Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells

Abstract

Respiratory tract resident memory T cells (T _RM ), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory T _RM . We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron–based nanoparticles. Here, we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influenced influenza-specific cell–mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 T _RM in the lung and draining lymph nodes. Contralateral, compared with ipsilateral, intramuscular boosting broadened the distribution of lymph node T _RM and T follicular helper cells but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory but augmented distribution to the respiratory mucosa. Combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung T _RM . Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung T _RM that can be further expanded by an additional intranasal immunization.

Abstract

Intramuscular mRNA vaccination induces pulmonary resident memory T cells that can be further expanded with intranasal boosting.

Boosting up flu-specific lung T cells

Despite the rapid embrace of mRNA vaccine technologies catalyzed by the COVID-19 pandemic, the extent of the resident memory T cell (TRM) response in the lung after different routes of mRNA vaccination remains uncertain. By immunizing mice with a self-amplifying mRNA vaccine for influenza nucleoprotein encapsulated in dendritic nanoparticles, Künzli and O’Flanagan et al. assessed how various routes of vaccine administration affected CD4 and CD8 TRM responses. While intramuscular prime and boost immunizations were sufficient to induce respiratory TRM, an additional intranasal boost further expanded both circulating and lung resident memory CD4 and CD8 T cells. These findings indicate that optimization of the routes of administration and sequence of mRNA vaccine doses can elicit robust antibody and lung TRM responses to pathogenic respiratory viruses. –IRW