The degree of protection provided by COVID-19 vaccines, which were created after the start of the pandemic, has successfully decreased SARS-CoV-2 infections. Neutralizing antibodies still show strong cross-protection against COVID-19 despite the vaccine’s efficacy waning over time and new variations inducing humoral immunity.

The number of resident memory T cells that are specific to SARS-CoV-2 correlates with the degree of protection, and the cellular immunity elicited by SARS-CoV-2 infections has also been found in peripheral blood and as resident memory T cells in the lungs.

According to recent studies, the monovalent mRNA COVID-19 vaccines, such as mRNA-1273 and BNT162b2 made by Moderna and Pfizer/BioNTech, respectively, significantly increase peripheral blood levels of CD8+ and CD4+ T-cell responses, and interferon-gamma (IFN) responses against the SARS-CoV-2 spike protein.

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.