Toshiro Hirai

The G protein expressed on the surface of respiratory syncytial virus (RSV) is important for adhesion to host cells and as a vaccine target antigen. The corresponding vaccines can effectively eliminate RSV. However, they exacerbate pulmonary immunopathology including eosinophilic infiltration in the lungs after an RSV challenge in animal models, raising concerns about enhanced respiratory disease (ERD); thus, approaches that mitigate these effects are urgently needed. Herein, we aimed to examine the mechanisms of G protein vaccine-induced ERD in mice, using recombinant G protein as a vaccine antigen. After the RSV challenge, G protein-vaccinated mice exhibited lung weight gain, lung tissue damage, and increased infiltration of eosinophils, neutrophils, and CD4⁺ T cells into the lungs. We set lung weight gain as the endpoint for ERD and examined the impact of each infiltrating cell on lung weight gain. We observed that CD4⁺ T cells, but not eosinophils or neutrophils, that infiltrate the lungs are responsible for lung weight gain. In addition, T helper 2 cell-mediated IL-13 induced mucin hypersecretion and lung weight gain. Mucin hypersecretion may contribute to weight gain in the lungs. In conclusion, our results indicate a novel mechanism of G protein vaccine-induced ERD via IL-13 and mucin hypersecretion, which could lead to the development of safe G protein vaccines and the elucidation of the causes of ERD associated with other vaccines.

Intranasal vaccines are anticipated to be powerful tools for combating many infectious diseases, including SARS-CoV-2, because they induce not only systemic immunity but also mucosal immunity at the site of initial infection. However, they are generally inefficient in inducing an antigen-specific immune response without adjuvants. Here, we developed an adjuvant-free intranasal vaccine platform that utilizes the preexisting immunity induced by previous infection or vaccination to enhance vaccine effectiveness. We made RBD-HA, a fusion of the receptor-binding domain (RBD) of spike derived from SARS-CoV-2 as a vaccine target with HA derived from influenza A virus (IAV) as a carrier protein. Intranasal immunization of previously IAV-infected mice with RBD-HA without an adjuvant elicited robust production of RBD-specific systemic IgG and mucosal IgA by utilizing both HA-specific preexisting IgG and CD4⁺ T cells. Consequently, the mice were efficiently protected from SARS-CoV-2 infection. Additionally, we demonstrated the high versatility of this intranasal vaccine platform by assessing various vaccine antigens and preexisting immunity associated with a variety of infectious diseases. The results of this study suggest the promising potential of this intranasal vaccine platform to address problems associated with intranasal vaccines.

Tissue-resident memory T cells are a highly abundant, non-blood circulating subset of memory T cells. These appear to be the most protective population of memory T cells at barrier surfaces. Long-term retention and survival of tissue-resident memory CD8⁺ T cells (Trm) is determined by tissue-derived signals, such as keratinocyte-mediated activation of transforming growth factor β (TGFβ) in the epidermis. We found that T cell clones compete for limited amounts of active TGFβ and pre-existing Trm could be replaced with newly recruited effector T cells in the epidermis. On the other hand, when effector T cells transition into Trm, the presence of cutaneous cognate antigen increases the fitness of individual Trm clones in the epidermal niche. Thus, antigen-specific Trm are more efficiently retained than bystander Trm that have not encountered cognate antigens when they compete with newly recruited effector T cells for limited active TGFβ. Therefore, competition between T cells for active TGFβ represents a selective pressure that promotes the accumulation of antigen-specific Trm cells in the epidermal niche. Furthermore, our model implies that the epidermis offers a finite niche for maintaining Trm. Although the epidermal niche of Trm cannot represent the capacity of T cell-mediated immune memory in our body, these findings might suggest a challenge for the accommodation of memory T cells specific to multiple pathogens throughout a lifetime.

The cytokine interleukin-23 (IL-23) is critical for development and maintenance of autoimmune inflammation in nonlymphoid tissues; however, the mechanism through which IL-23 supports tissue-specific immunity remains unclear. In mice, we found that circulating memory T cells were dispensable for anamnestic protection from Candida albicans skin infection, and tissue-resident memory (T _RM ) cell–mediated protection from C. albicans reinfection required IL-23. Administration of anti–IL-23 receptor antibody to mice after resolution of primary C. albicans infection resulted in loss of CD69 ⁺ CD103 ⁺ tissue-resident memory T helper 17 (T _RM17 ) cells from skin, and clinical anti–IL-23 therapy depleted T _RM17 cells from skin of patients with psoriasis. IL-23 receptor blockade impaired T _RM17 cell proliferation but did not affect apoptosis susceptibility or tissue egress. IL-23 produced by CD301b ⁺ myeloid cells was required for T _RM17 maintenance in skin after C. albicans infection, and CD301b ⁺ cells were necessary for T _RM17 expansion during the development of imiquimod dermatitis. This study demonstrates that locally produced IL-23 promotes in situ proliferation of cutaneous T _RM17 cells to support their longevity and function and provides mechanistic insight into the durable efficacy of IL-23 blockade in the treatment of psoriasis.

The primary goal of vaccines that protect against respiratory viruses appears to be the induction of neutralizing antibodies for a long period. Although this goal need not be changed, recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have drawn strong attention to another arm of acquired immunity, CD8⁺ T cells, which are also called killer T cells. Recent evidence accumulated during the coronavirus disease 2019 (COVID-19) pandemic has revealed that even variants of SARS-CoV-2 that escaped from neutralizing-antibodies that were induced by either infection or vaccination could not escape from CD8⁺ T cell-mediated immunity. In addition, although traditional vaccine platforms, such as inactivated virus and subunit vaccines, are less efficient in inducing CD8⁺ T cells, newly introduced platforms for SARS-CoV-2, namely, mRNA and adenoviral vector vaccines, can induce strong CD8⁺ T cell-mediated immunity in addition to inducing neutralizing antibodies. However, CD8⁺ T cells function locally and need to be at the site of infection to control it. To fully utilize the protective performance of CD8⁺ T cells, it would be insufficient to induce only memory cells circulating in blood, using injectable vaccines; mucosal immunization could be required to set up CD8⁺ T cells for the optimal protection. CD8⁺ T cells might also contribute to the pathology of the infection, change their function with age and respond differently to booster vaccines in comparison with antibodies. Herein, we overview cutting-edge ideas on CD8⁺ T cell-mediated immunity that can enable the rational design of vaccines for respiratory viruses.