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Antibody and CD8+ T Cell Responses: How the Delta Variant Evades Immunity?

SARS-CoV-2 variants of concern (VOC) are defined by the World Health Organization (WHO) as forms of the virus with mutations that increase its transmission, virulence, associated COVID-19 disease severity, or decrease the efficacy of available therapeutics (e.g., vaccines and monoclonal antibodies). Currently, the WHO Virus Evolution Working Group lists four SARS-CoV-2 VOC, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta). Among these, the Delta variant has rapidly become a prevailing concern since its emergence in India and spread through the UK, Asia, and the USA. For example, the Delta variant’s prevalence in Singapore quickly rose since first detected in March, becoming the predominant strain (45.7%) within one month.

“SARS-CoV-2 lineages prevalent in Singapore in January to May 2021. The number of cases infected by various SARS-CoV-2 variants collected from January to May 2021 in Singapore with genomes sequenced and shared via GISAID are shown in both (A) timeline presentation and (B) Pie chart with percentages of each variant indicated.” Retrieved from Wang et al. 2021.(https://creativecommons.org/licenses/by/4.0/).

Similarly, data shared by the CDC in August revealed a rise in the prevalence of the SARS-CoV-2 Delta variant ranging from 97.7% to 99.8% in all USA regions.

Prevalence of SARS-CoV-2 Delta Variant by Region-USA. Retrieved from CDC COVID DATA TRACKER.

Antibody neutralization potency

Given the concurrent uptick in vaccine breakthrough COVID-19 cases, investigators are keen on understanding the mechanisms underscoring Delta’s ability to evade immunity. In a recent study, Wang and colleagues at various institutes in Singapore asked whether antibodies elicited by the BNT162b2 mRNA vaccine developed by Pfizer provide sufficient protection against the SARS-CoV-2 Delta variant.

Enabled by a pseudovirus assay, where SARS-CoV-2 Spike protein variants are expressed on the surface of lentiviruses for infection of cells expressing the ACE-2 receptor, Wang et al. directly tested the effects of Spike mutations on antibody neutralization activity. Investigators found that antibodies elicited by the BNT162b2 mRNA vaccine were significantly weaker in neutralizing pseudoviruses carrying Delta Spike variants (37% neutralization activity) than their neutralizing activity against Wuhan Spike expressing pseudoviruses (76%).

However, these findings are at odds with an earlier study by Liu et al., showing that BNT162b2 mRNA vaccine-induced antibodies remained neutralizing against most VOC. In this study, chimeric SARS-CoV-2 viruses modified to express VOC Spike sequences were used to evaluate antibody neutralizing activity in a plaque reduction neutralization test. Liu and colleagues found a modest decline in neutralizing antibody activity against the B.1.617.2 Delta variant (Liu et al. 2021).

Therefore, it remains conflictive whether immune evasion by the SARS-CoV-2 Delta variant is partly due to reduced antibody neutralizing activity in immunized individuals.

CD8+ T cell cytotoxic responses

Besides neutralizing antibody responses, it has been established that mRNA vaccines, such as BNT162b2 also induce protective cellular immunity, both CD4+ and CD8+ T cell responses (Sahin et al. 2021, Painter et al. 2021). Nevertheless, T cell immunity has also been shown to diminish against VOC (e.g., B.1.1.7 Alpha and B.1.351 Beta variants) in individuals immunized with mRNA vaccines from Moderna and Pfizer (Gallagher et al. 2021). Similarly, a new study supports reduced T cell immunity against the Delta variant (Zhang et al. 2021).

Because vaccine-induced T cell immunity is critical for curving disease severity and viral clearance, Zhang and colleagues analyzed how mutations in several VOC affect MHC-dependent peptide presentation and T cell responses (Tan et al. 2021). Synthetic peptides allowed the team to validate several SARS-CoV-2 peptides as CD8+ T cell epitopes. Among these validated peptides, four identified epitopes are known to be mutated in different VOC. For example, one epitope corresponds to a peptide within the Spike protein, which carries the mutation L452R in the Delta variant. Critically, Zhang et al. found that for the four CD8+ T cell validated epitopes, the presence of variant mutations significantly reduced their ability to activate T cells from CoronaVac vaccinated individuals (Zhang et al. 2021).

For the BNT162b2 mRNA vaccine, a recent study in the UK found a decline in its effectiveness to 88% among individuals fully vaccinated (i.e., two doses) and infected with the Delta variant (Lopez Bernal et al. 2021,). Nevertheless, the BNT162b2 mRNA vaccine remains sufficiently effective in preventing COVID-19 symptomatic disease due to infections with VOC. Overall, much more remains to be uncovered about the molecular mechanisms underscoring immune evasion by the current SARS-CoV-2 variants. Understanding the underlying mechanisms will help in addressing future immunization needs as more variants emerge.

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How much do you know about SARS-CoV2?

  1. A. Alpha
    B. Delta
    C. Gamma
  2. A. Virus of care
    B. Variant of consideration
    C. Variants of concern
  3. A. Neutralizing
    B. Monoclonal
    C. Bi-specific
  4. A. Moderna
    B. Novavax
    C. Pfizer
  5. A. Onset
    B. Duration
    C. Severity


Gallagher, K. M. E. et al. SARS -CoV-2 T-cell immunity to variants of concern following vaccination. bioRxiv  Prepr. Serv. Biol. (2021) doi:10.1101/2021.05.03.442455.

Liu, J. et al. BNT162b2-elicited neutralization of B.1.617 and other SARS-CoV-2 variants. Nature (2021) doi:10.1038/s41586-021-03693-y.

Lopez Bernal, J. et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N. Engl. J. Med. (2021) doi:10.1056/nejmoa2108891.

Painter, M.M. et al. Rapid induction of antigen-specific CD4+ T cells is associated with coordinated humoral and cellular immunity to SARS-CoV-2 mRNA vaccination. Immunity (2021) doi.org/10.1016/j.immuni.2021.08.001.

Sahin, U. et al. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature (2021) doi:10.1038/s41586-021-03653-6.

Tan, A. T. et al. Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients. Cell Rep. (2021) doi:10.1016/j.celrep.2021.108728.

Wang, B. et al. Resistance of SARS-CoV-2 Delta variant to neutralization by BNT162b2-elicited antibodies in Asians. The Lancet (2021) doi.org/10.1016/j.lanwpc.2021.100276.

Zhang, H. et al. Profiling CD8+ T cell epitopes of COVID-19 convalescents reveals reduced cellular immune responses to SARS-CoV-2 variants. Cell Reports (2021) doi.org/10.1016/j.celrep.2021.109708.

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