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Differential patterns of cross-reactive antibody response against SARS-CoV-2 spike protein detected for chronically ill and healthy COVID-19 naïve individuals

Jaago, Mariliis; Rähni, Annika; Pupina, Nadežda; Pihlak, Arno; Sadam, Helle; Tuvikene, Jürgen; Avarlaid, Annela; Planken, Anu; Planken, Margus; Haring, Liina; Vasar, Eero; Baćević, Miljana; Lambert, France; Kalso, Eija; Pussinen, Pirkko; Tienari, Pentti J.; Vaheri, Antti; Lindholm, Dan; Timmusk, Tõnis; Ghaemmaghami, Amir M.; Palm, Kaia


Mariliis Jaago

Annika Rähni

Nadežda Pupina

Arno Pihlak

Helle Sadam

Jürgen Tuvikene

Annela Avarlaid

Anu Planken

Margus Planken

Liina Haring

Eero Vasar

Miljana Baćević

France Lambert

Eija Kalso

Pirkko Pussinen

Pentti J. Tienari

Antti Vaheri

Dan Lindholm

Tõnis Timmusk

Kaia Palm


Immunity to previously encountered viruses can alter response to unrelated pathogens. We reasoned that similar mechanism may also involve SARS-CoV-2 and thereby affect the specificity and the quality of the immune response against the virus. Here, we employed high-throughput next generation phage display method to explore the link between antibody immune response to previously encountered antigens and spike (S) glycoprotein. By profiling the antibody response in COVID-19 naïve individuals with a diverse clinical history (including cardiovascular, neurological, or oncological diseases), we identified 15 highly antigenic epitopes on spike protein that showed cross-reactivity with antigens of seasonal, persistent, latent or chronic infections from common human viruses. We observed varying degrees of cross-reactivity of different viral antigens with S in an epitope-specific manner. The data show that pre-existing SARS-CoV-2 S1 and S2 cross-reactive serum antibody is readily detectable in pre-pandemic cohort. In the severe COVID-19 cases, we found differential antibody response to the 15 defined antigenic and cross-reactive epitopes on spike. We also noted that despite the high mutation rates of Omicron (B.1.1.529) variants of SARS-CoV-2, some of the epitopes overlapped with the describedmutations. Finally, we propose that the resolved epitopes on spike if targeted by re-called antibody response from SARS-CoV-2 infections or vaccinations can function in chronically ill COVID-19 naïve/unvaccinated individuals as immunogenic targets to boost antibodies augmenting the chronic conditions. Understanding the relationships between prior antigen exposure at the antibody epitope level and the immune response to subsequent infections with viruses from a different strain is paramount to guiding strategies to exit the COVID-19 pandemic.


Jaago, M., Rähni, A., Pupina, N., Pihlak, A., Sadam, H., Tuvikene, J., …Palm, K. (2022). Differential patterns of cross-reactive antibody response against SARS-CoV-2 spike protein detected for chronically ill and healthy COVID-19 naïve individuals. Scientific Reports, 12(1), Article 16817.

Journal Article Type Article
Acceptance Date Sep 20, 2022
Online Publication Date Oct 7, 2022
Publication Date Oct 7, 2022
Deposit Date Nov 10, 2022
Publicly Available Date Nov 10, 2022
Journal Scientific Reports
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 12
Issue 1
Article Number 16817
Public URL
Publisher URL


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