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. 2023 Jun 5;585:78–81. doi: 10.1016/j.virol.2023.04.014

Emergence of SARS-CoV-2 serotype(s): Is it a matter of time?

José Valter Joaquim Silva Júnior a,b,c,∗,1, Ricardo Durães-Carvalho d,e,∗∗,1, Joelma Rodrigues de Souza f, Luiz Mário Ramos Janini d, Rudi Weiblen a, Eduardo Furtado Flores a,∗∗∗
PMCID: PMC10240909  PMID: 37321144

Abstract

Since its identification in late 2019, SARS-CoV-2 has undergone numerous mutations, resulting in the emergence of several viral variants, which may differ in transmissibility, virulence and/or evasion from host immunity. Particularly, immunity-related changes have been well documented in the Omicron variant, including reports of escaping neutralizing antibodies induced by infection/vaccination with heterologous SARS-CoV-2 or used in serological therapy. These findings may encourage some discussions about the possibility that Omicron is a distinct SARS-CoV-2 serotype. To contribute to this issue, we combined concepts from immunology, virology and evolution and performed an interesting brainstorm on the hypothesis that Omicron is a distinct SARS-CoV-2 serotype. Furthermore, we also discussed the likelihood of emergence of SARS-CoV-2 serotypes over time, which may not necessarily be related to Omicron. Finally, insights into this topic may have direct implications for vaccine formulations, immunodiagnostic platforms and serological therapies, contributing to better management of future outbreaks or waves.

Keywords: Coronavirus, Evolution, Omicron, Spike protein

1. Introduction

Since its identification in late 2019, SARS-CoV-2 has undergone numerous mutations, resulting in the emergence of several viral variants, which may differ in transmissibility, virulence and/or evasion from host immunity (WHO, 2022). Immunity-related changes have been well described in the Omicron variant, including reports of escaping neutralizing antibodies (nAb) induced by infection/vaccination with heterologous SARS-CoV-2 or used in serological therapy (Evans et al., 2022; Planas et al., 2022), and also supported by the need for a bivalent vaccine composed of Wuhan (original) and Omicron strains (Chalkias et al., 2022; FDA, 2019). These findings may suggest the circulation of distinct SARS-CoV-2 serotypes; an issue that still lacks scientific support.

The serotype concept is used to describe variants within an infectious agent species that may be distinguished by humoral (antibody) immune response, as observed in feline coronavirus (FCoV), which have been differentiated in serotypes 1 and 2 by both serum or monoclonal antibody-based immunoassays (Hohdatsu et al., 1991; Hohdatsu et al., 1992; Shiba et al., 2007). In this perspective, proving the existence of different SARS-CoV-2 serotypes would require a rigorous serological study, using several well-characterized isolates and sera. Considering the number of SARS-CoV-2 variants identified so far (as well as their lineages and sublineages), it would be time consuming to investigate their possible antigenic profiles. Recognizing this difficulty and aiming to bring insights into this issue, we combined concepts from virology, immunology and evolution and performed an integrative analysis on the probability of emergence of SARS-CoV-2 serotypes over time, which would have direct implications for vaccine formulations, immunodiagnosis platforms and serological therapies.

2. How likely are SARS-CoV-2 serotypes to emerge?

The hypothesis of distinct SARS-CoV-2 serotypes was initially investigated from an evolutionary perspective by Simon-Loriere and Schwartz (Simon-Loriere and Schwartz, 2022). Briefly, the authors demonstrated a reasonable phylogenetic distance of the Spike (S) protein, as well as its receptor-binding domain (RBD), among Omicron and other variants (Alpha, Beta, Gamma and Delta). These findings led the authors to suggest the existence of two SARS-CoV-2 serotypes: serotype 1 (Alpha, Beta, Gamma and Delta) and serotype 2 (Omicron) (Simon-Loriere and Schwartz, 2022).

The emphasis to S protein and its RBD is supported by their high immunogenicity and participation in SARS-CoV-2 cell attachment (Premkumar et al., 2020). However, other S protein regions, although less immunogenic, may also be targeted for nAbs, making their analyses useful for the study of putative SARS-CoV-2 serotypes. In this regard, it would be interesting to dissect the S protein by performing phylogenetic analyses based also on the amino acid sequences of its subunits (S1 and S2), N-terminal domain (NTD) (at S1), receptor-binding motif (RBM, located at S1) and fusion peptide (at S2), focusing on each region individually. Such an approach would be justified by previous reports of nAbs against these targets or neighboring epitopes (Dacon et al., 2022; Errico et al., 2021; Fang et al., 2022; Low et al., 2022; Sun et al., 2022; Zhang et al., 2021) and by the location of Omicron mutations (Fig. 1 and Table 1 ). If Omicron remains evolutionarily distant from the other variants after this deepening, it would strengthen the hypothesis that it could indeed represent a distinct SARS-CoV-2 serotype.

Fig. 1.

Fig. 1

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Three-dimensional structural representation of the Spike protein of SARS-CoV-2 Omicron. The red spheres represent the S protein mutations in the Omicron BA.1 to BA.5 lineages (details in Table 1). The main targets of neutralizing antibodies are highlighted: N-terminal domain (NTD), fusion peptide (FP), receptor-binding domain (RBD) and receptor-binding motif (RBM). Changes in underpinning subdomain (SD) and heptad repeat 1 (HR-1) are also located in the figure, although their regions have not been indicated. The 3D spike protein image was generated with Visual Molecular Dynamics (VMD) v.1.9.3 (http://www.ks.uiuc.edu/Research/vmd/). The figure also lists key points to consider when discussing whether Omicron may represent a distinct SARS-CoV-2 serotype.

Table 1.

Profile of amino acid changes in Spike protein of Omicron lineages.

Image 1
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On the other hand, if further studies, including immunologically based assays, demonstrate that Omicron is not a distinct SARS-CoV-2 serotype, continued monitoring of this possibility is important. Considering Omicron's evolutionary distance, its current predominance, the continued reporting of its lineages and sublineages, as well as the escape from nAbs (WHO, 2022; Evans et al., 2022; Planas et al., 2022; Simon-Loriere and Schwartz, 2022), it is currently the main target of investigation. However, it can not be ruled out the possibility that another variant, with characteristics of a different SARS-CoV-2 serotype, could still emerge. In this perspective, we raise the following question: Does the probability of emergence of distinct SARS-CoV-2 serotypes increase or decrease over time? Given the complexity of this topic, we address some points that may contribute to further studies.

Despite discussions about the duration of immunity to SARS-CoV-2 from natural infection or vaccination (Peluso et al., 2022), it is reasonable to assume that both may result in some background immunity, which, to some extent, would reduce viral replication, decreasing the likelihood of viral mutations and, consequently, the risk of emergence of SARS-CoV-2 serotypes. Considering that adaptive immunity may improve after reinfection, vaccine booster or with the hybrid stimulus (Wratil et al., 2022), the plausible trend would be a decrease in the probability of emergence of SARS-CoV-2 serotypes over time.

The above inference is in line with the principles of immunology and virology, however it must be carefully interpreted, considering a multifactorial context. Herein, the continued emergence of SARS-CoV-2 lineages or sublineages suggests that immunity is (also) strengthening selection pressure, resulting in escape mutants, which may also be mediated by serological-based therapy. This scenario may also be indirectly influenced by mutations in non-structural proteins which could contribute to the evasion from innate immunity or to alter the proofreading function during genome replication (Pachetti et al., 2020; Ichikawa et al., 2022; Schindewolf et al., 2023), favoring viral replication and mutations in the S gene. Furthermore, the different mutation profiles may be joined by recombination events between different SARS-CoV-2 (Turakhia et al., 2022), making virus evolution an even more complex issue. From this perspective, it is reasonable to suggest that the probability of emergence of viral serotypes would increase over time.

Although much less likely, it should not be ignored the possibility of replacement of the SARS-CoV-2 S gene (total or partial) by the S gene from another coronavirus species, via viral recombination, which would result in considerable antigenic change and emergence of distinct SARS-CoV-2 serotypes. A similar evolutionary event has been suggested for FCoV, in which the replacement of the FCoV S gene by the respective canine enteric coronavirus (CCoV) gene would have resulted in the emergence of FCoV serotype 2 (Motokawa et al., 1996; Herrewegh et al., 1998; Jaimes et al., 2020). Considering that the risk of recombination involving SARS-CoV-2 increases as it circulates, this rationale also suggests that the probability of emergence of viral serotypes would increase over time.

3. Final considerations

Overall, considering the potential factors favoring or hampering viral evolution and linking them to mutation-selection mechanisms, we believe that the main bottlenecks for the emergence of SARS-CoV-2 serotypes are the dual consequence of infection, which may increase the risk of recombination and viral mutations, but also contribute to enhance immunity; and the dual action of the immune response, which may restrict or select viral replication. Understanding the complex and “contradictory” relationship between SARS-CoV-2 infection and immunity may help answer the issue: Is the emergence of SARS-CoV-2 serotypes a matter of time?

Authors’ contributions

Handling Editor: Ms. J Jasmine Tomar. JVJSJr: Conceptualization, Writing – original draft, Table. RDC: Conceptualization, Writing – original draft, Figure, Table. JRS: Writing – original draft, Table. LMRJ: Writing – review & editing. RW: Writing – review & editing. EFF: Supervision and critical revision. All authors read and approved the final version of the manuscript.

Data availability statement

The data that support the discussion of this study are available in WHO website at https://www.who.int/docs/default-source/coronaviruse/s.pdf?sfvrsn=990a05c2_14, Stanford Coronavirus Antiviral & Resistance Database at covdb.stanford.edu/variants and GISAID at https://www.epicov.org/epi3/frontend#e0075

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

JVJSJr was supported by Financiadora de Estudos e Projetos (FINEP) DTI-A-1. EFF (process 301414/2010-6) and RW (process 305867/2018-0) were supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) research fellowships. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (Brazil), finance code 001, partially supported the research. RD-C and LMRJ are supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Brazil, grants 2019/01255-9 and 2021/03684-4 (Programa Jovem Pesquisador) (RD-C) and 2020/08943-5 (LMRJ). The authors also thank the Laboratório Nacional de Computação Científico (LNCC) (Ministério da Ciência, Tecnologia e Inovações, MCTI, Brazil) for providing High Performance Computing resources of the Santos Dumont supercomputer (ID #45691, project “virusevolution”).

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the discussion of this study are available in WHO website at https://www.who.int/docs/default-source/coronaviruse/s.pdf?sfvrsn=990a05c2_14, Stanford Coronavirus Antiviral & Resistance Database at covdb.stanford.edu/variants and GISAID at https://www.epicov.org/epi3/frontend#e0075

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