Daily Respiratory Research Analysis

Animal models that accurately reflect COVID-19 are vital for understanding mechanisms of disease and advancing development of improved vaccines and therapeutics. Pigs are increasingly recognized as valuable models for human disease due to their genetic, anatomical, physiological, and immunological similarities to humans, and they present a more ethically viable alternative to non-human primates. However, pigs are not susceptible to SARS-CoV-2 infection which limits their utility as a model. To address this, we have developed transgenic pigs expressing human ACE2 that are susceptible to SARS-CoV-2 infection. Following challenge, clinical signs consistent with COVID-19, including fever, coughing and respiratory distress were observed, with virus replication detected in the nasal turbinates, trachea and lungs up to the study endpoint, seven days post-infection. Notably, examination of tissues revealed immunopathology in the lungs consistent with histological changes observed in fatal human COVID-19 cases. This study establishes human ACE2 transgenic pigs as a large animal model that accurately reflects many aspects of COVID-19 disease.

The development of safe and effective mucosal vaccines are hampered by safety concerns associated with adjuvants or live attenuated microbes. We previously demonstrated that targeting antigens to the human-Fc-gamma-receptor-I (hFcγRI) eliminates the need for adjuvants, thereby mitigating safety concerns associated with the mucosal delivery of adjuvant formulated vaccines. Here we evaluated the role of the route of immunization in the mucosal immunity elicited by the hFcγRI-targeted vaccine approach. To enable Ag targeting, PspA from Streptococcus pneumoniae (Sp) was genetically fused with the hFcγRI-targeting antibody (α-hFcγRI) to generate PspA-FP. Intranasal (IN) immunization with the PspA-FP induced significantly higher IgA, IgG, and memory T cell response in the lung mucosa compared to that of the intramuscular (IM) route, while both routes exhibited similar increase in the systemic IgG response. The IN immunization elicited better resistance against nasal colonization (NC) of Sp compared to the IM immunization. Additionally, the resistance to NC with the IN administered PspA-FP was higher than the PspA-Alum formulation administered by the IM route. While the protection form lethal pulmonary Sp infection correlated with the systemic Ab response, the resistance from NC (of Sp) correlated with the mucosal immune response. Similar to the pneumococcal pneumoniae model, the hFcγRI-targeted vaccine (based on HA as Ag) was equally protective against pulmonary Influenza virus infection via both routes. However, the IN route promoted better protection compared to the IM route against a lethal pulmonary infection with Francisella tularensis (Ft). The enhanced protection against Ft correlated with the superior mucosal immune response elicited by the IN route compared to the IM route. These observations showed a differential requirement for mucosal delivery for protection depending on the type of pathogen. Moreover, this study revealed that the hFcγRI-targeted vaccine platform is broadly-effective as an adjuvant-free mucosal vaccine platform against respiratory pathogens.

BACKGROUND: Despite the physiological advantages of positive end-expiratory pressure (PEEP), its optimal utilization during one-lung ventilation (OLV) remains uncertain. We aimed to investigate whether individualized PEEP titration by lung compliance is associated with a reduced risk of postoperative pulmonary complications during OLV. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials until April 1, 2024, to identify published randomized controlled trials that compared individualized PEEP titration by lung compliance with fixed PEEP during OLV. The primary outcome was a composite of postoperative pulmonary complications. Secondary outcomes included clinical outcomes (pneumonia, atelectasis, ARDS, cardiovascular complications, mortality), respiratory mechanics, gas exchanges, and hemodynamic variables. Subgroup analyses were conducted for the primary outcome according to the PEEP titration method (dynamic compliance vs. driving pressure/static compliance, stepwise decremental vs. incremental strategy). RESULTS: Ten trials involving 3426 patients were included. Compared with fixed PEEP, individualized PEEP titration by lung compliance was associated with reduced risk of a composite of postoperative pulmonary complications (eight trials, 3351 patients, risk ratio [RR] 0.55, 95% CI 0.38-0.78). Subgroup analyses suggested the association was evident in the subgroup with titration by dynamic compliance rather than driving pressure/static compliance and in the subgroup with PEEP titration by stepwise decremental but not stepwise incremental strategy. Individualized PEEP titration by lung compliance was also associated with a reduced risk of pneumonia (RR 0.71, 95% CI 0.52-0.96) and atelectasis (RR 0.63, 95% CI 0.45-0.88), higher dynamic compliance, PaO CONCLUSIONS: Compared with fixed PEEP, individualized PEEP titration by lung compliance is associated with a reduced risk of postoperative pulmonary complications during OLV, especially in PEEP titration by dynamic compliance or stepwise decremental strategy. It improves respiratory mechanics and oxygenation with no difference in hemodynamic variables. Trial registration number ClinicalTrials.gov (PROSPERO No. CRD42024529980).