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Abstract
More than 5 years have passed since the emergence of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), yet this virus continues to circulate globally, undergoing evolutionary changes. The effective control of SARS-CoV-2 necessitates an understanding of its antigenicity, replicative capacity, pathogenicity and transmissibility, as well as the development of preventive and treatment options. In this Review, we describe the origins and evolution of SARS-CoV-2, and outline variant and subvariant-specific characteristics. We also discuss the challenges faced in implementing prevention and treatment methods, such as the emergence of antigenically distinct variants and the phenomenon of immune imprinting. This Review provides insights into combating the ongoing COVID-19 pandemic and guidance for future research and vaccine development efforts.
© 2025. Springer Nature Limited.
Conflict of interest statement
Competing interests: Y.K. has received grant support from Daiichi Sankyo Pharmaceutical, Toyama Chemical, Tauns Laboratories, Shionogi, Otsuka Pharmaceutical, KM Biologics, Kyoritsu Seiyaku, Shinya Corporation and Fuji Rebio. Y.K. is a co-founder of FluGen. M.S.D. is a consultant or adviser for Inbios, Moderna, IntegerBio, Merck, GlaxoSmithKline and Akagera Medicines. The laboratory of M.S.D. has received unrelated funding support in sponsored research agreements from Moderna, Vir Biotechnology and IntegerBio. The other authors declare no competing interests.
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Sublineages are grouped within major lineages to enable visualization of key transitions. Pango lineage assignments applied to GISAID data for this graphic were based on UShER,. (A) Frequency shifts in major Pango lineages over time. The most recent global sweep was JN.1, and we are currently in a period of JN.1 diversification and sublineage transitions. (B) Weekly counts of sequences sampled in GISAID. The sampling peaks through March of 2023 correspond to the peaks in cases in time, but the magnitudes differ. The recent decline in sampling frequencies is evident, dropping from tens of thousands of sequences deposited each month, to just a few thousand a month in 2025, with very limited sampling from the Southern Hemisphere in the past year. (C) The variant frequency data in (A) is mapped onto the global case count data that was historically provided through the Johns Hopkins Center. These graphs are based on all available GISAD entries and visualized using the “Embers” tool available at .
(A) Mutations in the receptor binding domain (RBD) of Spike based on the consensus form of major variants. Amino acid substitutions are based on the consensus form of each variant. Pre-Omicon substitutions are indicated in black, post-Omicron are shown relative to BA.2 in grey, colored to highlight frequent recurrent mutations among major variants. A complete listing of Spike mutational patterns associated with key lineage is available in the supplemental information (Fig. S2). (B) Location of mutations detected in the RBD of the Spike protein relative to the ancestral strain (Protein Data Bank (PDB) 7KRR). “Δ” refers to a deletion. The red mutations are in the RBD region.
SARS-CoV-2 enters host cells by binding to the ACE2 receptor, utilizing two main entry routes: TMPRSS2-dependent membrane fusion and endocytosis. The binding affinity of the receptor binding domain (RBD) of the S protein to ACE2 is altered by several substitutions in various variants. Early omicron variants prefer to enter via endocytosis. After the viral gRNA is released into the cytoplasm, the translation of ORF1a and ORF1b leads to the expression of two polyprotein chains, which are then cleaved by nsp3 (papain-like protease; PLpro) and nsp5 (the main protease; 3CLpro) into functional non-structural proteins (nsps). RNA synthesis is performed by the RNA-dependent RNA polymerase (RdRP), which is formed by nsp12, with the assistance of two cofactors, nsp7 and nsp8. Mutations in nsp12 such as P323L (most SARS-CoV-2 variants) or P323L/G671S (delta variant) enhance RdRp activity. Viral RNAs are mainly replicated in double-membrane vesicles (DMVs), derived from the endoplasmic reticulum (ER) and formed by viral non-structural proteins. Within these DMVs, the replication-transcription complex is assembled (including nsp2–16), which contributes to the synthesis and proofreading of the viral RNA. Several variant mutations in nsp6 alter the viral RNA synthesis process. The (+) gRNA serves as a template for the synthesis of complementary (−)RNA, which is then used to produce more (+) gRNAs. Simultaneously, the subgenomic RNAs (sgRNAs) are generated. The exported sgRNAs encoding the S, E, and M proteins in the cytoplasm are translated into their respective membrane proteins within the ER. The sgRNAs encoding the N protein are translated in the cytosol, where the N protein subsequently associates with the newly replicated gRNA. These newly synthesized viral structural proteins (i.e., S, E, M, and the N-gRNA complex) are transported to the ER-Golgi intermediate compartment (ERGIC), where they assemble to form new virions. The mature virions are then transported out of the cell via exocytosis, completing the viral replication cycle.
(Left) During a primary humoral immune response in lymphoid tissues, B cell receptors on specific naïve B cells recognize antigen. In the context of signals from CD4+ T cells, antigen-specific B cells proliferate and can either differentiate into short-lived plasmablasts and plasma cells or enter the germinal center for rounds of TFH cell-dependent clonal expansion and somatic hypermutation, with the generation of memory B cells and long-lived plasma cells, the latter of which migrate to the bone marrow and constitutively secrete antibody that accumulates in the circulation. (Right) During a secondary humoral immune response with a related antigen that has both shared and unique epitopes, imprinting can occur. (Top) Under conditions of “strong” imprinting, existing MBCs from the primary exposure preferentially capture antigen such that the subsequent plasmablast and plasma cell response is dominantly cross-reactive, and few de novo generated “primary” B cells against the second antigen are generated. The outcome of this can be protective (broadened cross-neutralizing response), non-protective (original antigenic sin, cross-reactive response is not cross-neutralizing) or exacerbate disease (cross-reactive response promotes enhancement of infection; the latter phenomenon has been described for Dengue virus infections, where pre-existing or newly induced cross-reactive antibodies enhance infection in myeloid cells,. (Bottom) Under conditions of “mitigated” imprinting, the existing MBCs capture only a fraction of the variant antigen such that a more balanced anamnestic and de novo responses are generated with production of cross-reactive and type-specific antibodies by plasmablasts and plasma cells.
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