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Could nucleocapsid be a next-generation COVID-19 vaccine candidate?

Open AccessPublished:November 04, 2022DOI:https://doi.org/10.1016/j.ijid.2022.11.002

      Abbreviations:

      GISAID (Global Initiative on Sharing Avian Influenza Data)
      We have read with interest the article by
      • Oronsky B
      • Larson C
      • Caroen S
      • Hedjran F
      • Sanchez A
      • Prokopenko E
      • et al.
      Nucleocapsid as a next-generation COVID-19 vaccine candidate.
      about including the SARS-CoV-2 nucleocapsid (N) protein in future COVID-19 vaccines. One of the main reasons for this suggestion is that the N gene is much less vulnerable to mutation and may provide stronger immunity to novel viral variants. Although when the proteins of SARS-CoV-2 and SARS-CoV are compared, the N protein is more conserved than the spike (S) protein (
      • Dutta NK
      • Mazumdar K
      • Gordy JT.
      The nucleocapsid protein of SARS-CoV-2: a target for vaccine development.
      ); the current data we have analyzed about SARS-CoV-2 mutations show that the N gene is one of the most mutated genes (Figure 1). From the Global Initiative on Sharing Avian Influenza Data (GISAID) database, we collected 5,340,569 high-coverage SARS-CoV-2 genomes, available until June 27, 2022, and compared them with the reference SARS-CoV-2 genome (NC_045512.2) isolated in December 2019 from Wuhan-Hu-1. All the mutations were collected. For the N gene, 2551 nonsynonymous and 839 synonymous mutations were found. Because the length of the N gene is 1260 nucleotides, these values represent, respectively, 202.5 and 66.6 unique mutations per 100 nucleotides. As is shown in Figure 1, after the open reading frames that encode accessory proteins and the gene that encodes the leader peptide (nsp1), the N gene displays morenonsynonymous mutations and deletions than most of the SARS-CoV-2 genes, including the S gene. The genes with fewer nonsynonymous mutations are the helicase (nsp13), nsp10, nsp9, M-pro (nsp5), and RNA polymerase (nsp12) (Figure 1). Synonymous mutations are more uniform in SARS-CoV-2 genes, with between 55.6 and 71 mutations per 100 nucleotides. Insertions, on the other hand, are much less frequent.
      Figure 1
      Figure 1Unique mutations per 100 nucleotides in the SARS-CoV-2 genes. Deletions, nonsynonymous mutations, insertions, and synonymous mutations are shown in blue, yellow, green, and red, respectively. 5,340,569 high-coverage SARS-CoV-2 genomes, available at GISAID until 27 June 2022, were analyzed, and 84,176 mutations, 22,090 deletions, and 2328 insertions were obtained.
      The high mutation frequency of the N gene does not mean that it cannot be used to create future COVID-19 vaccines. Mutations in the N gene are not uniformly distributed (
      • Zhao H
      • Nguyen A
      • Wu D
      • Li Y
      • Hassan SA
      • Chen J
      • et al.
      Plasticity in structure and assembly of SARS-CoV-2 nucleocapsid protein.
      ). One of the most conserved regions is found in the central disordered linker proximal to the N-G215C mutation (
      • Zhao H
      • Nguyen A
      • Wu D
      • Li Y
      • Hassan SA
      • Chen J
      • et al.
      Plasticity in structure and assembly of SARS-CoV-2 nucleocapsid protein.
      ). Thus, this conserved region could be of use to create the vaccines.

      Declaration of competing interest

      The authors have no competing interests to declare.

      Funding

      This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 713679 and from the Universitat Rovira i Virgili (grant 2021PFR-URV-96).

      Acknowledgments

      The authors would like to acknowledge the authors of both the submitting and originating laboratories for the sequences from the Global Initiative on Sharing Avian Influenza Data (GISAID) database used in this study. The authors also acknowledge their university's English language service for proofreading and correcting this manuscript.

      Author contributions

      BS-E curated and analyzed the data and wrote the manuscript. SG-V conceptualized the study, organized the workflow, contributed to data curation, analyzed the data and contributed to the writing of the manuscript. GP analyzed the data and critically read the manuscript. GM helped with figure 1. All authors have read and agreed to the published version of the manuscript.

      References

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        • Mazumdar K
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        The nucleocapsid protein of SARS-CoV-2: a target for vaccine development.
        J Virol. 2020; 94 (e00647-20)
        • Oronsky B
        • Larson C
        • Caroen S
        • Hedjran F
        • Sanchez A
        • Prokopenko E
        • et al.
        Nucleocapsid as a next-generation COVID-19 vaccine candidate.
        Int J Infect Dis. 2022; 122: 529-530
        • Zhao H
        • Nguyen A
        • Wu D
        • Li Y
        • Hassan SA
        • Chen J
        • et al.
        Plasticity in structure and assembly of SARS-CoV-2 nucleocapsid protein.
        PNAS Nexus. 2022; 1 (pgac049)

      Linked Article

      • Could nucleocapsid be a next-generation COVID-19 vaccine candidate – author's reply
        International Journal of Infectious DiseasesVol. 125
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          This is in response to a letter to the editor by Saldivar-Espinoza et al. (2022) commenting on a short perspective that we wrote in the September 2022 issue of the International Journal of Infectious Disease entitled, “Nucleocapsid as a next-generation COVID-19 vaccine candidate” (Oronsky et al., 2022). The main point of this perspective was that nucleocapsid (N), being highly conserved among coronaviruses (CoVs), less mutable than spike (S), and strongly immunogenic, especially for T cells (Lineburg et al.
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