonal antibodies against spike
proteins obtained from COVID-19 patients. We found that there areantibodies that cause conformational change of the spike protein
and increase the infectivity of the SARS-CoV-2 simply by binding
to a specific site on the N-terminal region of the spike protein of
the SARS-CoV-2, which is completely different mechanism from thetraditional ADE mediated by the Fc receptor. Furthermore, infectivity-enhancing antibodies were found in severe COVID-19 patientsand in a small proportion of non-infected individuals, suggestingthat infectivity-enhancing antibodies may be a factor in the development of severe COVID-19.

▍ Significance of the research and Future perspective
This study revealed that some antibodies against SARS-CoV-2
exacerbate the infection for the first time. Infectivity-enhancing antibodies may be involved in the severity of SARS-CoV-2. Therefore,
the detection of infectivity-enhancing antibodies may be useful inP a t e n t Japanese Patent Application No.2020-202318
Liu, Yafei; Soh, Wai Tuck; Kishikawa, Jun-ichi et al. An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies. Cell 2021; 184:
Tr e a t i s e
3452–3466. DOI:10.1016/j.cell.2021.05.032
URL http://immchem.biken.osaka-u.ac.jp
K e y w o r d SARS-CoV-2, infectivity enhancing antibody, spike protein, vaccine, antibody-dependent enhancement (ADE)