SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S–specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19–vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.

Respiratory tissue resident–like CD8 ⁺ T cells are associated with chronic lung sequelae post-acute COVID-19.

Postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) represent an urgent public health challenge and are estimated to affect more than 60 million individuals globally. Although a growing body of evidence suggests that dysregulated immune reactions may be linked with PASC symptoms, most investigations have primarily centered around blood-based studies, with few focusing on samples derived from affected tissues. Furthermore, clinical studies alone often provide correlative insights rather than causal mechanisms. Thus, it is essential to compare clinical samples with relevant animal models and conduct functional experiments to understand the etiology of PASC. In this study, we comprehensively compared bronchoalveolar lavage fluid single-cell RNA sequencing data derived from clinical PASC samples and a mouse model of PASC. This revealed a pro-fibrotic monocyte-derived macrophage response in respiratory PASC, as well as abnormal interactions between pulmonary macrophages and respiratory resident T cells, in both humans and mice. Interferon-γ (IFN-γ) emerged as a key node mediating the immune anomalies in respiratory PASC. Neutralizing IFN-γ after the resolution of acute SARS-CoV-2 infection reduced lung inflammation and tissue fibrosis in mice. Together, our study underscores the importance of performing comparative analysis to understand the cause of PASC and suggests that the IFN-γ signaling axis might represent a therapeutic target.

Background: Image-guided percutaneous thermal ablation is an established treatment option for early-stage lung cancer in medically inoperable patients but carries a high risk of pleura-related complications, particularly pneumothorax. Objective: This study aimed to determine if image-guided transbronchial microwave ablation (tMWA) is a feasible approach to treat peripheral stage 1 lung cancer. Method: A prospective, single-arm, multicenter study sought to enroll 40 adults who were medically inoperable or declined surgery for peripheral stage 1 lung tumors (≤20 mm). Ablation was performed using navigational bronchoscopy and a flexible MWA probe, guided by cone-beam CT with augmented fluoroscopy. Follow-up at 1, 6, and 12 months included CT imaging of the ablation zone and possible tumor recurrence, adverse events (AEs), pulmonary function, and quality of life. Results: Across 2 sites, 11 tumors (10 NSCLC, 1 carcinoid) were treated in 10 enrolled patients. Median tumor diameter was 13 × 14 mm (7–19 mm) and median minimum ablative margin was 11 mm (5–19 mm). Technical success and technique efficacy were achieved in all patients. No tumor recurrence was seen during 12-month follow-up. No pneumothorax, pleural effusion, or bronchopleural fistula were noted. Minor AEs included scant hemoptysis, pain, cough, and dyspnea. Two serious AEs occurred ≤30 days of ablation and included a COPD exacerbation (day 9) and a death of unknown cause (day 15). The death led the sponsor to halt enrollment. Pulmonary function and quality-of-life indices remained stable. Conclusions: Image-guided tMWA is a technically feasible approach for peripheral early-stage lung cancer but warrants further evaluation of safety and efficacy in larger cohorts.