SARS-CoV-2 Omicron variant: recent progress and future perspectives

Abstract

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, there have been a few variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), one of which is the Omicron variant (B.1.1.529). The Omicron variant is the most mutated SARS-CoV-2 variant, and its high transmissibility and immune evasion ability have raised global concerns. Owing to its enhanced transmissibility, Omicron has rapidly replaced Delta as the dominant variant in several regions. However, recent studies have shown that the Omicron variant exhibits reduced pathogenicity due to altered cell tropism. In addition, Omicron exhibits significant resistance to the neutralizing activity of vaccines, convalescent serum, and most antibody therapies. In the present review, recent advances in the molecular and clinical characteristics of the infectivity, pathogenicity, and immune evasion of Omicron variant was summarized, and potential therapeutic applications in response to Omicron infection were discussed. Furthermore, we highlighted potential response to future waves and strategies to end the pandemic.

Fig. 1

The sub-lineages of the SARS-CoV-2 Omicron variant. a The Omicron variant has evolved into three sub-lineages: BA.1, BA.2, and BA.3. b Venn diagram showing the mutations located on the S protein RBD of BA.1, BA.2, and BA.3. c Transmission speed of SARS-CoV-2 wild-type, Delta, and Omicron variants

Fig. 2

The different entry routes and pathogenesis between SASR-CoV-2 WT or previous variants and Omicron variant. Left: SASR-CoV-2 WT or previous variants mainly infect lung epithelial cells, which are TMPRSS2 high expressed cells, and enter host cells by plasma membrane route. In the plasma membrane entry route, virus first binds to ACE2, then binds to TMPRSS2 and is cleaved at the S proteins. Next, the S protein anchors to the cell membrane and mediates fusion of the viral membrane with the cell membrane. Finally, a pore is formed in the membrane and the viral genome is released into the cell. Right: SASR-CoV-2 Omicron variant mainly infects the upper airway epithelial cells, which are TMPRSS2 low-expressed cells, and enter host cells by the endosomal route. In the endosomal entry route, a virus first binds to ACE2 and the virus–ACE2 complex is internalized via endocytosis into the endosomes, where S protein is cleaved by Cathepsin L. Then the viral and endosomal membranes are fused together to form a pore and release the viral genome

Fig. 3

Vaccine-induced immunity against SARS-CoV-2 Omicron. a SARS-CoV-2 Omicron escapes vaccine immunity. The major vaccine candidates targeting SARS-CoV-2 induce antibodies after vaccination that can neutralize SARS-CoV-2 WT but are less effective against Omicron. b T-cell immune responses induced by SARS-CoV-2 infection or vaccination are effective against Omicron infection. c Booster vaccination or Heterologous booster vaccination can induce increased antibodies, which can provide adequate neutralization against Omicron

Fig. 4

Mechanisms of antiviral drugs and potential treatments against SARS-CoV-2 Omicron. Extracellularly, soluble ACE2, neutralizing antibodies, and palmitoylated ACE2-enriched EVs can capture SARS-CoV-2 viruses and inhibit SARS-CoV-2 interaction with cell-surface ACE2, resulting in reduced infection. Intracellularly, on the one hand, the released viral genome is translated to produce the polyproteins, which are cleaved by proteases to yield the RNA replicase–transcriptase complex. Then viral genome is duplicated and mRNA encoding structural proteins are transcribed. The protease inhibitors and RNA polymerase inhibitors can be used to inhibit the process of cleavage, transcription, and replication. On the other hand, the N protein of SARS-CoV-2 undergoes LLPS with RNA, which inhibits the aggregation and Lys-63-linked poly-ubiquitination of MAVS and thereby suppresses the innate antiviral immune response. The usage of interfering peptides disrupting N protein droplets can restore the impaired immune response