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Antibody response may depend on past infections and could be too vigorous in hospitalized patients

SARS-CoV-2 belongs to the family of coronaviruses. This family comprises two other viruses highly pathogenic to humans (SARS-CoV and MERS-CoV) but also viruses causing benign illnesses in the community (such as colds). COVID-19 is a disease of variable clinical evolution: some people infected remain asymptomatic, while others have clinical signs such as fever, anosmia (loss of sense of smell), diarrhea, breathing difficulties, pneumonia, while in a small percentage of cases, the illness can lead to patient death. Understanding the differences between antibody responses is essential to improve diagnosis, treatment and vaccines against SARS-CoV-2.

In a new study, researchers analysed the epitopes targeted by antibodies against SARS-CoV-2. An epitope is the part recognized by the antibody of the antigen (a substance that is foreign to the organism capable of causing an immune reaction).

This can be represented schematically as follows:

The serum of 232 patients infected by SARS-CoV-2 and 190 non-infected patients (serum collected prior to the COVID-19 epidemic) was studied, using a database of antibody targets (epitopes), enabling the testing of more than 100 million epitopes-antibody interactions.

First of all, analysis of SARS-CoV-2 proteins reveals that the antibodies of infected patients primarily target the spike protein and the nucleocapsid protein. Most individuals have antibodies targeting the same regions of the virus. For example, a spike region (811-830) is recognized in 79,9% of COVID-19 patients. Most patients develop antibodies 2 weeks after the first appearance of symptoms, and some after only one week.

The epitopes targeted by the antibodies of patients were classified in 2 categories: the “private” epitopes, that is to say those recognized by the antibodies in a small number of individuals only, and the “public” epitopes, recognized by the antibodies in a large number of individuals. For example, 6 epitopes were mapped in a certain region of the nucleocapsid protein. A third of infected patients possess antibodies targeting one of these 6 epitopes whereas less than 2% of patients possess antibodies directed against the 5 other epitopes.

Antibodies capable of recognizing coronaviruses responsible for colds were also detected, and certain are present in the serum of patients not infected by SARS-CoV-2. This result was expected since most people have already been infected by a benign coronavirus and different coronaviruses tend to have some regions in common. In addition, in the serum of patients infected by SARS-CoV-2, antibodies against SARS-CoV and the MERS-CoV and against the 3 coronaviruses of bats were detected.

Scientists then analyzed whether antibody response to SARS-CoV-2 was related to the severity of the illness. Patients included in this study were classified in 2 groups: those hospitalized and the others not. A stronger, more vigorous antibody response against the spike and nucleocapsid proteins was noted in hospitalized patients. This over-activation could be linked to immune complications observed in the most seriously ill patients.

Exposure to certain viral infections may also alter the immune system. In order to examine this hypothesis, scientists looked at the virome, that is to say all those viruses encountered by an individual. Results showed that the serum of non-hospitalized patients contains antibodies targeting common viruses such as the rhinovirus, the influenza virus or the enterovirus. On the other hand, the serum of hospitalized patients contains antibodies directed against the cytomegalovirus (CMV) and the herpes simplex 1 (HSV-1) virus. These observations need to be qualified since they may be influenced by the different geographical origins of hospitalized or non-hospitalized patients.

Mapping of SARS-CoV-2 epitopes:

More generally, the study showed that the antibody response to nearly all viruses, except SARS-CoV-2, is weaker in hospitalized as compared to non-hospitalized patients. In addition, the age, sex and origin of the patient is linked to the illness’ severity. So older non-Caucasian men are over-represented in the group of hospitalized patients. And hospitalized men have a larger antibody response against the nucleocapsid protein than women.

In conclusion, this detailed study of viral epitopes targeted by infected patients’ antibodies will help guide development of diagnostic methods or future treatment. The study has also shown that the severity of the illness may also be linked to the nature and the intensity of the immune response to past viral infections. 

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