Covid-19 Omicron's impact on humoral and cellular immunity induced by vaccination or antibody-based drugs

In recent weeks, the medical community has been confronted with the newly emerged COVID-19 coronavirus strain dubbed 'Omicron' (B.1.1.529).  Given the highly unstable nature of RNA virus' genome, the likelihood of COVID-19 virus adopting novel mutations was largely anticipated.  Despite the above, the majority of the anti-COVID-19 vaccines developed to date by the biopharmaceutical industries target a single protein, i.e. spike protein.  These include Moderna's as well as Pfizer-BioNTech's mRNA vaccines encoding the recombinant COVID-19 full-length spike protein (conformation-stabilized), Johnson & Johnson's (Janssen) replication-incompetent adenovirus expressing the spike protein, etc. (Mateus et al., 2021).

Following the identification of the coronavirus that causes respiratory diseases in Wuhan (China) in late 2019, multiple variants arose globally.  The most notable among them are Alpha (B.1.1.7; United Kingdom), Beta (B.1.351; South Africa), Gamma (P.1; Brazil), and Delta (B.1.617.2; India).  The continued emergence of variants has fueled multiple 'waves of outbreaks' experienced since then (Tao et al., 2021).

A high number of mutations found in the genome of Omicron (B.1.1.529) coronavirus has necessitated further classification into the sublineages BA.1​/B.1.1.529.1, BA.2​/B.1.1.529.2, and BA.3​/B.1.1.529.3.  Among the sixty mutations identified are 50 nonsynonymous (alters amino acid), 8 synonymous (amino acid remains unchanged), and 2 non-coding types, which impact various viral genes (Nsp3, Nsp4, Nsp5, Nsp6, Nsp12, Nsp14, membrane protein, nucleocapsid protein, envelope protein).  A significant fraction of these mutations (3 deletions, 1 insertion; 30 amino acid-changing) occurred in the spike protein, with 15 in the receptor-binding domain alone, raising the speculation whether vaccination may have imposed selection pressure on the virus to evolve (Chen et al., 2021).  Further, 6 mutations (A1892T, P314L, I189V, K38R, V57V, T492I) affect RNA-dependent RNA polymerase (RdRP) (Bansal et al., 2021).

Subsequently, it was found that the novel mutations in Omicron may abrogate the humoral immunity acquired either naturally (via exposure to the prior COVID-19 strains) or through vaccination.  Humoral immunity relies on the antibodies secreted by B cells to neutralize incoming viruses, thus playing a key role in blocking infectivity.  One report utilizing a topology-based artificial intelligence model predicted that Omicron may be more infectious than Delta coronavirus (Chen et al., 2021).

Another report determined that the efficacy of mRNA vaccine prepared by Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) diminished considerably (as well as other vaccines targeting the spike protein) against Omicron (Cameroni et al., 2021).   The potential benefit of lessening the impact through booster (for mRNA vaccine) was described (Garcia-Beltran et al., 2021). 

Similarly, the activity of most antibody-based drugs targeting the spike protein was lost against Omicron though a handful of them retained activity.  The efficacy of antibody drugs targeting a region outside the receptor-binding motif was less impacted (Sotrovimab) (Cameroni et al., 2021).

Interestingly, the decline in humoral response was lesser (5 times) for those who have been previously infected with COVID-19 (plus vaccinated), suggesting that the antibody-based immunity targeting multiple antigenic sites (in addition to spike protein) may provide greater protection (Cameroni et al., 2021).

Cellular immunity is based on T cells and involves the activation of cytotoxic T cells (CTL), activation of macrophages and natural killer cells, and secretion of cytokines in response to antigen.  A critical component of cellular immunity is cytotoxic T lymphocyte recognizing specific antigens.  Previously, the ability of mRNA vaccine (ex. mRNA-1273 by Moderna) to induce CD4+ T helper cells and CD8+ CTLs was documented in vaccinated individuals (Mateus et al., 2021).

To determine if the T cell-based immunity was compromised, the investigators at the Johns Hopkins School of Medicine (USA) examined the Omicron sequence encoding viral epitopes recognized by CD8+ T-cells (Redd et al., 2021).  They showed that only 1 of 50 Omicron-associated mutations occurred in the epitope (GVYFASTEK) recognized by CD8+ T-cells.  Further, the epitope (recognized by HLA type HLA*A03:01 and HLA*A11:01) represents a "low-prevalent" target.  The study involved 30 COVID-19 infected individuals, accounting for 52 unique COVID-19 epitopes.  The retaining of T cell-based immunity may account for lesser severity and hospitalization observed despite the greater transmissibility of Omicron.  Its impact on cancer patients remains to be determined.

Gene recombinations resulting in mutations of the spike proteins, in particular the receptor-binding domain (RBD) appears to be the cause for transmissions of the virus between different hosts (A collection of known mutations). 

Omicron amino acid substitutions and prevalence

Amino acid substitutions and their prevalence in the Omicron RBD sequences reported in GIAID as of December 9,2021 (ambiguous amino acid substitutions are indicated with strike through cells [/]). Shown are also the substitutions found in other variants. K417N mutation in Delta is found only in a fraction of sequences. K417N mutation in Delta is found only in a fraction of sequences (Adapted from Cameroni et al.;  PMC).

 Omicron VOC, as of December 9, 2021 VOC VOI

References

Bansal K, Kumar S.  Mutational cascade of SARS-CoV-2 leading to evolution and emergence of omicron variant.  bioRxiv (2021). Preprint.  doi: https://doi.org/10.1101/2021.12.06.471389

Cameroni E, Saliba C, et al.  Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift.  bioRxiv. 2021 Dec 14:2021.12.12.472269.  (2021) Preprint.  PMID: 34931194

Chen J, Wei GW et al. Omicron (B.1.1.529): Infectivity, vaccine breakthrough, and antibody resistance.  ArXiv.  Dec 1:arXiv:2112.01318v1 (2021).  Preprint.  PMID: 34873578

Garcia-Beltran WF, St Denis KJ, et al.   mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant.   medRxiv. Dec 14:2021.12.14.21267755 (2021).  Preprint.  PMID: 34931201

Mateus J, Dan JM, et al.  Low-dose mRNA-1273 COVID-19 vaccine generates durable memory enhanced by cross-reactive T cells.  Science.  374(6566):eabj9853  (2021).  PMID: 34519540

Redd AD, Nardin A, et al. Minimal cross-over between mutations associated with Omicron variant of SARS-CoV-2 and CD8+ T cell epitopes identified in COVID-19 convalescent individuals.  bioRxiv. Dec 9:2021.12.06.471446. (2021).  Preprint.  PMID: 34909772

Tao K, Shafer RW, et al. The biological and clinical significance of emerging SARS-CoV-2 variants.  Nat Rev Genet. (12):757-773 (2021).  PMID: 34535792