Safety and efficacy of the intranasal spray SARS-CoV-2 vaccine dNS1-RBD: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The live-attenuated influenza virus vector-based intranasal SARS-CoV-2 vaccine (dNS1-RBD, Pneucolin; Beijing Wantai Biological Pharmacy Enterprise, Beijing, China) confers long-lasting and broad protection in animal models and is, to our knowledge, the first COVID-19 mucosal vaccine to enter into human trials, but its efficacy is still unknown. We aimed to assess the safety and efficacy (but not the immunogenicity) of dNS1-RBD against COVID-19. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, adaptive design, phase 3 trial at 33 centres (private or public hospitals, clinical research centres, or Centre for Disease Control and Prevention) in four countries (Colombia, Philippines, South Africa, and Viet Nam). Men and non-pregnant women (aged ≥18 years) were eligible if they had never been infected with SARS-CoV-2, and if they did not have a SARS-CoV-2 vaccination history at screening or if they had received at least one dose of other SARS-CoV-2 vaccines 6 months or longer before enrolment. Eligible adults were randomly assigned (1:1) to receive two intranasal doses of dNS1-RBD or placebo administered 14 days apart (0·2 mL per dose; 0·1 mL per nasal cavity), with block randomisation via an interactive web-response system, stratified by centre, age group (18-59 years or ≥60 years), and SARS-CoV-2 vaccination history. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary outcomes were safety of dNS1-RBD in the safety population (ie, those who had received at least one dose of dNS1-RBD or placebo) and efficacy against symptomatic SARS-CoV-2 infection confirmed by RT-PCR occurring 15 days or longer after the second dose in the per-protocol population (ie, those who received two doses, were followed up for 15 days or longer after the second dose, and had no major protocol deviations). The success criterion was predefined as vaccine efficacy of more than 30%. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2100051391) and is completed. FINDINGS: Between Dec 16, 2021, and May 31, 2022, 41 620 participants were screened for eligibility and 31 038 participants were enrolled and randomly assigned (15 517 in the vaccine group and 15 521 in the placebo group). 30 990 participants who received at least one dose (15 496 vaccine and 15 494 placebo) were included in the safety analysis. The results showed a favourable safety profile, with the most common local adverse reaction being rhinorrhoea (578 [3·7%] of 15 500 vaccine recipients and 546 [3·5%] of 15 490 placebo recipients) and the most common systemic reaction being headache (829 [5·3%] vaccine recipients and 797 [5·1%] placebo recipients). We found no differences in the incidences of adverse reactions between participants in the vaccine and placebo groups. No vaccination-related serious adverse events or deaths were observed. Among 30 290 participants who received two doses, 25 742 were included in the per-protocol efficacy analysis (12 840 vaccine and 12 902 placebo). The incidence of confirmed symptomatic SARS-CoV-2 infection caused by omicron variants regardless of immunisation history was 1·6% in the vaccine group and 2·3% in the placebo group, resulting in an overall vaccine efficacy of 28·2% (95% CI 3·4-46·6), with a median follow-up duration of 161 days. INTERPRETATION: Although this trial did not meet the predefined efficacy criteria for success, dNS1-RBD was well tolerated and protective against omicron variants, both as a primary immunisation and as a heterologous booster. FUNDING: Beijing Wantai Biological Pharmacy Enterprise, National Science and Technology Major Project, National Natural Science Foundation of China, Fujian Provincial Science and Technology Plan Project, Natural Science Foundation of Fujian Province, Xiamen Science and Technology Plan Special Project, Bill & Melinda Gates Foundation, the Ministry of Education of China, Xiamen University, and Fieldwork Funds of Xiamen University.

Blood eosinophilia as predictor for patient outcomes in chronic obstructive pulmonary disease (COPD) exacerbations

INTRODUCTION: The eosinophilic phenotype of chronic obstructive pulmonary disease (COPD) has been demonstrated to respond better to corticosteroids and associated with better outcomes. This review aims to clarify the correlation of blood eosinophilia and outcomes patients with COPD exacerbations. METHODS: This is a review of cohorts and case-control studies that looked into eosinophilia and outcomes in exacerbations using the meta-analysis of observational studies in epidemiology (MOOSE) guidelines. The primary study outcome was length of hospitalization; other outcomes include readmission and mortality rate within one year, in-patient mortality, and need for mechanical ventilation. RESULTS: Six studies were included in the review. Patients with blood eosinophilia had significantly shorter hospital stay compared to non-eosinophilic patients (mean difference 0.68 days [95% CI 1.09,0.27]). Eosinophilic patients had significantly less frequent readmissions (OR 0.69 [95% CI 0.55,0.87]) but there was no statistically significant difference in the one-year mortality rate (OR 0.88 [95% CI 0.73, .06]). Analysis showed a trend toward lower in-patient mortality among eosinophilic patients (OR 0.53 [95% CI 0.27,1.05]). Furthermore, COPD patients with eosinophilia had significantly less need for mechanical ventilation during an exacerbation (OR 0.56 [95% CI 0.35,0.89]). CONCLUSION: COPD patients with blood eosinophilia had significantly shorter hospital stay, less frequent readmissions, and are less likely to require mechanical ventilation compared to the non-eosinophilic phenotype. 

Efficacy of tiotropium as add-on therapy for adults with uncontrolled asthma

@#<p style="text-align: justify;"><strong>OBJECTIVE:</strong> The study aimed to evaluate efficacy of tiotropium as add-on therapy on top of standard regimens for uncontrolled asthma, specifically in terms of FEV1, morning and evening PEF, reduction in exacerbations, rescue medication use, and quality of life improvement.<br /><strong>METHODS:</strong> A search was done for eligible trials after which validity screen and data extraction was performed. Results were presented as mean differences, standard errors, and 95% confidence intervals, and graphically as forest plots. Estimates were pooled using the random effects model with I2 and Chi2 tests used to assess heterogeneity. Adverse events were reported as dichotomous variables.<br /><strong>RESULTS:</strong> Four studies were included totaling 1617 participants. The tiotropium group had statistically significant improvement in FEV1 (95% Cl, 0.14 [0.09, 0.19], p<0.00001), morning (95% Cl, 20.03 [11.71, 28.35], p<0.00001) with trend towards benefit in reduction of rescue medications (95% Cl, 0.12 [-0.17,0.4],p=0.42) and quality of life improvements (95% Cl, 0.1 [-0.05,0.25], p=0.20). Homogeneity (I2= 0%, Chi2= 0.47-3.22) was found across studies.<br /><strong>CONCLUSION:</strong> Tiotropium is associated with significant improvement in pulmonary function among patients with uncontrolled asthma, with possible benefit in reduction of rescue medications and quality of life improvement.</p>

Predictors of Outcome and Severity in Adult Filipino Patients with Febrile Neutropenia.

Aim. The study aimed to describe the profile of Filipino febrile neutropenia patients and to determine parameters associated with severe outcomes. Methods. This is a retrospective study of Filipino febrile neutropenia patients admitted to the Philippine General Hospital. Patients were described in terms of clinical presentation and stratified according to the presence or absence of severe outcomes. Prognostic factors were then identified using regression analysis. Results. 115 febrile episodes in 102 patients were identified. Regression analysis yielded prolonged fever >7 days prior to admission (OR 2.43; 95% CI, 0.77-7.74), isolation of a pathogen on cultures (OR 2.69; 95% CI, 1.04-6.98), and nadir absolute neutrophil count (ANC) < 100 during admission (OR 1.96; 95% CI, 0.75-5.12) as significant predictors of poor outcome. Factors that significantly correlated with better outcome were granulocyte colony-stimulating factor (G-CSF) use (OR 0.31; 95% CI, 0.11-0.85) and completeness of antibiotic therapy (OR 0.26; 95% CI, 0.10-0.67). Conclusion. Prolonged fever >7 days prior to admission, positive pathogen on cultures, and nadir ANC < 100 during admission predicted severe outcomes, whereas G-CSF use and complete antibiotic therapy were associated with better outcomes. These prognostic variables might be useful in identifying patients that need more intensive treatment and monitoring.