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Introduction: Combination of daratumumab (Dara) and lenalidomide (Len) may enhance the function of teclistamab (Tec), potentially resulting in improved antimyeloma activity in a broader population. We present initial safety and efficacy data of Tec-Dara- Len combination in patients with multiple myeloma (MM) in a phase 1b study (MajesTEC-2;NCT04722146). Method(s): Eligible patients who received 1-3 prior lines of therapy (LOT), including a proteasome inhibitor and immune-modulatory drug, were given weekly doses of Tec (0.72-or- 1.5 mg/kg with step-up dosing) + Dara 1800 mg + Len 25 mg. Responses per International Myeloma Working Group criteria, adverse events (Aes) per CTCAE v5.0, and for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT guidelines, were assessed. Result(s): 32 patients received Tec-Dara- Len (0.72 mg/kg, n = 13;1.5 mg/kg, n = 19). At data cut-off (11 July 2022), median follow-up (range) was 5.78 months (1.0-10.4) and median treatment duration was 4.98 months (0.10-10.35). Median age was 62 years (38-75);87.5% were male. Median prior LOT was 2 (1-3), 18.8% were refractory to Dara and 28.1% refractory to Len. CRS was most frequent AE (81.3% [n = 26], all grade 1/2), 95% occurred during cycle1. Median time to onset was 2 days (1-8), median duration was 2 days (1-22). No ICANS were reported. Frequent Aes (>=25.0% across both dose levels) were neutropenia (75.0% [n = 24];grade 3/4: 68.8% [n = 22]), fatigue (43.8% [n = 14];grade 3/4: 6.3% [n = 2]), diarrhoea (37.5% [n = 12];all grade 1/2), insomnia (31.3% [n = 10];grade 3/4: 3.1% [n = 1]), cough (28.1% [n = 9];all grade 1/2), hypophosphatemia (25.0% [n = 8];all grade 1/2), and pyrexia (25% [n = 8];grade 3/4: 6.3% [n = 2]). Febrile neutropenia frequency was 12.5% (n = 4). Infections occurred in 24 patients (75.0%;grade 3/4: 28.1% [n = 9]). Most common were upper respiratory infection (21.9% [n = 7]), COVID-19 (21.9% [n = 7]), and pneumonia (21.9% [n = 7]). Three (9.4%) had COVID-19 pneumonia. One (3.1%) discontinued due to COVID-19 infection and this patient subsequently died of this infection. Overall response rate (ORR, median follow-up) was 13/13 (8.61 months) at 0.72 mg/kg and 13/16 evaluable patients (less mature at 4.17 months) at 1.5 mg/kg. 12 patients attained very good/better partial response at 0.72 mg/kg dose, and response was not mature for 1.5 mg/kg group. Median time to first response was 1.0 month (0.7-2.0). Preliminary pharmacokinetic concentrations of Tec-Dara- Len were similar as seen with Tec monotherapy. Tec-Dara- Len- treatment led to proinflammatory cytokine production and T-cell activation. Conclusion(s): The combination of Tec-Dara- Len has no new safety signals beyond those seen with Tec or Dara-Len individually. Promising ORR supports the potential for this combination to have enhanced early disease control through the addition of Tec. These data warrant further investigation.
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Background & Aim: Liposomes are spherical-shaped vesicles composed of one or more lipid bilayers. The ability of liposomes to encapsulate hydro- or lipophilic drugs allowed these vesicles to become a useful drug delivery system. Natural cell membranes, such as Bioxome, have newly emerged as new source of materials for molecular delivery systems. Bioxome are biocompatible and GMP-compliant liposome-like membrane that can be produced from more than 200 cell types. Bioxome self-assemble, with in-process self-loading capacity and can be loaded with a variety of therapeutic compounds. Once close to the target tissue, Bioxome naturally fuse with the cell membrane and release the inner compound. Orgenesis is interested in evaluating the potential of Bioxome as new drug delivery system for treatment of several diseases, including skin repair, local tumour or COVID19. Methods, Results & Conclusion(s): Bioxome were obtained from adipose- derived Mesenchymal Stem Cells, with a process of organic- solvent lipid extraction, followed by lyophilization and sonication assemblage. During the sonication process, Bioxome were charged or not with several cargos. Size distribution of empty Bioxome was detected by Particle Size Analyzer (NanoSight). Electron Microscopy (EM) was performed to assess Bioxome morphology. Lipid content was evaluated by electrospray ionization system. Dose response in vitro test on human lung fibroblasts treated or not with Bioxome encapsulating a specific cargo (API) against COVID19 were performed. NanoSight analysis showed that nanoparticle size in Bioxome samples ranged between 170+/-50 nm, with a concentration ranging between 109-1010+/-106 particles/mL. EM clearly showed the double phospholipid layers that composes the Bioxome. Stability study demonstrated that Bioxome are stable in size and concentration up to 90 days at +4Cdegree or even at RT. No change in size between encapsulated Bioxome with small size (~340 Da) cargo vs empty Bioxome was observed up to 30 days storage. Lipidomic analysis approach revealed that the yield of lipids and their composition are satisfactory for a therapeutic product using Bioxome. Lastly, in the in vitro model of COVID19, Bioxome encapsulating API effectively saved cells from death (20x vs untreated cells) and at lower doses of API than these of non-encapsulated cargo (0.005 microM vs 0.1 microM). Bioxome seems to be an excellent candidate for liposome mimetic tool as drug delivery system for targeting specific organs and diseases treatment.Copyright © 2023 International Society for Cell & Gene Therapy
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Background: Significant evidence suggests that SARS-CoV-2 can be transmitted via respiratory aerosols, which are known to vary as a function of respiratory activity. Most animal models examine disease presentation following inhalation of small-particle aerosols similar to those generated during quiet breathing or speaking. However, despite evidence that particle size can influence dose-infectivity relationships and disease presentation for other microorganisms, no studies have examined the infectivity of SARS-CoV-2 contained in larger particle aerosols similar to those produced during coughing, singing, or talking. Therefore, the aim of the present study was to assess the influence of aerodynamic diameter on the infectivity and virulence of aerosols containing SARS-CoV-2 in a hamster model of inhalational COVID-19. Methods: Dose-response relationships were assessed for two different aerosol particle size distributions, with mass median aerodynamic diameters (MMADs) of 1.3 and 5.2 µm in groups of Syrian hamsters exposed to aerosols containing SARS-CoV-2. Results: Disease was characterized by viral shedding in oropharyngeal swabs, increased respiratory rate, decreased activity, and decreased weight gain. Aerosol particle size significantly influenced the median doses to induce seroconversion and viral shedding, with both increasing â¼30-fold when the MMAD was increased. In addition, disease presentation was dose-dependent, with seroconversion and viral shedding occurring at lower doses than symptomatic disease characterized by increased respiratory rate and decreased activity. Conclusions: These results suggest that aerosol particle size may be an important factor influencing the risk of COVID-19 transmission and needs to be considered when developing animal models of disease. This result agrees with numerous previous studies with other microorganisms and animal species, suggesting that it would be generally translatable across different species. However, it should be noted that the absolute magnitude of the observed shifts in the median doses obtained with the specific particle sizes utilized herein may not be directly applicable to other species.
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Intro: Mass gathering events (MGEs) are associated with the transmission of COVID-19. The world's largest mass gathering hajj pilgrimage 2022 was held after two years of major disruption caused by the COVID pandemic, with one million pilgrims of different ages, health statuses, hygiene sophistication and close contact. This study aimed to estimate the Prevalence of COVID-19 among returning Pakistani pilgrims at Islamabad International Airport, its association with these MGEs and to quantify the potential risk factors associated. Method(s): A retrospective cohort study was carried out at Islamabad International Airport from 14th July to 13th August 2022. A representative sample of 1100 people with potential exposure at Hajj 2022 was surveyed by a questionnaire to obtain information about attendance at hajj and COVID-19 disease. In addition, Rapid antigen testing (RAT) against SARS-Cov-2 was implemented. Statistical analysis was done using Epi info version 7. Finding(s): A total of 1100 subjects participated in the questionnaire survey and underwent rapid antigen testing. The mean age was 49.7+/-10.4. Almost 17.9% of the respondents experienced Covid-like symptoms with sore throat and fever as the most frequent symptoms. Three cases were detected by RAT with an attack rate (AR) of 0.3%;79.7% were female. Considering MGE exposure, AR was 0.2 %. All participants were fully vaccinated with 86.5% boosted with one dose. A dose- response relationship was found between MGE attendance and the disease, (adjusted relative risk [ARR] = 3.4- 5% confidence interval [CI] 2.25-3.5). Associated risk factors with the incidence were co-morbidity (RR=5.2) and non- use of face masks (RR=9). Conclusion(s): The study highlights the significance of MGEs in COVID-19 transmission. Vaccination and booster shots significantly reduced the risk of Covid-19 transmission among the returning pilgrims. With surveillance, screening and Rapid antigen testing at Points of entry, risk of future pandemics is significantly reduced.Copyright © 2023
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The theoretical model of the relationship among dose-response function parameters, quantum emission rate, and basic reproductive number for SARS-CoV-2 was constructed. Then, using this model, infection fields and pathways for SARS-CoV-2 and its variant were estimated. The parameters of the time activity, the number of contacts by the microenvironments and groups, and the COVID-19 risk from multiple pathways in near and far fields were used. Consequently, in lower transmissibility, droplet spray transmission in the near field was dominant, whereas in higher transmissibility, transmission from inhalation of smaller aerosols in the far field was dominant. Moreover, it was suggested that transmission from droplet spray, indirect contacts, and inhalation of smaller aerosols in the near field and inhalation of smaller aerosols in the far field was dominant for the wild-type strain, while transmission from inhalation of smaller aerosols in the far field were dominant for the Delta variant. © 2022 17th International Conference on Indoor Air Quality and Climate, INDOOR AIR 2022. All rights reserved.
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Aim: To develop a simple, inexpensive antiviral screening assay, applicable to SARS-CoV-2, using a plate-based bioassay approach to assess the in-vitro activity of compounds against HCoV-OC43. Background(s): Despite the successful deployment of vaccines against SARS-CoV-2 there remains a need for effective antivirals for acute infection treatment. A distinct problem facing the search for new anti-coronavirus compounds is the cost of antiviral screening, compounded by the biosecurity concerns of live SARSCoV- 2 culture. In concert with low pathogenic surrogate virus use, the resazurin reduction assay, which is often employed for compound cytotoxicity assessments can be employed for safe, rapid and inexpensive antiviral screening. Method(s): In-vitro cell based resazurin reduction assays were optimised using remdesivir as a control compound for the assessment of anti-HCoV-OC43 activity. Following optimisation, 246 purified natural compounds from the University of Western Australia's compound collection,were screened using the resazurin bioassay as a primary screen, under pre-treatment and cotreatment conditions. Five compounds, which demonstrated anti- HCoV-OC43 activity, were chosen for secondary screening with dose responses determined using qRT-PCR. Result(s): Primary screens of the 246 compounds using the resazurin bioassay identified five compounds with a relative viral inhibition >60% and a relative cell viability >70% (Table 1). The Z factor of the pre-treatment and co-treatment assays was >0.5 (average +/- SD;0.85 +/- 0.07, 0.91 +/- 0.03 respectively). Further dose response analysis of the top five compounds identified one compound with an IC50 value <10 muM. Conclusion(s): The method developed is an appropriate primary screening tool for the identification of novel compounds with anti-HCoV-OC43 activity.Copyright © 2023 Southern Society for Clinical Investigation.
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Corticosteroids (CS) have been used in the management regimens for COVID-19 disease to mitigate the cytokine storm and ill effects of the pulmonary inflammatory cascade. With the rampant use of CS, clinicians started reporting the occurrence of osteonecrosis of the femoral head (OFH). In this systematic review, we aim to analyze the literature and identify the definitive cumulative dose and duration of CS needed for the development of OFH based on the SARS model and generate a risk-based screening recommendation for OFH in convalescent COVID-19 patients to facilitate early identification and management. An electronic database search was conducted until December 2022 in PubMed, Web of Science, Embase, and CNKI (China Knowledge Resource Integrated Database). Studies involving CS therapy and osteonecrosis data in SARS patients were included. Three authors independently extracted the data from the included studies and a dose-response meta-analysis was performed for various doses and duration of CS utilized in the included studies. We selected 12 articles with 1728 patients in the analysis. The mean age was 33.41 (±4.93) years. The mean dosage of CS administered was 4.64 (±4.7) g which was administered for a mean duration of 29.91 (±12.3) days. The risk of osteonecrosis increases at pooled OR of 1.16 (95% CI 1.09-1.23, p < 0.001) per 2.0 g increase in the cumulative dose of CS usage. Similarly, the risk increases at pooled OR of 1.02 (95% CI 1.01-1.03, p < 0.001) per 5 days of increase in the cumulative duration of CS usage. A cumulative dosage of 4 g and a duration of 15 days were determined as the critical cut-off for the non-linear dose-response relationship observed. Appropriate and frequent screening of these individuals at regular intervals would help in the identification of the disease at an early stage in order to treat them appropriately.
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Background: Corticosteroids are standard of care for moderate-to-severe COVID-19. However, the optimal dosing is unclear. Our objective was to compare higher dose corticosteroids to lower dose corticosteroids in patients with moderate-to-severe COVID-19. Method(s): We searched for randomized trials of adult patients with moderate-to-severe COVID-19 that compared corticosteroids versus placebo, standard care or that compared alternative doses of corticosteroids. We performed both a frequentist network and dose-response meta-analysis. We assessed risk of bias using a modified version of the Cochrane RoB 2.0 and used GRADE to assess the certainty of evidence. Result(s): We included 21 randomized trials with 9,640 patients. Our dose response analysis found that higher dose corticosteroids probably reduce mortality compared to lower dose (risk difference 13 fewer deaths per 1000 (95% CI 22.6 to 3.92 fewer);moderate certainty), may decrease the need of mechanical ventilation dose (risk difference 10 fewer per 1000 (95% CI 20.5 to 4.8 fewer) and probably decreases risk of infections (16.7 fewer infections per 1000 (95% CI 25 to 5.4 fewer);moderate certainty). Our network meta-analysis found that high dose corticosteroids probably reduce the duration of mechanical ventilation as compared to low dose (6.9 fewer days (95% CI 8.5 to 5.2 fewer);moderate certainty). The results of our network and dose response analysis were consistent. Conclusion(s): High dose corticosteroids is more effective than than low dose in reducing mortality.
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It has been proven that mRNA vaccines are highly effective against the COVID-19 outbreak, and low prevalence of side effects has been shown. However, there are still many gaps in our understanding of the biology and biosafety of nucleic acids as components of lipid nanoparticles (LNPs) most often used as a system for inctracellular delivery of mRNA-based vaccines. It is known that LNPs cause severe injection site inflammation, have broad biodistribution profiles, and are found in multiple tissues of the body, including the brain, after administration. The role of new medications with such pharmacokinetics in inflammation developing in inaccessible organs is poorly understood. The study was aimed to assess the effects of various doses of mRNA-LNP expressing the reporter protein (0, 5, 10, and 20 microg of mRNA encoding the firefly luciferase) on the expression of neuroinflammation markers (Tnfalpha, Il1beta, Gfap, Aif1) in the prefrontal cortex and hypothalamus of laboratory animals 4, 8, and 30 h after the intramuscular injection of LNP nanoemulsion. It was shown that mRNA-LNP vaccines in a dose of 10-20 microg of mRNA could enhance Aif1 expression in the hypothalamus 8 h after vaccination, however, no such differences were observed after 30 h. It was found that the Gfap, l11beta, Tnfalpha expression levels in the hypothalamus observed at different times in the experimental groups were different. According to the results, mRNA-LNPs administered by the parenteral route can stimulate temporary activation of microglia in certain time intervals in the dose-dependent and site specific manner.Copyright © 2022 Pirogov Russian National Research Medical University. All rights reserved.
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Background: Around 80% of patients who developed COVID-19-driven ARDS present lung ailment. There is a lack of knowledge of the mechanisms that mediate the pulmonary outcomes. Aim(s): To characterize the factors linked to diffusion impairment in survivors of severe COVID-19. Method(s): Prospective cohort study including 87 COVID-19-induced ARDS survivors. A complete pulmonary evaluation was performed 3 months after hospital discharge. 364 proteins were quantified using the proximity extension assay (PEA). Partial least square-discriminant analysis (PLS-DA) and random forest (RF) were used for multivariable analyses. Result(s): Moderate to severe diffusion impairment (DLCO<60% predicted) was observed in the 30% of the cohort. 15 proteins were differentially detected [false discovery rate (FDR)<0.05] in the univariate analysis. Pleiotrophin showed the highest differences (fold change=2.22 and FDR=0.001). In continuous analysis, proteins were inversely and independently associated with DLCO, and in some cases showed a robust dose-response relationship. PLS-DA and RF identified proteomic profiles related to the severity of diffusion capacity. Clusters identified were enriched in mediators of cell proliferation and differentiation, tissue remodeling, angiogenesis, coagulation, inflammation, immune response and fibrosis. Proteins are expressed in immune and non-immune lung cells. Conclusion(s): In survivors of COVID-19-driven ARDS, lung dysfunction is linked to plasma factors involved in injury and repair mechanisms. The host proteomic profile provides a novel understanding of post-acute sequelae and may be source of therapeutic strategies and biomarkers.
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Background: Treprostinil is a prostacyclin analogue which has been approved in the EU for intravenous (i.v.) and subcutaneous (SC) administration in patients with PAH. LIQ861 is a dry powder formulation of treprostinil which can be used for inhalation via a handheld device. Objectives and methods: LTI-201 was a multicentre, Phase 2, open-label, dose-escalation study to evaluate the HD dose-response and safety of LIQ861, followed by an open-label extension period. In "Part A" HD response was measured by right heart catheterization for 120 minutes after a single 26.5 or 53 mug dose of LIQ861. In "Part B" patients were titrated to symptomatic relief (<=159 mug QID) and were reassessed after 16 weeks using right heart catheterization and clinical assessments. Result(s): Fifteen PAH Patients (60 % female, mean age 56 +/- 14.3 years, mean pulmonary vascular resistance (PVR) 605+/-246 dynes/sec/cm-5) were included. In Part A HD measures (PVR and mean pulmonary arterial pressure) improved with a peak response after 15 minutes for both doses. The study was stopped early due to the COVID19 pandemic with only 6 patients completing Part B. At Week 16, these HD responses also improved and clinical assessments improved or remained stable for these patients. All doses of LIQ861 were generally well-tolerated with only one serious adverse event (short episode of hypoxia after inhalation). The most frequently reported adverse events were cough and throat irritation and most were assessed as mild in severity. Conclusion(s): LIQ861 was overall safe and well tolerated. An expected improvement in HD measures was seen with acute and chronic dosing.
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Background: COVID-19 vaccination has been suggested as very effective in patients with Inflammatory Bowel Disease (IBD), but most studies assess antibody levels within a few weeks after vaccination and do not use the most recent recommendations as seroconversion cut-off. The objective of VACOVEII study is to evaluate the antibody response to vaccination at 6 months using these recommendations, the improvement after a booster dose and the effect of the immunosuppressive therapy (IST). We present the intermediate results of the study. Method(s): Spanish multicentre, prospective and case-control study. 18 years or older IBD patients fully vaccinated against COVID-19 were included. Those with previous COVID infection were not included, but not excluded for the next analyses if the infection was subsequent. Main outcomes were anti-SARS-CoV-2 spike protein antibody (anti S) concentrations and rate of seroconversion (defined above the protection threshold of 260 BAU/mL), measured 6 months after vaccination at a single centralized laboratory. The effect of IST on the main outcomes was analysed, adjusted by age, vaccine type and COVID infection. Groups of treatment considered for the analysis were: Patients without IST (without treatment or under salicylates alone), anti-TNF in combination with immunomodulators (IMM), anti-TNF in monotherapy, IMM in monotherapy, ustekinumab and anti-integrin. Result(s): We included 313 patients with IBD (46.5% ulcerative colitis and 52.3% Crohn's disease, median age 49 years) vaccinated either with non-mRNA vaccines (14%) or mRNA vaccines (86%). Baseline therapy was: 124 patients without IST, 21 with anti-TNF plus IMM, 67 with anti-TNF in monotherapy, 54 with IMM in monotherapy, 28 with ustekinumab and 19 with anti-integrin. Mean anti S concentrations were significant lower in patients with anti-TNF compared with patients without IST (Figure 1). In multivariable analysis, lower antibody concentrations were independently associated with anti-TNF treatment, non-mRNA vaccines and older age. Within the patients with no COVID infection during the follow-up, we found very low rates of seroconversion in patients with anti-TNF (14.1%), ustekinumab (30.8%) and IMM in monotherapy (34.9%), compared with patients without IST (51.5%) (Table 1). In multivariable analysis, anti-TNF treatment, non-mRNA vaccines and older age were independently associated with lower rates of seroconversion, as well as ustekinumab and IMM in monotherapy (Table 2). Conclusion(s): COVID-19 vaccine-induced antibody seroconversion in patients with IBD, measured at 6 months and according to >260 BAU as protection threshold, is clearly lower than previously reported, with a profound impact by some IST therapies, mainly anti-TNF, besides age and type of vaccine.
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Understanding the mechanistic dynamics of transmission is key to designing more targeted and effective interventions to limit the spread of infectious diseases. A well-described within-host model allows explicit simulation of how infectiousness changes over time at an individual level. This can then be coupled with dose-response models to investigate the impact of timing on transmission. We collected and compared a range of within-host models used in previous studies and identified a minimally-complex model that provides suitable within-host dynamics while keeping a reduced number of parameters to allow inference and limit unidentifiability issues. Furthermore, non-dimensionalised models were developed to further overcome the uncertainty in estimates of the size of the susceptible cell population, a common problem in many of these approaches. We will discuss these models, and their fit to data from the human challenge study (see Killingley et al. (2022)) for SARS-CoV-2 and the model selection results, which has been performed using ABC-SMC. The parameter posteriors have then used to simulate viral-load based infectiousness profiles via a range of dose-response models, which illustrate the large variability of the periods of infection window observed for COVID-19.
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COVID-19 , SARS-CoV-2 , Humans , Computer Simulation , Disease SusceptibilityABSTRACT
Social distancing is widely acknowledged as an effective public health policy combating the novel coronavirus. But extreme forms of social distanc-ing, like isolation and quarantine, have costs, and it is not clear how much social distancing is needed to achieve public health effects. In this article we develop a design-based framework to test the causal null hypothesis and make inference about the dose-response relationship between reduction in social mobility and COVID-19 related public health outcomes. We first dis-cuss how to embed observational data with a time-independent, continuous treatment dose into an approximate randomized experiment and develop a randomization-based procedure that tests if a structured dose-response relationship fits the data. We then generalize the design and testing procedure to a longitudinal setting and apply them to investigate the effect of social distancing during the first phased reopening in the United States on public health outcomes using data compiled from Unacast™, the United States Census Bu-reau, and the County Health Rankings and Roadmaps Program. We rejected a primary analysis null hypothesis that stated the social distancing from April 27, 2020 to June 28, 2020, had no effect on the COVID-19-related death toll from June 29, 2020 to August 2, 2020 (p-value < 0.001), and found that it took more reduction in mobility to prevent exponential growth in case num-bers for nonrural counties compared to rural counties. © Institute of Mathematical Statistics, 2023.
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To provide a scientific basis for improved exercise-based immunity, a meta-analysis was used to explore the dose-response relationship between physical activity (PA) and the risk of severe illness and mortality related to COVID-19 (coronavirus disease 2019). To this end, we searched PubMed, Web of Science databases from January 2020 through April 2022. 14 observational studies met the criteria for inclusion in the meta-analysis, including 2840 cases of severe illness and death from COVID-19. Categorical dose-relationship analysis showed that the risks of severe illness and mortality from COVID-19 were, respectively, 46% (risk ratio (RR): 0.54; confidence intervals (CIs): 0.41-0.68) and 59% (RR = 0.41; 95%CI: 0.23-0.58) lower for the highest dose of PA compared with the lowest dose of PA. The results of the continuous dose-response analysis show an inverse nonlinear relationship (Pnon-linearity < 0.05) between PA and both the risk of severe illness and mortality from COVID-19. For PA below 10 MET-h/week (MET-h/week: metabolic equivalent of task-hours/week), an increase of 4 MET-h/week (1 h of moderate-intensity or 0.5 h of high-intensity PA) was associated with 8% and 11% reductions in the risk of severe illness and mortality from COVID-19. PA above 10 MET-h/week lowered the risk of severe illness and mortality from COVID-19 by 7% and 9%, respectively, for each 4 MET-h/week increase. Doses of WHO-recommended PA levels (10 MET-h/week) may be required for more substantial reductions in the risk of severe illness and mortality from COVID-19.
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PURPOSE/HYPOTHESIS: Given the economic and health impact of COVID-19, it is critical to develop optimal inpatient programs to prevent its long term sequalae.1,2 Current guidelines advocate the use of pulmonary rehabilitation (PR) in patients with COVID-19.3 However, there is a lack of concrete information on PR in an inpatient setting for COVID-19. Therefore, we synthesized literature on the safety, feasibility and efficacy of inpatient PR on pulmonary outcomes and quality of life (QoL) in individuals with COVID-19. We hypothesized that inpatient PR would improve outcomes in this population. NUMBER OF SUBJECTS: The pooled sample consisted of 718 participants (F=35.2%, age=36-71 y). MATERIALS AND METHODS: Using PubMed, Web of Science, Cochrane Library and Embase, 3 researchers screened 474 articles for eligibility with the search terms: (covid-19 or coronavirus or 2019-ncov or sars-cov-2 or cov-19 *) AND (respiratory or pulmonary) AND (physical therapy or physiotherapy or rehabilitation). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used. Nine articles were finalized using the inclusion criteria: publication date >2019, age >18 y, inpatient setting, and English language. Subsequently, reviewers extracted relevant information and appraised using the Physiotherapy Evidence Database (PEDro) score. RESULT(S): Studies were mainly retrospective (retrospective chart review=5, prospective observational=4);and had PEDro score of 4/10. Inpatient PR ranged from 2 to 12 weeks. The primary outcomes included six-minute walk distance (6MWD), pulmonary function and QoL. Within group analyses (n = 9) showed that inpatient PR improved 6MWD statistically and clinically (mean improvement 111-204.7 m). In all the studies (n = 3) that offered comparisons with a no PR group (n = 3), inpatient PR offered a statistically significantly benefit in this population. Further analysis showed improvements in exercise capacity were in a dose-response fashion and were related to disease severity (n = 2). Within group changes were noted in FEV1 and FVC values (n = 3). For QoL data (n = 6), within group improvements were noted only in 3 studies. Inpatient PR was reported to be safe by all studies that reported adverse events (n = 4). CONCLUSION(S): Current review suggests that inpatient PR was safe, feasible and induced large improvements in exercise capacity in individuals with COVID-19. These findings concur with data on the use of PR in chronic pulmonary diseases.4 This is important as exercise capacity is regarded as a strong predictor of cardiovascular mortality.5 The divergent results on pulmonary function and QoL may be due to the heterogeneity of PR duration, QoL measures and disease severity.6,7 Limitations included retrospective designs, small sample size and variance in protocols. Future research should be directed on improving methodological rigor of studies. CLINICAL RELEVANCE: Our study provides valuable evidence that inpatient PR is safe and may accelerate improvement in exercise capacity in individuals with COVID-19.
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Background. We developed a COVID-Influenza Combination (CIC) vaccine, comprising recombinant SARS-CoV-2 Spike (rS) and quadrivalent influenza hemagglutinin (HA) protein nanoparticles (qNIV), and Matrix-MTM adjuvant. rS/Matrix-M previously demonstrated efficacy against COVID-19 in Phase 3 trials, while qNIV/ Matrix-M previously demonstrated induction of broadly cross-reactive antibodies. Here we report preliminary safety and immunogenicity results of a first-ever Phase 1/2 CIC dose-finding trial. Methods. Seropositive (COVID-19 vaccinated >= 8 weeks prior) participants (N=642) aged 50-70 years were randomized equally, to receive two intramuscular doses, 56 days apart, to 1 of 14 different dose/formulations of CIC using a design of experiments approach (dose range: rS 2.5-22.5ug, HA5-60ug;and 50ug Matrix-M), or to 1 of 2 reference formulations of either standalone rS with Matrix-M [2 doses] or qNIV with Matrix-M [1 dose only]. Pre- and post-vaccination (Days 0, 28, 56, 70, 84, 182) immunogenicity assessments including SARS-CoV-2 anti-S IgG and influenza HAI antibodies to vaccine-homologous strains. Reactogenicity was assessed 7 days following each dose, and safety outcomes assessed through Day 70. Multiple regression was used to create predictive models to assess antibody response surfaces and for dose optimization. Results. All CIC formulations were well tolerated, with a reactogenicity and safety profile generally comparable to standalone rS or qNIV. Regression modelling of post-first dose responses revealed that both rS and HA antigens in a CIC formulation modestly interfered with each other, however, interference was overcome with dose adjustment across a range of rS/HA doses. Specifically, higher rS dose ( >20ug), in a dose dependent fashion, overcame HA interference, closely matching standalone rS IgG reference responses (GMEU 16,818), whereas lower, intermediate HA dose overcame rS interference, closely matching standalone HA reference HAI responses for H3N2 (GMT 145), H1N1 (GMT 134), and B-Victoria (GMT 66);while modestly (at least 34%) lower than the reference B-Yamagata response (GMT 101). Conclusion. CIC formulations were well tolerated and immunogenic, with various dose combinations achieving response comparable to standalone vaccines.
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Background. COVID-19 continues to cause substantial morbidity and mortality globally. It is likely that booster vaccinations will be needed in future years to protect older adults and those with chronic medical conditions. We present interim topline results of a phase 1/2 study of IVX-411 [ACTRN12621000738820.;ACTRN12621000882820], an investigational VLP protein subunit SARS-CoV-2 vaccine, in adults aged 18-69 years (Figure 1). Methods. In Part 1, 84 SARS-CoV-2-naive adults were randomized to receive two doses on Days 0 and 28 of either IVX-411 (5, 25, or 125mug) +/- adjuvant, or placebo (Figure 2a). In Part 2, 84 subjects received a single dose of either IVX-411 +/- adjuvant or placebo 3-6 months after completion of a primary licensed vaccine regimen (Figure 2b). Solicited adverse events (AEs) were collected for 7 days after each dose, with immunogenicity assessed on Days 0, 28, and 49 [(Part 1) and on Days 0, 7 and 28 (Part 2). Primary outcomes in both parts were solicited and unsolicited AEs, neutralizing antibody titers, and spike protein-specific IgG antibody titers. Results. Demographics were similar in the IVX-411 groups vs placebo. In Part 1 and Part 2, local reactogenicity was mild-to-moderate, with higher rates of AEs with increasing doses and addition of adjuvant (Figure 3a). Rates of systemic AEs were similar to placebo across groups (Figure 3b). No vaccine-related severe or serious AEs were noted. IVX-411 was immunogenic in both primary and booster vaccination: in SARS-CoV-2-naive subjects, a limited dose effect was seen, with significantly higher antibody titers in the groups receiving adjuvanted IVX-411 vaccine (p< 0.01;Figure 4a). The magnitude of antibody responses was similar to, or below, Human Convalescent Sera levels. In previously vaccinated subjects, IVX-411 boosted baseline antibody titers, with no conclusive dose or adjuvant effect (Figure 4b). Immunogenicity was observed across all variants of concern (beta, delta, and omicron) in both parts, with up to 7- fold rises from baseline (Figure 5). Conclusion. The study met all primary safety and immunogenicity objectives, with acceptable tolerability profiles in primary and booster vaccination. A clear adjuvant effect was observed in SARS-CoV-2-naive subjects.