Scientists explore associations between SARS-CoV-2 neutralizing antibodies and receptor-binding domain-selective proliferative memory CD4 T cells

In a recent article posted to the medRxiv* preprint server, researchers depicted the correlations between receptor-binding domain (RBD)-selective proliferative memory CD4 T cells and neutralizing antibodies in coronavirus disease 2019 (COVID-19) vaccinees and convalescent patients.

Study: High titre neutralizing antibodies in response to SARS-CoV-2 infection require RBD-specific CD4 T cells that include proliferative memory cells. Image Credit: Corona Borealis Studio/Shutterstock
Study: High titre neutralizing antibodies in response to SARS-CoV-2 infection require RBD-specific CD4 T cells that include proliferative memory cells. Image Credit: Corona Borealis Studio/Shutterstock

Background

The comprehension of the protective capacity of vaccine-induced and convalescent immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global relevance. This is underscored by the repeated waves of SARS-CoV-2 infections, with frequencies of population-wide immunity against re-infection ranging from 50 to 80% in 2020, based on age, and an anticipated 60% immunity toward symptomatic re-infection with the immuno-elusive Omicron strain.

To stop the COVID-19 pandemic, a sizable section of the community must be immune against the virus or, if they contract the virus, they must develop an immune reaction that reduces signs and symptoms, virus shedding, and subsequent viral transmission. In short, a substantial portion of the population must have long-standing immunity to SARS-CoV-2 infection, comprising immunity triggered by T cells and neutralizing antibodies, to lessen the ongoing COVID-19 burden.

About the study

In the present study, the researchers looked into the relationship between neutralizing antibody levels and memory CD8 and CD4 T cells in recovered COVID-19 patients. The team methodically examined SARS-CoV-2-specific CD8 and CD4 T cell proliferation to determine the extent of long-lasting memory cells in recovered COVID-19 patients.

The scientists examined 25 ADAPT participants from the first SARS-CoV-2 wave between May and October 2020, three months after COVID-19 using recombinant SARS-CoV-2 RBD protein and influenza lysate as a control antigen to evaluate memory CD4 T cell reactions post-SARS-CoV-2 infection. Cryopreserved serum and peripheral blood mononuclear cell (PBMC) samples of an extra 24 ADAPT volunteers were examined to validate the link between RBD-specific CD4 T cell reactions and increased antibody levels. Besides, these PBMC samples were divided into two representative cohorts of 12 participants each, with established low and high SARS-CoV-2 neutralizing titers, in the third month. 

The authors expanded the assessment of T cell reactions to other SARS-CoV-2 antigens employing peptide pools. This approach facilitated them to alter the CD25/OX40 CD4 evaluation to incorporate the recognition of antigen-specific CD8 T cells by including the co-expression of CD137 and CD69 surface markers. They identified ex vivo phenotypic variations in the B and T cell subsets of the antibody high and low cohorts using 20-parameter flow cytometry.

After stimulation with peptide pools at 44 hours, the investigators separated CD25+CD134+ CD4 T cells from four representative participants from the group with elevated antibodies to fully comprehend these antigen-specific CD4 T cells, particularly those selective for RBD. They used bulk T cell receptor (TCR) sequencing on T cells proliferated in response to spike (S), nucleocapsid protein (NP), and RBD versus an unstimulated control from the same four 10X transcriptomics patients. This was to look at the clonal variability of proliferative CD4 T cell subsets and validate the single cell ribonucleic acid sequencing (RNAseq) clonotype data.

Finally, the team examined if COVID-19 vaccination might enhance adaptive immune reaction across the low antibody ADAPT SARS-CoV-2 convalescent participants.

Results and conclusions

The study results showed that higher RBD-specific CD4 T cell levels, notably specific memory cells with vigorous proliferation in vitro, were substantially correlated with higher concentrations of convalescent neutralizing antibodies. On the other hand, about half of the recovered patients exhibited a lack of memory CD4 T cells that were specific for RBD and low neutralizing antibody titers.

These low antibody participants had other, non-RBD, S-specific CD4 T cells. Yet, they exhibited a more inhibitory CTLA-4+ and Foxp3+ cell profile instead of the effector cytotoxic granzymes+, T-bet+, and perforin+ cells identified in high antibody subjects.

Single-cell transcriptomics of antigen-selective CD4+ T cells from subjects with high levels of antibodies revealed heterogeneous RBD-specific CD4+ T cells, including transitional memory, central memory, and regulatory T cells (Tregs). The team also found cytotoxic clusters with a variety of TCR repertoires in these subjects, which were absent in participants with low levels of antibodies.

Nevertheless, SARS-CoV-2 vaccination in low antibody convalescent patients improved RBD-specific memory CD4 T cells somewhat but substantial augmentation in neutralizing antibody titers. According to the current findings, COVID-19 booster vaccination strategies should prioritize addressing CD4 T cell epitopes close to and inside the RBD region.

Overall, the present research illustrated that people with low SARS-CoV-2 neutralizing antibody titers might be at risk of contracting SARS-CoV-2 again. This was due to a lack of a top-quality RBD-selective CD4 T cell reaction, including memory CD4 T cells that proliferate in vitro in the vicinity of RBD and are, therefore, a crucial target for COVID-19 vaccine development.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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