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The efficacy and safety of coronavirus disease 2019 (COVID-19) booster vaccines remain limited. We investigated the immunogenicity and adverse events of the third dose of mRNA vaccines in healthy adults.Volunteers vaccinated with two doses of the adenoviral vaccine (ChAdOx1) 12 weeks before were administered with an mRNA COVID-19 vaccine. These were divided into three groups, full-dose mRNA-1273 (group 1); half-dose mRNA-1273 (group 2); and full-dose BNT-162b2 (group 3). Primary outcomes included serum anti-SARS-CoV-2 spike immunoglobulin G (IgG) titers and neutralizing antibody titers against B.1.1.7 (alpha), B.1.617.2 (delta), and B.1.1.529 (omicron) variants. Secondary outcomes included the evaluation of humoral and cellular immunity and vaccine-associated adverse events after the boost.Totally 300 participants were recruited, and 298 participants were enrolled. For all three groups, an increase in anti-SARS-CoV-2 spike IgG geometric mean titers (30.12- to 71.80-fold) and neutralizing antibody titers against the alpha variant (69.80- to 173.23-folds), delta variant (132.69- to 324.63-folds), and omicron variant (135.36- to 222.37-folds) were observed on day 28. All groups showed robust T- and B-cell responses after boosting. Adverse events were overall mild and transient but with higher prevalence and severity in group 1 participants than in other groups.Third dose mRNA COVID-19 vaccines markedly enhanced cellular and humoral responses and were safe. Immunological responses and adverse events were higher in individuals receiving the full-dose mRNA-1273 vaccine, followed by a half-dose mRNA-1273 vaccine and BNT-162b2 vaccine.

Antigen-specific lung-resident memory T cells (TRMs) constitute the first line of defense that mediates rapid protection against respiratory pathogens and inspires novel vaccine designs against infectious pandemic threats, yet effective means of inducing TRMs, particularly via non-viral vectors, remain challenging. Here, we demonstrate safe and potent induction of lung-resident TRMs using a biodegradable polymeric nanoshell that co-encapsulates antigenic peptides and TLR9 agonist CpG-oligodeoxynucleotide (CpG-ODN) in a virus-mimicking structure. Through subcutaneous priming and intranasal boosting, the combinatorial nanoshell vaccine elicits prominent lung-resident CD4+ and CD8+ T cells that surprisingly show better durability than live viral infections. In particular, nanoshells containing CpG-ODN and a pair of conserved class I and II major histocompatibility complex-restricted influenza nucleoprotein-derived antigenic peptides are demonstrated to induce near-sterilizing immunity against lethal infections with influenza A viruses of different strains and subtypes in mice, resulting in rapid elimination of replicating viruses. We further examine the pulmonary transport dynamic and optimal composition of the nanoshell vaccine conducive for robust TRM induction as well as the benefit of subcutaneous priming on TRM replenishment. The study presents a practical vaccination strategy for inducing protective TRM-mediated immunity, offering a compelling platform and critical insights in the ongoing quest toward a broadly protective vaccine against universal influenza as well as other respiratory pathogens.

Antigen-specific lung-resident memory T cells (TRMs) constitute the first line of defense that mediates rapid protection against respiratory pathogens and inspires novel vaccine designs against infectious pandemic threats, yet effective means of inducing TRMs, particularly via non-viral vectors, remain challenging. Here, we demonstrate safe and potent induction of lung-resident TRMs using a biodegradable polymeric nanoshell that co-encapsulates antigenic peptides and TLR9 agonist CpG-oligodeoxynucleotide (CpG-ODN) in a virus-mimicking structure. Through subcutaneous priming and intranasal boosting, the combinatorial nanoshell vaccine elicits prominent lung-resident CD4+ and CD8+ T cells that surprisingly show better durability than live viral infections. In particular, nanoshells containing CpG-ODN and a pair of conserved class I and II major histocompatibility complex-restricted influenza nucleoprotein-derived antigenic peptides are demonstrated to induce near-sterilizing immunity against lethal infections with influenza A viruses of different strains and subtypes in mice, resulting in rapid elimination of replicating viruses. We further examine the pulmonary transport dynamic and optimal composition of the nanoshell vaccine conducive for robust TRM induction as well as the benefit of subcutaneous priming on TRM replenishment. The study presents a practical vaccination strategy for inducing protective TRM-mediated immunity, offering a compelling platform and critical insights in the ongoing quest toward a broadly protective vaccine against universal influenza as well as other respiratory pathogens., Graphical Abstract, Nanoshell vaccines encapsulating CpG and both MHC-I and MHC-II-restricted conserved peptides derived from influenza virus proteomes can elicit robust CD4+ and CD8+ lung-resident memory T cells (TRMs) and circulatory memory T cells through the subcutaneous priming and intranasal boosting strategy to protect against influenza viruses of different strains and subtypes.