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Researchers at the University of Wisconsin-Madison have conducted a study showing that infection with severe acute respiratory syndrome coronavirus 2 (SARS-C0V-2) triggers robust immune responses to epitopes throughout the viral proteome.
SARS-CoV-2 is the agent responsible for the current coronavirus disease 2019 (COVID-19) pandemic that continues to have a devastating effect on global public health and the economy.
Irene Ong and colleagues say that the study’s findings suggest that viral membrane protein (M), particularly the 1-M-24 epitope, as well as other highly reactive epitopes should be further studied as potential targets in the development of diagnostics, vaccines and therapies for SARS-CoV-2.
These epitopes could also be useful in developing diagnostics, vaccines and therapies for other dangerous coronaviruses that may emerge in the future, they add.
A pre-printed version of the paper is available on the server. bioRxiv *, while the article undergoes peer review.
Control sera show reactivity frequently to CCCoV and rarely to SARS-CoV, MERS-CoV, and SARS-CoV-2. Sera from 20 control subjects collected prior to 2019 were analyzed for IgG binding to complete 9 CoV proteomes on a peptide microarray. Viral proteins are shown aligned with the SARS-CoV-2 proteome, each virus having an individual panel; The amino acid position (aa) of SARS-CoV-2 is represented on the x-axis. Binding was measured as reactivity that was> 3 standard deviations above the mean for the normalized matrix data by log2 quantile.
“Antibody-based options may need to be expanded”
All coronaviruses have four major structural proteins (pico [S], on [E], membrane [M] and nucleocapsid [N]), as well as numerous non-structural proteins and accessory proteins.
In the case of SARS-CoV-2, antibodies against S and N have received the most attention so far.
However, not all infected individuals generate detectable levels of antibodies against these proteins, suggesting that antibody-based options may need to be expanded.
Much less is known about antibody responses to other SARS-CoV-2 proteins, although data from studies of other coronaviruses suggest that these proteins may be important. For example, some experimental vaccines for SARS-CoV-1 and Middle East respiratory syndrome (MERS-CoV) trigger the generation of antibodies against the accessory protein orf8.
In addition, previous studies have shown that there is a humoral cross-reactivity between coronaviruses, which could be protective. However, the cross-reactivity of the whole proteome has not yet been investigated.
What did the current study involve?
Now, Ong and his colleagues have used a peptide microarray they designed to assess the proteome of SARS-CoV-2 and other human and animal coronaviruses to determine antibody specificity and cross-reactivity between viruses.
The microarray was used to profile immunoglobulin G (IgG) antibodies among 40 patients who had recovered from COVID-19 and 20 SARS-CoV-2 naïve controls.
“Our goal was to map the full extent of antibody binding induced by SARS-CoV-2 infection and to rank the epitopes identified in terms of probability of importance and immunodominance,” the team writes.
The researchers identified 79 B cell epitopes on the structural proteins S, M, N, the polyprotein orf1ab, and the accessory proteins orf3a, orf6, and orf8.
The highest ranking epitope was 1-M-24, which is found at the N-terminal end of M.
The patients’ sera showed high magnitude reactivity between other epitopes on S, M, N and orf3a and lesser reactivity between epitopes on other proteins.
Epitopes with the highest reactivity in S were found in the fusion peptide, while less reactive epitopes were found in the receptor-binding domain.
Four of the epitopes exhibit potent neutralizing activity.
Four of the detected epitopes have previously demonstrated potent neutralizing activity, and all of them are within the top 10 epitopes of this study.
The team also found that anti-SARS-CoV-2 antibodies cross-reacted with homologous epitopes in the proteomes of other human and animal coronaviruses.
The researchers note that “hundreds of CoV [coronaviruses] they have been discovered in bats and other species, making contagion effects inevitable in the future. “
The highest number (70) of cross-reactive epitopes was found in the bat betacoronavirus RaTG13, which is the virus most closely related to SARS-CoV-2 (96% nucleotide identity). This was followed by the pangolin coronavirus (51 epitopes) and SARS-CoV-1 (40 epitopes).
A region corresponding to the SARS-CoV-2 epitope 807-S-26 was cross-reactive in all coronaviruses, and a region corresponding to the SARS-CoV-2 epitope 1140-S-25 was cross-reactive in all betacoronaviruses.
What are the implications of the study?
The researchers say the results suggest that the structural M protein, particularly the 1-M-24 epitope, and the other new epitopes identified here should be explored as important targets in the development of improved diagnostics, vaccines and therapies for SARS-CoV- 2 and other dangerous coronaviruses that may emerge in the future.
Furthermore, “the broad cross-reactivity that we observe in some homologous peptide sequences may help guide the development of pan-CoV vaccines, especially given that antibodies that bind to 807-S-26 and 1140-S-25, the motifs of epitopes show cross-reactivity between all CoVs and all β-CoVs, respectively, are known to be potently neutralizing ”, says the team.
*Important news
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behavior, or be treated as established information.
