Daily Respiratory Research Analysis

Leptomeningeal metastasis (LM) is a severe neurological complication in patients with lung adenocarcinoma (LUAD), typically indicating terminal stage and poor survival. Optimal treatments for patients with LM-LUAD rely on accurately predicting treatment efficacy and dynamically adjusting regimens. Here, we collected 301 cerebrospinal fluid (CSF) samples from 125 patients with LM-LUAD via the Ommaya reservoir at baseline and during the treatment course to systematically explore the clinical significance of CSF circulating tumor DNA (ctDNA). At baseline, the positive detection rate of CSF ctDNA (99.2%) was significantly higher than that of plasma ctDNA (57.6%). By evaluating the association between varying magnitudes of ctDNA dynamic changes and clinical responses at each time interval during the treatment, we discovered that when the change in ctDNA reached 20%, the consistency with clinical assessment could exceed 90%. Moreover, we further analyzed the significance of different values of CSF ctDNA mutation frequencies at baseline and various time points, as well as the trends of ctDNA changes relative to the baseline levels, in predicting patient prognosis. Accordingly, we constructed a CSF ctDNA-based prognostic map and developed a multi-feature model that exhibited outstanding performance in predicting and assessing the clinical responses of patients. To the best of our knowledge, this work represents the most systematic large-scale study on CSF ctDNA-based dynamic monitoring of patients with LM-LUAD, which is of great significance for guiding clinical treatments to extend patient lives.

The highly pathogenic avian influenza H5N1 virus clade 2.3.4.4b has been spreading globally since 2022, causing mortality and morbidity in domestic and wild birds, as well as in mammals, which underscores its potential to cause a pandemic. Here, we generate a panel of anti-hemagglutinin (HA) human monoclonal antibodies (mAbs) against the H5 protein of clade 2.3.4.4b. To develop human chimeric antibodies, H2L2 Harbor Mice®, which express human immunoglobulin germline genes, were immunized with H5 and N1 recombinant proteins from A/mallard/New York/22-008760-007- original/2022 H5N1 virus. Through hybridoma technology, sixteen fully human mAbs are generated, most of which show cross-reactivity against H5 proteins from different clade 2.3.4.4 virus variants. Fourteen out of the sixteen mAbs neutralize the virus in vitro. The mAbs with the strongest hemagglutination inhibition activity also demonstrate greater neutralizing capacity and show increased protective effects in vivo when administered prophylactically or therapeutically in a murine H5N1 challenge model. Using cryo-electron microscopy, we identify a cross-clonotype conserved motif that bound a hydrophobic groove on the head domain of H5 HA. Akin to mAbs against severe acute respiratory syndrome coronavirus 2 during the coronavirus 2019 pandemic, these mAbs could serve as treatments in case of a widespread H5N1 epidemic or pandemic.

Mucosal immunity may be required to prevent the ongoing transmission of SARS-CoV-2 emerging variants of concern. To define the most efficient way to induce protective mucosal immunity, we compared three different forms of mucosal antigen exposure in mRNA pre-immunized rhesus macaques. Two vaccine groups received an oropharyngeal spray immunization with either an adenoviral vector or a live-attenuated SARS-CoV-2 vaccine (LAV). A third group was infected with SARS-CoV-2 Delta variant as a comparator group representing the exposure history of most humans. Profound levels of SARS-CoV-2-specific IgA antibodies and mucosal T cell responses in the bronchoalveolar lavage next to systemic IgG antibodies were induced after the adenoviral vector boost and the delta infection, but not after LAV immunization. Consequently, these two groups were better protected against a challenge infection with an immune-escape variant of the Omicron lineage EG.5.1.1 showing almost no upper and lower respiratory tract infection. The adenoviral vector vaccine would be a promising candidate for booster vaccinations to interrupt ongoing viral transmission and could generate similar levels of protection as a natural encounter with heterologous SARS-CoV-2.