T-cell-inducing mRNA COVID-19 vaccine improves effectiveness

In a recent study published in Nature Communications, researchers develop a lipid nanoparticle (LNP)-formulated messenger ribonucleic acid (mRNA)-based T-lymphocyte-inducing antigen encoding three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peptides derived from SARS-CoV-2 non-structural proteins (NSP), thereby enriching class I human leukocyte antigen (HLA-I) epitopes (HLA-EPs).

Study: An mRNA-based T-cell-inducing antigen strengthens COVID-19 vaccine against SARS-CoV-2 variants. Image Credit: medienspot / Shutterstock.comStudy: An mRNA-based T-cell-inducing antigen strengthens COVID-19 vaccine against SARS-CoV-2 variants. Image Credit: medienspot / Shutterstock.com


Herd immunization attained through mass-scale vaccinations can effectively prevent the spread of infectious diseases. However, most of the coronavirus disease 2019 (COVID-19) vaccines that are currently authorized for use comprise SARS-CoV-2 Wuhan-Hu-1 strain spike (S) protein or S receptor-binding domain (RBD).

Many novel SARS-CoV-2 variants possess S protein mutations that facilitate evasion of humoral antibody-mediated immunity, thereby rendering these vaccines less effective. Furthermore, humoral immunity wanes with time; therefore, antigens that induce cell-mediated immunity, regulated by T lymphocytes, may be incorporated into COVID-19 vaccines to improve their efficacy and reduce the global burden of COVID-19.

About the study

In the present study, researchers investigate whether the induction of broad and potent cell-mediated immunity by the LNP-formulated mRNA-based vaccine could be a practical approach to strengthen COVID-19 vaccine effectiveness.

Serum samples were obtained from COVID-19 convalescents, from which peripheral blood mononuclear cells (PMBCs) were isolated and memory-type cluster of differentiation 8+ (CD8+) T-lymphocytes were expanded.

BALB/c mice, HLA-A*11:01/DR1 transgenic mice, HLA-A*02:01/DR1 transgenic mice, and rhesus macaques were used for SARS-CoV-2 challenge and vaccination experiments. Functional SARS-CoV-2 HLA-I epitopes were analyzed to identify epitope-enriched fragments with 50% inhibitory concentrations (IC50) below 10 nanomolar (nM).

The epitopes were predicted to correspond to the 78 most frequent HLA-I alleles. Further, human embryonic kidney 293T (HEK293T) cells were transfected with plasmids encoding the predicted fragments of SARS-CoV-2 open reading frames (ORFs). These cells were co-cultured with HLA genotype-matched memory T-lymphocytes from COVID-19 convalescents and sorted using flow cytometry.

The mRNAs were synthesized in vitro using T7 polymerase-mediated deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) transcription and naked mRNA expression in HEK193T cells was validated. Subsequently, LNP formulations were prepared.

To detect mRNA-LNP distribution in vivo, BALB/c mice were intramuscularly inoculated with luciferase mRNA-LNP. Further, HLA-A*02:01/DR1 and HLA-A*11:01/DR1 transgenic mice were randomly allotted to receive LNP-HLA-EPs, LNP comprising the SARS-CoV-2 Beta variant of concern (VOC), RBD (LNP-RBDbeta), or both. Rhesus macaques received similar injections.

Enzyme-linked immunosorbent assays (ELISAs) were performed to determine serological anti-RBD immunoglobulin G (IgG) titers. In addition, SARS-CoV-2 pseudoviruses were generated and neutralization assays were performed to assess SARS-CoV-2 VOC neutralization.

ELISpot assays of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) were performed. Cells in the spleen and lymph nodes were profiled, and C-X-C chemokine receptor 5 (CXCR5) and C-X-C motif chemokine ligand 13 (CXCL13) levels in the lymph nodes were assessed.

HLA tetramer assays were performed. Tissues obtained following vaccination and SARS-CoV-2 challenge were subjected to histopathological examination. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed for viral load determination.


The recombinant mRNA transcript was coded for HLA-EPs representing the NSP-31443–1605, NSP-4232–444, and NSP-61-201 sites. The reporter cells presenting the epitopes activated cognate CD8+ T-lymphocytes, which secreted granzyme B (GzB) and induced apoptosis in the reporter cells.

LNP-HLA-EPs-vaccinated HLA-transgenic mice exhibited significant increases in the frequencies of CD8+ T-lymphocytes and helper T-cell type 1 (Th1)-based responses.

Vaccination significantly expanded the population of CD8+ CD44+ CD62L+ central memory T-cells (Tcm) and effector memory T-lymphocytes (Tem) in both HLA-transgenic murine models, thus indicating the activation of cell-based immunity by HLA-Eps. In addition, the fraction of epitope-specific IFN-γ- and tumour necrosis factor-alpha (TNF-α)-producing splenocytes enlarged following HLA-EP stimulation.

HLA-EPs induced potent cell-mediated responses against SARS-CoV-2 in HLA-transgenic mice. Notably, HLA-EP sequences were highly preserved in the SARS-CoV-2 variants.

Among the transgenic murine animals and macaques, dual vaccination with the HLA-EP-encoding LNP-based mRNAs and RBDbeta was more effective in preventing SARS-CoV-2 infection by Alpha, Beta, Gamma, and Delta VOCs, as well as the BA.1 sub-VOC of Omicron than LNP-RBDbeta vaccination only.

This was confirmed by the significantly increased CXCR5 and CXCL13 expression in the lymph nodes and minimal histopathological damage in dually immunized animals. HLA-EP immunogenicity was not affected by SARS-CoV-2 VOC mutations.


Based on the study findings, stimulating cell-mediated and humoral immune responses could improve COVID-19 vaccine effectiveness against the SARS-CoV-2 ancestral strain and novel VOCs. Next-generation vaccines must comprise cytotoxic lymphocyte-inducing S protein and non-S protein antigenic fragments that are highly conserved among SARS-CoV-2 VOCs for broad and potent action.

Journal reference:
  • Tai, W., Feng, S., Chai, B. et al. (2023). An mRNA-based T-cell-inducing antigen strengthens COVID-19 vaccine against SARS-CoV-2 variants. Nature Communications 14(2962). doi:10.1038/s41467-023-38751-8
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.


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