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Could nucleocapsid be a next-generation COVID-19 vaccine candidate – author's reply

Open AccessPublished:November 04, 2022DOI:https://doi.org/10.1016/j.ijid.2022.11.001
      This is in response to a letter to the editor by
      • Saldivar-Espinoza B
      • Macip G
      • Pujadas G
      • Garcia-Vallve S
      Could nucleocapsid be a next-generation COVID-19 vaccine candidate?.
      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 B
      • Larson C
      • Caroen S
      • Hedjran F
      • Sanchez A
      • Prokopenko E
      • Reid T.
      Nucleocapsid as a next-generation COVID-19 vaccine candidate.
      ). 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 KE
      • Grant EJ
      • Swaminathan S
      • et al.
      CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal coronaviruses.
      ), which persist for much longer than waning antibodies, is a primary target for a broader and more cross-protective vaccine.
      Based on an analysis of the Global Initiative to Share All Influenza Data repository, Salvidar-Espinoza et al. responded with thought-provoking evidence that N is, in fact, highly mutation-prone in certain regions, second only to S, which, in theory, may jeopardize the efficacy, and universality, of CoV vaccines that incorporate N as an antigen. However, we are skeptical about the clinical relevance of this analysis for the following reasons.
      Mutations are common in RNA viruses, such as SARS-CoV-2 (
      • Duffy S.
      Why are RNA virus mutation rates so damn high?.
      ). Their rapid evolution is responsible for the accumulation of genetic changes, particularly when the host is immunodeficient. However, most mutations impact viral fitness deleteriously, especially those involving indispensable proteins, such as N, which not only binds to and protects the RNA genome from degradation but also functions as an antagonist of interferon, one of the main mechanisms of the host innate immune defense (
      • Wu C
      • Qavi AJ
      • Hachim A
      • Kavian N
      • Cole AR
      • Moyle AB
      • Wagner ND
      • Sweeney-Gibbons J
      • Rohrs HW
      • Gross ML
      • Peiris JSM
      • Basler CF
      • Farnsworth CW
      • Valkenburg SA
      • Amarasinghe GK
      Leung DWCharacterization of SARS-CoV-2 nucleocapsid protein reveals multiple functional consequences of the C-terminal domain.
      ).
      That this protein shares 90% homology with the SARS-CoV-1 N protein implies a conserved mechanism of N formation for CoVs (
      • Bai Z
      • Cao Y
      • Liu W
      • Li J.
      The SARS-CoV-2 nucleocapsid protein and its role in viral structure, biological functions, and a potential target for drug or vaccine mitigation.
      ). It also suggests that any nonsynonymous mutations in N, which change the amino acid sequence, and decrease the interaction between N and RNA or that interferes with N formation as a result will negatively impact the fitness of the virus and vice versa. That said, genes do not operate in isolation but in concert with an array of other genes, and the synergic and antagonistic effects of epistatic interactions may profoundly impact whether these N mutations evolve under positive or negative selection due to their impact on basic reproduction number, immune evasion, generation time, etc.
      Accordingly, it is difficult, if not impossible, to attempt to predict the fate of individual mutations and their relationship to a fitness phenotype; it is especially difficult to determine which specific epitopes to include in a CoV vaccine, given the myriad variables that are involved, including population size, disease prevalence, within-host factors, and epistatic gene-gene interactions. For this reason, we are in favor of a self-replicating adenovirus-based vaccine that encodes the whole N gene, including the regions “in the central disordered linker proximal to the N-G215C 28 mutation” identified by Saldivar-Espinoza et al. as the most conserved and stable.

      Declaration of competing interest

      The authors have no competing interests to declare.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethical approval

      Not applicable.

      Author contributions

      BO and TR conceived and wrote the first draft of the manuscript; CL and SC contributed to manuscript revision, read and approved the submitted version.

      References

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

      • Could nucleocapsid be a next-generation COVID-19 vaccine candidate?
        International Journal of Infectious DiseasesVol. 125
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          We have read with interest the article by Oronsky et al. (2022) 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 et al., 2020); 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).
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