In a recent study published in the journal of Science Translational Medicine, researchers examined neutralizing antibody and T cell responses in 44 South African coronavirus disease 2019 (COVID-19) patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Beta variant or before its emergence to offer an overall assessment of immune evasion. They found that Beta-infected individuals had significant spike-specific CD4 and CD8 T cell responses, similar to the patients from the first wave of the COVID-19 pandemic.
SARS-CoV-2 variants that can evade neutralization have evolved in recent times, posing a threat to COVID-19 vaccine efficacy. T cell responses are important for protection against reinfection and severe illness, but the impact of spike mutations on T cell immunity is unknown.
About the study
During the first wave of the COVID-19 pandemic before the advent of the Beta variant, and during the second wave of the pandemic after the Beta variant became the dominant lineage, neutralizing antibodies and T cell responses to SARS-CoV-2 spikes were assessed in hospitalized COVID-19 patients. First, the researchers looked at the extent of CD4 and CD8 T cell responses to SARS-CoV-2's spike protein in first and second-wave patients. Also, examined the production of IFN-, TNF-, and IL-2 in response to a peptide pool encompassing the entire ancestral spike protein using flow cytometry.
The researchers compared the frequency of ancestral SARS-CoV-2 spike-, nucleocapsid (N)-, and membrane (M)-specific CD4 and CD8 T cells in convalescent COVID-19 patients to see if similar patterns were maintained in convalescent COVID-19 donors. The patterns of spike-specific T cell responses were also compared cross-sectionally across acute and convalescent COVID-19 patients.
The researchers tested the recognition of peptide pools selectively spanning the variable areas of the spike, one made of ancestral peptides ('WT pool') and the other Beta-mutated peptides ('Beta pool') because Beta-associated mutations occur only at a few residues of the spike protein. Then, in patients infected with the Beta lineage, they examined peptide responses.
They further evaluated participants' neutralizing antibody responses to the ancestral and Beta spike proteins to get an overall score of immunological escape. The identification of WT and Beta peptide pools by CD8 T cells were then defined.
Responses to specific epitopes were evaluated in first wave COVID-19 patients to acquire a better understanding of CD4 cell recognition of variable spike epitopes in patients responding to the WT pool.
Predicted HLA class II restriction for each epitope was established in silico and compared to HLA class II molecules expressed in the study group to discover potential HLA restriction related to the recognition of the L18, D80, and D215 epitopes.
Results and conclusion
The results showed that infection with the Beta variant elicits robust T cell responses that are comparable to those induced by ancestral strains. Also, the Beta spike mutations alter the identification of epitopes by CD4 T lymphocytes targeting variable spike areas in patients infected with ancestral lineages. The loss of the identification of Beta mutant spike epitopes, on the other hand, had only a minimal impact on the CD4 Th1 cell response overall. Furthermore, alterations in Beta had little effect on CD8 T cell responses to spike.
Regardless of the SARS-CoV-2 protein tested, the researchers found similar T cell response rates in first- and second-wave convalescent donors for both CD4 and CD8 T cells, implying that T cell responses to Beta were not dampened in general.
Three epitopes comprising the D215, L18, or D80 residues were shown to be uniquely recognized by CD4 T lymphocytes, and mutated Beta variants were linked to a loss of response. The expected MHC class II alleles restricting the D215 epitope were discovered using HLA genotyping, and in silico analyses indicated that mutations would no longer be restricted by those alleles.
The researchers discovered that mutations in Beta had no effect on spike-specific CD8 responses. In three of the cohort members, a single epitope was anticipated to account for the CD8 response to the WT or Beta pool. The mutation fell outside the core binding pattern for the projected restricted Class I HLA molecules expressed by these donors, which was consistent with the identification of both WT and mutant pools. These findings highlight the importance of HLA polymorphism in limiting the effect of T cell escape on SARS-CoV-2 immunity to viral variants.
In conclusion, the researchers show that viral mutations have a minimal effect on T cell immunity, which could explain the protection provided by vaccination against severe COVID-19, despite the significant loss of neutralizing antibodies. The current and previous studies have demonstrated that vaccine-induced T cell immunity identifies SARS-CoV-2 variants well. While SARS-CoV-2 variant-based second-generation vaccines are desirable, they may not be required to increase T cell responses.