Researchers analyze targets of human T cell recognition against all coronaviruses

By Neha MathurReviewed by Aimee MolineuxJan 9 2023

In a recent study posted to the bioRxiv* preprint server, researchers analyzed T cell reactivity against alpha and beta common cold coronaviruses (CoVs) [(CCC)] to inform the development of pan-CoV vaccine concepts.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

The CoV family encompasses many viruses with the potential to infect humans, particularly betaCoVs having viruses with zoonotic spillover potential and causing pandemics. Beta CoV, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the ongoing pandemic, and Middle Eastern respiratory syndrome CoV caused another previously. Thus, there is an urgent need for vaccines to combat potential CoV outbreaks in the future.

Several studies conducted during the SARS-CoV-2-induced pandemic generated a wealth of knowledge that could be particularly useful in this context. Studies found that early broad and polyantigenic T-cell responses could resolve SARS-CoV-2 infection and contribute towards reducing viral loads. Most importantly, studies found that while neutralizing antibodies (nAbs) wane over time, T-cell reactivity against SARS-CoV-2 variants remains. Though they do not prevent reinfection, T cells protect against severe coronavirus disease 2019 (COVID-19). In addition, they remain effective in individuals with agammaglobulinemia and low B cell counts.

Based on this data, scientists have proposed that conserved immunodominant T cell regions (across multiple CoVs) could effectively induce a panCoV response alongside the induction of broadly reactive nAb responses. Grifoni et al. found that over 100 studies have extensively explored SARS-CoV-2-induced T cell epitope catalogs. However, there is a shortage of data on antigens dominantly recognized in T-cell responses elicited by CCC infection.

Strikingly, CCC T cell immunity exists in the vast majority of the general population unknowingly exposed to CCC and persists over time. Data on the pattern of antigen’s immunodominance and T cell epitope catalogs identified by the global population following CCC exposure could greatly help the development of future pan-CoV vaccines.

About the study

In the present study, researchers explored pan-CoV vaccines that could elicit broadly cross-reactive cluster of differentiation (CD)4+ T cell responses. They used alpha (NL63) and beta (OC43) viruses as alpha and beta CCC virus prototypes, respectively, which could serve as CCC CD4+ T cell targets.

The researchers collected peripheral blood mononuclear cells (PBMCs) from 88 healthy adults (First Cohort) with a median age of 46 years and a 52:48 female-to-male ratio between March 2020 and February 2021. They were seronegative for spike (S) protein of SARS-CoV-2 at sample collection. The team used immunoglobulin G enzyme-linked immunosorbent assay (ELISA) to measure antibodies to OC43 and NL63.

Furthermore, the researchers performed an extensive T-cell epitope screening. For 18 epitopes, they also experimentally assessed the T cell capability to cross-recognize sequences from other CoV groups, e.g., non-beta-non-sarbecoCoVs. In this way, the researchers determined which PBMC samples elicited broad T-cell responses that recognized antigens and epitopes.

Study findings

The researchers investigated common antigenic targets across multiple CoVs. The current study results revealed that structural proteins, S, membrane (M), nucleocapsid (N), and the non-structural protein, NSP3 were immunodominant for both prototype viruses. Regarding immunodominance specific to CCC, they identified NL63- specific T cell responses prominently recognized NSP2, and OC43-specific T cells recognized NSP12.

The present study also identified the epitope repertoire of human CCC-specific memory CD4+ T cells. The team identified 78 OC43 and 87 NL63-specific epitopes, with an average breadth of seven epitopes per PBMC sample. The lower number of CCC-specific epitopes detected in the present study reflects that the sample donors had less recent exposure to a presumably unknown CoV.

Of the total 165 epitopes identified by ex vivo reactivity in NL63 and OC43, only two epitopes showed a substantial overlap, as assessed by a 67% sequence homology. The remaining NL63 and OC43 epitope repertoire showed a 4% overlap compared to SARS-CoV-2-specific epitopes described earlier. The researchers pursued immunodominant T cell regions conserved across multiple CoVs for inducing a panCoV T cell response. The study tested 594 CoV epitope sequences, the largest dataset to date, and found T cell cross-reactivity in 29/40 CoV-conserved epitopes tested, i.e., in 73% of cases.

Conversely, with sarbecoCoVs, they found T cell cross-reactivity in only six of 12 epitopes tested, i.e., in 50% of cases. There were fewer T cell cross-reactivity cases, even when the observed sequence conservation was relatively higher. Indeed, previous exposure was another critical determinant of T cell cross-reactivity alongside the degree of sequence homology conservation for sarbecoCoVs, including SARS-CoV-2.

Since all the study samples were SARS-CoV-2-seronegative samples, the lack of previous exposure to sarbecoCoVs was associated with a lower degree of T cell cross-reactivity amongst different representatives of sarbecoCoV sequences.

Conclusions

The researchers observed that previous exposure to CoVs, including betaCoV, such as SARS-CoV-2, also determined T cell cross-reactivity besides sequence conservation. SARS-CoV-2 has infected the vast majority of the world population, so it appears feasible to generate a dataset comprising information on epitopes and antigens of high immunodominance so that they effectively induce cross-reactive CD4+ T cells against several different CoVs. Overall, the study data could prove immensely useful in designing vaccines against sarbecoCoVs of zoonotic origin and potential pandemic concern.

*Important notice: bioRxiv 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.