CodonBERT large language model for mRNA vaccines.

mRNA-based vaccines and therapeutics are gaining popularity and usage across a wide range of conditions. One of the critical issues when designing such mRNAs is sequence optimization. Even small proteins or peptides can be encoded by an enormously large number of mRNAs. The actual mRNA sequence can have a large impact on several properties, including expression, stability, immunogenicity, and more. To enable the selection of an optimal sequence, we developed CodonBERT, a large language model (LLM) for mRNAs. Unlike prior models, CodonBERT uses codons as inputs, which enables it to learn better representations. CodonBERT was trained using more than 10 million mRNA sequences from a diverse set of organisms. The resulting model captures important biological concepts. CodonBERT can also be extended to perform prediction tasks for various mRNA properties. CodonBERT outperforms previous mRNA prediction methods, including on a new flu vaccine data set.

Human sperm rotate with a conserved direction during free swimming in four dimensions.

Head rotation in human spermatozoa is essential for different swimming modes and fertilisation, as it links the molecular workings of the flagellar beat with sperm motion in three-dimensional (3D) space over time. Determining the direction of head rotation has been hindered by the symmetry and translucent nature of the sperm head, and by the fast 3D motion driven by the helical flagellar beat. Analysis has been mostly restricted to two-dimensional (2D) single focal plane image analysis, which enables tracking of head centre position but not tracking of head rotation. Despite the conserved helical beating of the human sperm flagellum, human sperm head rotation has been reported to be uni- or bi-directional, and even to intermittently change direction in a given cell. Here, we directly measure the head rotation of freely swimming human sperm using multi-plane 4D (3D+t) microscopy and show that: (1) 2D microscopy is unable to distinguish head rotation direction in human spermatozoa; (2) head rotation direction in non-capacitating and capacitating solutions, for both aqueous and viscous media, is counterclockwise (CCW), as seen from head to tail, in all rotating spermatozoa, regardless of the experimental conditions; and (3) head rotation is suppressed in 36% of spermatozoa swimming in non-capacitating viscous medium, although CCW rotation is recovered after incubation in capacitating conditions within the same viscous medium, possibly unveiling an unexplored aspect of the essential need of capacitation for fertilisation. Our observations show that the CCW head rotation in human sperm is conserved. It constitutes a robust and persistent helical driving mechanism that influences sperm navigation in 3D space over time, and thus is of critical importance in cell motility, propulsion of flagellated microorganisms, sperm motility assessments, human reproduction research, and self-organisation of flagellar beating patterns and swimming in 3D space.

Representations of lipid nanoparticles using large language models for transfection efficiency prediction.

MOTIVATION: Lipid nanoparticles (LNPs) are the most widely used vehicles for mRNA vaccine delivery. The structure of the lipids composing the LNPs can have a major impact on the effectiveness of the mRNA payload. Several properties should be optimized to improve delivery and expression including biodegradability, synthetic accessibility, and transfection efficiency. RESULTS: To optimize LNPs, we developed and tested models that enable the virtual screening of LNPs with high transfection efficiency. Our best method uses the lipid Simplified Molecular-Input Line-Entry System (SMILES) as inputs to a large language model. Large language model-generated embeddings are then used by a downstream gradient-boosting classifier. As we show, our method can more accurately predict lipid properties, which could lead to higher efficiency and reduced experimental time and costs. AVAILABILITY AND IMPLEMENTATION: Code and data links available at: https://github.com/Sanofi-Public/LipoBART.

Long-term segmentation-free assessment of head-flagellum movement and intracellular calcium in swimming human sperm.

Human spermatozoa are the archetype of long-term self-organizing transport in nature and are critical for reproductive success. They utilize coordinated head and flagellar movements to swim long distances within the female reproductive tract in order to find and fertilize the egg. However, to date, long-term analysis of the sperm head-flagellar movements, or indeed those of other flagellated microorganisms, remains elusive due to limitations in microscopy and flagellar-tracking techniques. Here, we present a novel methodology based on local orientation and isotropy of bio-images to obtain long-term kinematic and physiological parameters of individual free-swimming spermatozoa without requiring image segmentation (thresholding). This computer-assisted segmentation-free method evaluates, for the first time, characteristics of the head movement and flagellar beating for up to 9.2 min. We demonstrate its powerful use by showing how releasing Ca2+ from internal stores significantly alters long-term sperm behavior. The method allows for straightforward generalization to other bio-imaging applications, such as studies of bull sperm and Trypanosoma, or indeed of other flagellated microorganisms - appealing to communities other than those investigating sperm biology.

Infection Due to Saksenaea vasiformis Following a Spider Bite.

Cutaneous mucormycosis due to Saksenaea vasiformis species is exceptional. There have been about 40 reported cases worldwide, with most being fatal. We report an exceptional nonlethal case of mucormycosis due to S. vasiformis following a spider bite. The patient was in an immunosuppressed state owing to previous chemotherapy and diabetes mellitus. The origin of the inoculation was the bite of a Loxosceles laeta spider, which caused loxoscelism. The initial skin injury was quickly progressive, requiring amputation of the right upper limb. After surgical intervention and suitable antifungal treatment, the patient was discharged with resolution of accompanying pulmonary disease. Infections due to S. vasiformis are probably underdiagnosed. To avoid fatal outcomes, a high index of clinical suspicion in patients with quickly progressive necrotic lesions of soft tissues and systemic dissemination is important.

MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 µg MAGE-A3 antigen plus 420 µg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

Testing interaction between treatment and high-dimensional covariates in randomized clinical trials.

In this paper, we considered different methods to test the interaction between treatment and a potentially large number (p) of covariates in randomized clinical trials. The simplest approach was to fit univariate (marginal) models and to combine the univariate statistics or p-values (e.g., minimum p-value). Another possibility was to reduce the dimension of the covariates using the principal components (PCs) and to test the interaction between treatment and PCs. Finally, we considered the Goeman global test applied to the high-dimensional interaction matrix, adjusted for the main (treatment and covariates) effects. These tests can be used for personalized medicine to test if a large set of biomarkers can be useful to identify a subset of patients who may be more responsive to treatment. We evaluated the performance of these methods on simulated data and we applied them on data from two early phases oncology clinical trials.

A predictive enrichment procedure to identify potential responders to a new therapy for randomized, comparative controlled clinical studies.

To evaluate a new therapy versus a control via a randomized, comparative clinical study or a series of trials, due to heterogeneity of the study patient population, a pre-specified, predictive enrichment procedure may be implemented to identify an "enrichable" subpopulation. For patients in this subpopulation, the therapy is expected to have a desirable overall risk-benefit profile. To develop and validate such a "therapy-diagnostic co-development" strategy, a three-step procedure may be conducted with three independent data sets from a series of similar studies or a single trial. At the first stage, we create various candidate scoring systems based on the baseline information of the patients via, for example, parametric models using the first data set. Each individual score reflects an anticipated average treatment difference for future patients who share similar baseline profiles. A large score indicates that these patients tend to benefit from the new therapy. At the second step, a potentially promising, enrichable subgroup is identified using the totality of evidence from these scoring systems. At the final stage, we validate such a selection via two-sample inference procedures for assessing the treatment effectiveness statistically and clinically with the third data set, the so-called holdout sample. When the study size is not large, one may combine the first two steps using a "cross-training-evaluation" process. Comprehensive numerical studies are conducted to investigate the operational characteristics of the proposed method. The entire enrichment procedure is illustrated with the data from a cardiovascular trial to evaluate a beta-blocker versus a placebo for treating chronic heart failure patients.

Synchronization using environmental coupling in mercury beating heart oscillators.

We report synchronization of Mercury Beating Heart (MBH) oscillators using the environmental coupling mechanism. This mechanism involves interaction of the oscillators with a common medium/environment such that the oscillators do not interact among themselves. In the present work, we chose a modified MBH system as the common environment. In the absence of coupling, this modified system does not exhibit self sustained oscillations. It was observed that, as a result of the coupling of the MBH oscillators with this common environment, the electrical and the mechanical activities of both the oscillators synchronized simultaneously. Experimental results indicate the emergence of both lag and the complete synchronization in the MBH oscillators. Simulations of the phase oscillators were carried out in order to better understand the experimental observations.

Extensive study of shape and surface structure formation in the mercury beating heart system.

A phenomenological study of the mercury beating heart system in a three electrode electrochemical cell configuration forced with a harmonic perturbation is presented. The system is controlled via a potentiostat, where the mercury drop is electrically connected to a platinum wire and acts as the working electrode. This configuration exhibits geometrical shapes and complex surface structures when a harmonic signal is superimposed to the working electrode potential. This study involves a wide range of frequencies and amplitudes of the forcing signal. Differents levels of structure complexity are observed as a function of the parameters of the applied perturbation. At certain amplitudes and frequencies, rotational behavior is also observed.

Tenoscopy for the Treatment of Hand Intratendinous Ganglion: Technique Description and Case Report.

Synovial or ganglion cysts are the most common soft tissue tumors of the wrist and hand and can arise from joints or tendons. Intratendinous synovial cysts, in contrast, are rare and their pathogenesis is still a matter of debate. The treatment of synovial cysts of articular origin using arthroscopy is commonly used with good results. For cysts of tendon origin, that is, extra-articular, when located at the ankle, shoulder, knee, and wrist, endoscopic treatment has also been described in a procedure called tenoscopy. We describe the technique and the good results using tenoscopy for a patient treated for an intratendinous synovial cyst located at the extensor communis tendon of the third digit. It is a reproducible, safe technique with low morbidity, and the patient has had no complications or recurrence.

Predicting the translation efficiency of messenger RNA in mammalian cells.

The degree to which translational control is specified by mRNA sequence is poorly understood in mammalian cells. Here, we constructed and leveraged a compendium of 3,819 ribosomal profiling datasets, distilling them into a transcriptome-wide atlas of translation efficiency (TE) measurements encompassing >140 human and mouse cell types. We subsequently developed RiboNN, a multitask deep convolutional neural network, and classic machine learning models to predict TEs in hundreds of cell types from sequence-encoded mRNA features, achieving state-of-the-art performance (r=0.79 in human and r=0.78 in mouse for mean TE across cell types). While the majority of earlier models solely considered 5' UTR sequence, RiboNN integrates contributions from the full-length mRNA sequence, learning that the 5' UTR, CDS, and 3' UTR respectively possess ~67%, 31%, and 2% per-nucleotide information density in the specification of mammalian TEs. Interpretation of RiboNN revealed that the spatial positioning of low-level di- and tri-nucleotide features (i.e., including codons) largely explain model performance, capturing mechanistic principles such as how ribosomal processivity and tRNA abundance control translational output. RiboNN is predictive of the translational behavior of base-modified therapeutic RNA, and can explain evolutionary selection pressures in human 5' UTRs. Finally, it detects a common language governing mRNA regulatory control and highlights the interconnectedness of mRNA translation, stability, and localization in mammalian organisms.

Fluid flow reconstruction around a free-swimming sperm in 3D.

We investigate the dynamics and hydrodynamics of a human spermatozoa swimming freely in 3D. We simultaneously track the sperm flagellum and the sperm head orientation in the laboratory frame of reference via high-speed high-resolution 4D (3D+t) microscopy, and extract the flagellar waveform relative to the body frame of reference, as seen from a frame of reference that translates and rotates with the sperm in 3D. Numerical fluid flow reconstructions of sperm motility are performed utilizing the experimental 3D waveforms, with excellent accordance between predicted and observed 3D sperm kinematics. The reconstruction accuracy is validated by directly comparing the three linear and three angular sperm velocities with experimental measurements. Our microhydrodynamic analysis reveals a novel fluid flow pattern, characterized by a pair of vortices that circulate in opposition to each other along the sperm cell. Finally, we show that the observed sperm counter-vortices are not unique to the experimental beat, and can be reproduced by idealised waveform models, thus suggesting a fundamental flow structure for free-swimming sperm propelled by a 3D beating flagellum.

Feature-based 3D+t descriptors of hyperactivated human sperm beat patterns.

The flagellar movement of the mammalian sperm plays a crucial role in fertilization. In the female reproductive tract, human spermatozoa undergo a process called capacitation which promotes changes in their motility. Only capacitated spermatozoa may be hyperactivated and only those that transition to hyperactivated motility are capable of fertilizing the egg. Hyperactivated motility is characterized by asymmetric flagellar bends of greater amplitude and lower frequency. Historically, clinical fertilization studies have used two-dimensional analysis to classify sperm motility, despite the inherently three-dimensional (3D) nature of sperm motion. Recent research has described several 3D beating features of sperm flagella. However, the 3D motility pattern of hyperactivated spermatozoa has not yet been characterized. One of the main challenges in classifying these patterns in 3D is the lack of a ground-truth reference, as it can be difficult to visually assess differences in flagellar beat patterns. Additionally, it is worth noting that only a relatively small proportion, approximately 10-20% of sperm incubated under capacitating conditions exhibit hyperactivated motility. In this work, we used a multifocal image acquisition system that can acquire, segment, and track sperm flagella in 3D+t. We developed a feature-based vector that describes the spatio-temporal flagellar sperm motility patterns by an envelope of ellipses. The classification results obtained using our 3D feature-based descriptors can serve as potential label for future work involving deep neural networks. By using the classification results as labels, it will be possible to train a deep neural network to automatically classify spermatozoa based on their 3D flagellar beating patterns. We demonstrated the effectiveness of the descriptors by applying them to a dataset of human sperm cells and showing that they can accurately differentiate between non-hyperactivated and hyperactivated 3D motility patterns of the sperm cells. This work contributes to the understanding of 3D flagellar hyperactive motility patterns and provides a framework for research in the fields of human and animal fertility.

Quenching of oscillations via attenuated coupling for dissimilar electrochemical systems.

The coupled dynamics of two similar and disparate electrochemical cells oscillators are analyzed. For the similar case, the cells are intentionally operated at different system parameters such that they exhibit distinct oscillatory dynamics ranging from periodic to chaotic. It is observed that when such systems are subjected to an attenuated coupling, implemented bidirectionally, they undergo a mutual quenching of oscillations. The same holds true for the configuration wherein two entirely different electrochemical cells are coupled via bidirectional attenuated coupling. Therefore, the attenuated coupling protocol seems to be universally efficient in achieving oscillation suppression in coupled oscillators (similar or heterogeneous oscillators). The experimental observations were verified by numerical simulations using appropriate electrodissolution model systems. Our results indicate that quenching of oscillations via attenuated coupling is robust and therefore could be ubiquitous in coupled systems with a large spatial separation prone to transmission losses.

Scaphoid fracture non-union: a systematic review of the arthroscopic management.

BACKGROUND AND AIM: There is no consensus regarding the most appropriate treatment of scaphoid nonunion. This systematic review aimed to investigate whether wrist arthroscopy exerts a positive influence on bone union and clinical outcomes. METHODS: We searched the literature on Medline (PubMed), Web of Science, Embase and Scopus databases using the combined keywords "scaphoid" AND "arthroscopy" AND "pseudoarthrosis" OR "nonunion". Eighteen studies were finally included in our review. The quality of the studies was assessed using the Coleman Methodological Score. RESULTS: Our systematic review has shown that arthroscopic management of scaphoid nonunion achieves a high rate of union and satisfactory clinical outcomes with minimal complications. CONCLUSIONS: There is need to perform randomized controlled trials reporting on the use of arthroscopy. In addition, the different pattern of pseudoarthrosis should be better classified to manage the patients who will benefit after the management.

Differentiation potential of human postnatal mesenchymal stem cells, mesoangioblasts, and multipotent adult progenitor cells reflected in their transcriptome and partially influenced by the culture conditions.

Several adherent postnatal stem cells have been described with different phenotypic and functional properties. As many of these cells are being considered for clinical therapies, it is of great importance that the identity and potency of these products is validated. We compared the phenotype and functional characteristics of human mesenchymal stem cells (hMSCs), human mesoangioblasts (hMab), and human multipotent adult progenitor cells (hMAPCs) using uniform standardized methods. Human MAPCs could be expanded significantly longer in culture. Differences in cell surface marker expression were found among the three cell populations with CD140b being a distinctive marker among the three cell types. Differentiation capacity towards adipocytes, osteoblasts, chondrocytes, and smooth muscle cells in vitro, using established protocols, was similar among the three cell types. However, only hMab differentiated to skeletal myocytes, while only hMAPCs differentiated to endothelium in vitro and in vivo. A comparative transcriptome analysis confirmed that the three cell populations are distinct and revealed gene signatures that correlated with their specific functional properties. Furthermore, we assessed whether the phenotypic, functional, and transcriptome features were mediated by the culture conditions. Human MSCs and hMab cultured under MAPC conditions became capable of generating endothelial-like cells, whereas hMab lost some of their ability to generate myotubes. By contrast, hMAPCs cultured under MSC conditions lost their endothelial differentiation capacity, whereas this was retained when cultured under Mab conditions, however, myogenic capacity was not gained under Mab conditions. These studies demonstrate that hMSCs, hMab, and hMAPCs have different properties that are partially mediated by the culture conditions.

3D+t feature-based descriptor for unsupervised flagellar human sperm beat classification.

Human spermatozoa must swim through the female reproductive tract, where they undergo a series of biochemical and biophysical reactions called capacitation, a necessary step to fertilize the egg. Capacitation promotes changes in the motility pattern. Historically, a two-dimensional analysis has been used to classify sperm motility and clinical fertilization studies. Nevertheless, in a natural environment sperm motility is three-dimensional (3D). Imaging flagella of freely swimming sperm is a difficult task due to their high beating frequency of up to 25 Hz. Very recent studies have described several sperm flagellum 3D beating features (curvature, torsion, asymmetries, etc.). However, up to date, the 3D motility pattern of hyperactivated spermatozoa has not been characterized. The main difficulty in classifying these patterns in 3D is the lack of a ground truth reference since differences in flagellar beat patterns are very difficult to assess visually. Moreover, only around 10-20% of induced to capacitate spermatozoa are truly capacitated, i.e., hyperactivated. We used an image acquisition system that can acquire, segment, and track spermatozoa flagella in 3D+t. In this work, we propose an original three-dimensional feature vector formed by ellipses describing the envelope of the 3D+t spatio-temporal flagellar sperm motility patterns. These features allowed compressing an unlabeled 3D+t dataset to separate hyperactivated cells from others (capacitated from non-capacitated cells) using unsupervised hierarchical clustering. Preliminary results show three main clusters of flagellar motility patterns. The first principal component of these 3D flagella measurements correlated with 2D OpenCASA head determinations as a first approach to validate the unsupervised classification, showing a reasonable correlation coefficient near to 0.7. Clinical relevance- The novelty of this work is defining a 3D+t feature-based descriptor consisting of a set of ellipses enveloping the flagellar motion of human sperm for its unsu-pervised classification. This is a new promising tool to determine the viability of human sperm to fertilize the egg.

Computer-Assisted Surgery Enables Beginner Surgeons, Under Expert Guidance, to Achieve Long-Term Clinical Results not Inferior to Those of a Skilled Surgeon in Knee Arthroplasty.

Purpose: The purpose of this study is to determine whether the use of a surgical navigation system in total knee replacement (TKR) enables beginner and intermediate surgeons to achieve clinical PROM outcomes as good as those conducted by expert surgeons in the long term. Methods: We enrolled 100 consecutive patients whose total navigated knee arthroplasty (TKA) was performed in our institution from 2008 to 2010. According to the principal surgeon's surgical experience, the patients were divided into three groups: (1) beginner surgeons, with no more than 30 previous knee replacement performances, (2) intermediate surgeons, with more than 30 but not more than 300, and (3) expert surgeons, with more than 300 knee replacements. Demographic data collected on the cohort included gender, laterality, age, and body mass index (BMI). The outcome measures assessed were Forgotten Joint Score (FJS), implant positioning, limb alignment, and prosthesis survival rate. A margin of equivalence of ± 18.5 points in the FJS scale was prespecified in terms of the minimal clinically important difference (MCID) to compare the FJS results obtained in the long period between the groups of interest. Results: The mean follow-up was 11.10 ± 0.78, 10.86 ± 0.66, and 11.30 ± 0.74 years, respectively, for each of the groups. The long-term FJS mean score was 80.86 ± 21.88, 81.36 ± 23.87, and 90.48 ± 14.65 for each group. The statistical analysis proved noninferiority and equivalence in terms of the FJS results reported in the long term by patients in Groups 1 or 2 compared to those in Group 3. More specifically, it has been proved that the mean difference between groups is within the interval of equivalence defined in terms of the MCID. The overall prostheses survival rate was 93.7%. Conclusion: Navigated assisted TKA, under expert guidance, can be as effective when performed by beginner or intermediate surgeons as performed by senior surgeons regarding the accuracy of implant positioning, limb alignment, and long-term clinical outcome.

A detailed analysis of possible efficacy signals of NTHi-Mcat vaccine against severe COPD exacerbations in a previously reported randomised phase 2b trial.

BACKGROUND: An investigational vaccine containing non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) surface proteins did not show vaccine efficacy (VE) against combined moderate and severe (moderate/severe) exacerbations in a randomised, observer-blinded, placebo-controlled phase 2b trial of patients with chronic obstructive pulmonary disease (COPD). Nevertheless, observations on rates of severe exacerbations and hospitalisations encouraged further evaluation. METHODS: Patients with stable COPD (moderate to very severe airflow limitation, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2-4), 40-80 years and at least one moderate/severe exacerbation in the last year received two doses of NTHi-Mcat vaccine or placebo plus standard care. Secondary analyses were conducted on VE against exacerbations according to severity. Potential predictive factors at baseline for VE against severe exacerbations were explored in post-hoc analyses. RESULTS: Of 606 patients enrolled, 571 were included in the efficacy analysis (279 in NTHi-Mcat vaccine group, 292 in placebo group). VE against severe acute exacerbations of COPD (AECOPD) in various subgroups was 52.11 % (p = 0.015; frequent exacerbators), 65.43 % (p = 0.015; baseline GOLD grade 4), 38.24 % (p = 0.034; previous pneumococcal and/or influenza vaccination). VE was 52.49 % (p = 0.044) for the 6-12 months period after 1 month post-dose 2. Multivariable analysis identified two factors (frequent exacerbator status plus inhaled corticosteroid use at baseline) associated with significant VE against severe AECOPD; in this subpopulation, VE was 74.99 % (p < 0.001). CONCLUSION: Results suggest potential efficacy with the NTHi-Mcat vaccine against severe exacerbations in certain patients with COPD, in particular those who have frequent exacerbations and use inhaled corticosteroids. This potential signal requires confirmation in an appropriately designed prospective clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03281876.