COVID mRNA vaccines fall short in eliciting lung resident memory T cells compared to natural infection

By Dr. Chinta SidharthanReviewed by Danielle Ellis, B.Sc.Apr 10 2023

In a recent study published in the journal Nature Communications, researchers investigated whether coronavirus disease 2019 (COVID-19) messenger ribonucleic acid (mRNA) vaccines induce long-term resident memory T cells in the lungs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Limited induction of polyfunctional lung-resident memory T cells against SARS-CoV-2 by mRNA vaccination compared to infection. Image Credit: piccreative / Shutterstock

Background

While COVID-19 vaccines developed after the onset of the pandemic have successfully reduced SARS-CoV-2 infections, the level of protection these vaccines remains unclear. Despite declining vaccine efficacy over time and new variants eliciting humoral immunity, neutralizing antibodies still exhibit significant cross-protection against COVID-19.

Furthermore, the cellular immunity induced by SARS-CoV-2 infections has been detected in peripheral blood and as resident memory T cells in the lungs, with the number of SARS-CoV-2-specific resident memory T cells correlating to the level of protection.

Recent research indicates that the monovalent mRNA COVID-19 vaccines, such as mRNA-1273 and BNT162b2 produced by Moderna and Pfizer/BioNTech, respectively, induce significant levels of CD8⁺ and CD4⁺ T-cell responses in peripheral blood, and the interferon-gamma (IFNγ) responses against the SARS-CoV-2 spike protein increase after booster doses of the mRNA vaccine. However, whether these mRNA vaccines elicit long-lasting SARS-CoV-2-specific memory T cells that reside in the lungs remains to be explored.

About the study

In the present study, the researchers compared paired lung cross-sections and peripheral blood samples from four cohorts — individuals that were unvaccinated but were also uninfected, unvaccinated individuals who were under long-term SARS-CoV-2 convalescence, individuals who had received two or three doses of the mRNA vaccine in the long term but had not been infected, and uninfected individuals who had received three or four doses of the mRNA vaccine in the short term. The lung cross-sections were obtained when the participants underwent lung resections for unrelated reasons, such as suspected malignancies.

Peptide pools consisting of the SARS-CoV-2 membrane, spike, and nucleotide proteins were used to stimulate the cellular suspensions derived from the lung tissue and the peripheral blood mononuclear cells (PBMC) obtained from the participants to examine the cellular immune responses such as those of interleukins (IL)-10, IL-4, and IFNγ. The levels of SARS-CoV-2 spike-protein-specific T cells in lung and peripheral blood samples were also compared.

Chemoattraction assays using chemokine ligands (CCL) 19 and 21 and sphingosine-1-phosphate (S1P) were used to attract the SARS-CoV-2 membrane, spike, and nucleotide-specific T cells in the lung tissue to assess the nature of the antigen-specific resident T cells in the lungs. The ability of the mRNA vaccine to induce polyfunctional SARS-CoV-2 spike-specific T-cell responses in the lungs and blood was also examined.

The focus of the study was to identify T cell responses against SARS-CoV-2 in paired blood and lung tissue samples of patients that recovered from COVID-19 between 4 to 12 months ago (convalescent infection, left panel) and patients that were uninfected and mRNA vaccinated either between 4 to 10 months ago (LT long term, right panel) or between 1 and 2 months ago (ST short term, right panel). Left: Infection with SARS-CoV-2 triggers the immune system to respond against multiple viral proteins, including the M, N, and S proteins. In the blood of convalescent patients, CD4⁺ T cells responded to M, N, and S peptides by producing IFNγ and both CD4⁺ and CD8⁺ T cells responding to M and N peptides by producing IFNγ and CD107a. Moreover, in the lung of these patients, we found T cells with mainly T_RM (CD69⁺CD103⁺ and CD69⁺CD103^-) phenotypes producing IFNγ or a combination of IFNγ and CD107a. Right: mRNA-vaccinated patients are only exposed to mRNA encoding for the SARS-CoV-2 S protein. In the blood of LT vaccinated patients, CD8⁺ T cells responded to S peptides by producing CD107a and CD4⁺ and CD8⁺ producing IFNγ and CD107a. In the blood of ST-vaccinated patients, the response to S peptides mainly consisted of CD4⁺ T cells producing IFNγ and CD4⁺ and CD8⁺ producing IFNγ and CD107a. In contrast to T cell responses in the lung of convalescent-infected patients, both LT and ST mRNA-vaccinated patients showed a less prominent IFNγ response mainly produced by CD69⁺CD103^- T_RM cells and non-T_RM cells. Last, CD69⁺CD103⁺ T_RM producing IFNγ and CD107a were virtually absent in the lungs of these vaccinated patients.

Results

The results indicated that while the responses of the IFNγ-secreting CD4⁺ T cells against the SARS-CoV-2 spike protein were similar in the lung samples obtained from convalescing individuals and individuals immunized with the mRNA vaccine, the resident memory T cell phenotype presented less frequently in the lung responses from the vaccinated individuals as compared to those of the convalescing individuals. Furthermore, the polyfunctional resident memory T cells exhibiting IFNγ and granulation marker CD107a were almost absent in the long-term and short-term vaccinated individuals.

The cellular immunity induced by symptomatic SARS-CoV-2 infection also seems stronger since the magnitude of immune responses against the SARS-CoV-2 membrane and nucleotide proteins was higher than that against the spike protein. However, the study did detect an increase in the responses of the IFNγ-secreting T cells after recent booster doses of the mRNA vaccine and enhanced IFNγ⁺ T cells in the lungs of short-term vaccinated individuals as compared to long-term vaccinated individuals.

The researchers believe that the incorporation of other SARS-CoV-2 peptide fragments, such as those of the nucleocapsid protein, and the use of mucosal delivery in future vaccines could establish optimal resident memory T cells in the lungs.

Conclusions

Overall, the results indicated that mRNA vaccines do not elicit comparable resident memory T cell responses or polyfunctional resident memory T cell responses against SARS-CoV-2 in the lungs as SARS-CoV-2 infections. Strategies for future vaccines could consider mucosal delivery routes and the incorporation of other SARS-CoV-2 proteins to ensure more effective memory T-cell responses.