Combination of intramuscular and intranasal mRNA vaccination induces more lung-resident memory T cells

In response to COVID-19 outbreaks, mRNA vaccine technology has been rapidly developed and successfully applied. the standard method of immunization with the SARS-CoV-2 mRNA vaccine consists of two intramuscular injections of immunization at 21 or 28 days intervals, followed by a booster immunization several months later.

Advantages of mRNA vaccines include:

* Strong immunogenicity against CD8+ T and CD4+ T cells

* No carrier immunity, allowing for homologous boosting

* Can be produced rapidly on a large scale

mRNA vaccines for additional diseases, including as influenza and cancers, are now being developed. Although mRAN vaccine activation of T cells in the blood has been thoroughly explored, there has been minimal study targeting antigen-specific T cells in local locations such as the lung. Vaccine stimulation of memory T cells in the lung is a supplementary technique for successful neutralizing antibody production that may potentially provide protection in immunocompromised individuals. However, it is uncertain if mRNA immunization may induce resident memory T cells in the lung.

The University of Minnesota's David Masopust's team released an article in Science Immunology titled "Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells". The study examines the impact of various immunization methods on mRNA vaccination-induced tissue resident memory CD4+ and CD8+ T lymphocytes.

To investigate whether mRNA vaccine is capable of producing memory T cells, the authors first sensitized mice with 5ug of influenza virus mRNA, followed by a 5ug treatment 28 days later. Antigen-specific CD8+ and CD4+ T cells were tracked in individual tissues using MHC I (H-2Kb NP366-375) and MHC II (I-Ab NP261-277) tetramers. The assay was performed more than 28 days after the last administration. The booster shot increased CD8+ memory T cells in the spleen compared to a single immunization. I-Ab NP261-277 tetramers and CD4 memory T cells were also induced in the lung parenchyma after booster immunization. 38 days after vaccination, the authors subjected mice to intranasal influenza virus infection and found a significant reduction in mortality after immunization.

The authors also compared the effects of different immunization routes on local memory T cells. Compared to intramuscular injection, intranasal immunization induced more CD103 CD8 T cells in the lung parenchyma as well as in the draining lymph nodes, suggesting that the immunization route affects the T cell phenotype induced by local immunization. Given the effects of intranasal immunization on CD8+ T cells, the authors also explored the effects of different immunization routes on antigen-specific CD4+ T cell phenotypes. In contrast, intranasal immunization was found to induce long-lived T follicular helper cells in the draining lymph nodes but not in the lungs.

Intranasal immunization induces more memory CD4+ T cells compared to intramuscular injection. Although different routes resulted in different numbers of memory T cells being produced, both routes were able to induce sufficient resident memory T cells. Finally, the authors tried a combination of two intramuscular and a third booster intranasal mRNA vaccines, and the analysis found that this combination induced higher levels of circulating and lung-resident memory T cells.

This study systematically compared the distribution characteristics of antigen-specific CD8+ and CD4+ memory T cells induced by intramuscular as well as intranasal mRNA vaccination. These data provide possible strategic support for future optimization of vaccines to achieve long-term protective potential.