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Review 2: "Development of antibodies to pan-coronavirus spike peptides in convalescent COVID-19 patients"

This study investigates whether antibodies present in COVID19 patients cross-react with spike proteins from other coronaviruses and demonstrates activity against MERS-CoV. Implications of these findings are narrow due to limited testing and poorly described methods.

Published onOct 02, 2020
Review 2: "Development of antibodies to pan-coronavirus spike peptides in convalescent COVID-19 patients"
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key-enterThis Pub is a Review of
Development of antibodies to pan-coronavirus spike peptides in convalescent COVID-19 patients

Coronaviruses are sharing several protein regions notable the spike protein (S) on their enveloped membrane surface, with the S1 subunit recognizing and binding to the cellular receptor, while the S2 subunit mediates viral and cellular membrane fusion. This similarity opens the question whether infection with one coronavirus will confer resistance to other coronaviruses? Investigating patient serum samples after SARS-CoV-2 infection in cross-reactivity studies of immunogenic peptides from Middle East respiratory syndrome coronavirus (MERS-CoV), we were able to detect the production of antibodies also recognizing MERS virus antigens. The cross-reactive peptide comes from the heptad repeat 2 (HR2) domain of the MERS virus spike protein. Indeed, the peptide of the HR2 domain of the MERS spike protein, previously proven to induce antibodies against MERS-CoV is sharing 74% homology with the corresponding sequence of SARS-CoV-19 virus. Sera samples of 47 convalescent SARS-CoV-2 patients, validated by RT-PCR-negative testes 30 days post-infection, and samples of 40 sera of control patients (not infected with SARS-CoV-2 previously) were used to establish eventual cross-bind reactivity with the MERS peptide antigen. Significantly stronger binding (p<0.0001) was observed for IgG antibodies in convalescent SARS-CoV-2 patients compared to the control group. If used as an antigen, the peptide of the HR2 domain of the MERS spike protein allows discrimination between post-Covid populations from non-infected ones by the presence of antibodies in blood samples. This suggests that polyclonal antibodies established during SARS-CoV-2 infection has the ability to recognize and probably decrease infectiveness of MERS-CoV infections as well as other coronaviruses. The high homology of the spike protein domain suggests in addition that the opposite effect can also be true: coronaviral infections producing cross-reactive antibodies affective against SARS-CoV-19. The collected data prove in addition that despite the core HR2 region being hidden in the native viral conformation, its exposure during cell entry makes it highly immunogenic. Since inhibitory peptides to this region were previously described, this opens new possibilities in fighting coronaviral infections.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



COVID-19 is caused by SARS-CoV-2 and is still unfolding as a global pandemic. It is known that humoral immunity, especially, IgG responses play critical roles for the patients to recover from COVID-19. SARS-CoV-2 specific IgG responses target a variety of proteins and, among them, spike proteins are on the top list because of their high functional significance and their high immunogenicity. However, spike proteins are conserved among the 7 known human coronaviruses, i. e., SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-HKU1, HCoV-NL63 and HCoV-229E. The identification of shared or unique IgG responses among these 7 human coronaviruses is of great interest, because of the potential for guiding the development of accurate diagnosis, effective neutralization antibodies and vaccines. When targeting SARS-CoV-2 spike proteins for therapeutic purpose, other areas except the RBD (receptor biding domain) also have the potential to be targets, for example, the heptad repeat domains (HR1 and HR2) on S2.

In this study, the authors tried to test the IgG cross-reactivity between SARS-CoV-2 and MERS-CoV. This direction is important and of broad interest. Based on their previous study, they argued that a peptide from MERS-CoV HR2 could also be recognized by IgG from COVID-19 patients. Indeed, significant bindings were observed for COVID-19 sera but not the control sera against the MERS-CoV peptide—for IgG but not IgA, IgM and IgE. Overall the study is potentially informative.

Major concerns:

1. For a clinical study, the sample design is critical. However, in this case, the sample information is missing, for example, age and gender. For the control samples, more relevant details are needed, for example, the history of infection with other human coronaviruses.

2. Since only MERS-CoV was tested, the claim of “pan-coronavirus spike peptides…” is not appropriate. The claim needs to be tuned down or the authors need to show more data on the cross-reactivities among other human coronaviruses.

3. Practically, it is almost impossible for a person who was infected by MERS-CoV then SARS-CoV-2 or vice versa. Thus, the finding of this study is not actionable. With the pandemic being what it is, the current most important task is to combat COVID-19, one suggestion is that the authors focus on how to apply the peptide for treating COVID-19.

4. The discussion part is totally irrelevant. T cell immunity is also very important for COVID-19, however, the results are only about B cell immunity, especially IgG responses. What is the purpose of the authors majorly talking about T cell immunity in the discussion section?

Minor concerns:

1. Better use “SARS-CoV” instead of “SARS-CoV-1”.

2. There is no such virus as “SARS-CoV-19”.

The suggestion for this manuscript is Major Revision.

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