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Supplementary Information | The online version contains supplementary material available at 10.1186/s13075-023-03177-6. | PMC10577982 |
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Keywords | PMC10577982 |
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Background | rheumatoid arthritis, GCA, active disease, anterior ischemic optic neuropathy or stroke, RA | RHEUMATOID ARTHRITIS, POLYMYALGIA RHEUMATICA (PMR), RECRUITMENT, GIANT CELL ARTERITIS, PRIMARY SYSTEMIC VASCULITIS, GCA, CORONAVIRUS, PATHOGENESIS, COMPLICATIONS | Giant cell arteritis (GCA) is the most common primary systemic vasculitis in people above 50 years of age and is more frequently reported in Caucasians and in females [Patients with GCA may present with constitutional, polymyalgia, or cranial symptoms. Ischemic complications, such as anterior ischemic optic neuropathy or stroke, may occur if treatment is delayed [Glucocorticoids (GCs) are an integral part of the treatment of GCA [The role of interleukin-6 (IL-6) is well documented in the pathogenesis of GCA, with increased IL-6 levels found in the temporal artery tissues of patients with active disease. In addition, circulating IL-6 is elevated in untreated GCA and correlates with poor clinical response [Sarilumab, another IL-6Ri, is approved worldwide for the treatment of rheumatoid arthritis (RA) and for polymyalgia rheumatica (PMR) in the USA [This study (NCT03600805) was designed to evaluate the efficacy and safety of sarilumab in patients with active GCA over 52 weeks. Although the protracted recruitment timelines exacerbated by the pandemic of coronavirus disease-2019 (COVID-19) led to premature discontinuation of the trial by the sponsor, we report the available findings herein. | PMC10577982 |
Methods | PMC10577982 |
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Study design and population | large-vessel vasculitis | PMR, GCA | This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 52-week study with a 24-week post-treatment follow-up phase (NCT03600805) (Fig. Study design. Patients were included in the study if they had a diagnosis of GCA according to the following criteria: ≥ 50 years of age; history of erythrocyte sedimentation rate (ESR) ≥ 50 mm/h (or C-reactive protein [CRP] > 25 mg/L); unequivocal cranial symptoms of GCA or PMR; and presence of at least one of the following: temporal artery biopsy (TAB) revealing features of GCA, evidence of large-vessel vasculitis by angiography or cross-sectional imaging (angiography, computed tomography angiography [CTA], magnetic resonance angiography [MRA], or positron emission tomography-computed tomography [PET-CT], ultrasound, etc.). Patients either had new-onset active GCA (diagnosis within 6 weeks of baseline) or refractory active GCA (diagnosis > 6 weeks before baseline and previous treatment with ≥ 40 mg/day prednisone [or equivalent] for at least consecutive 2 weeks at a time). The detailed inclusion and exclusion criteria are summarized in Additional file | PMC10577982 |
Sample size determination | Based on the results from the GiACTA trial [ | PMC10577982 |
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Changes in conduct of study | RECRUITMENT | The study enrolled the first patient on 20 Nov 2018 but was prematurely discontinued on 21 Jul 2020 due to protracted recruitment, exacerbated by the COVID-19 pandemic; all randomized patients had to stop their study participation in 12 weeks and have a follow-up visit at 6 weeks following treatment cessation (and no later than 24 Nov 2020). As the majority of enrolled patients had the opportunity to reach the week 24 visit, and it was considered a clinically meaningful timepoint to evaluate response, the following additional endpoints were added at week 24: the proportion of patients achieving SR; components of SR composite measure; and GTI (CWS and AIS). | PMC10577982 |
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Analysis populations | The primary endpoint analysis of the patients who achieved SR at week 52 was limited to the cohort of patients who had an opportunity to complete the 52-week treatment period (i.e., week 52 analysis set). This cohort of patients was defined as the patients with a randomization date prior to 16 Oct 2019.The intent-to-treat (ITT) population (i.e., all randomized patients) was used for the efficacy analysis at week 24. The safety population included all randomized patients who received at least one dose of the study medication. The PK population consisted of all patients in the safety population with at least one post-dose, non-missing serum sarilumab concentration. | PMC10577982 |
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Statistical analyses | Due to the small sample size, only descriptive summaries by four treatment groups are presented for all baseline characteristics and endpoints. All analyses were performed with SAS Enterprise Guide Version ENGLISH 9.4. | PMC10577982 |
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Results | PMC10577982 |
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Patient disposition | Of 125 patients screened, a total of 83 patients were randomized and treated in the study (i.e., ITT population): 27 patients in the SAR200 + 26W taper group, 14 patients in the SAR150 + 26W taper group, 28 patients in the PBO + 52W taper group, and 14 patients in the PBO + 26W taper group (Fig. Patient disposition. Of the 83 patients, only 36 were randomized prior to 16 Oct 2019 and were included in the week 52 analysis set: 13 patients in the SAR200 + 26W taper group, 7 patients in the SAR150 + 26W taper group, 10 patients in the PBO + 52W taper group, and 6 patients in the PBO + 26W taper group. Of these 36 patients, 29 completed the 52-week treatment period (8 patients in the SAR200 + 26W taper group, 6 patients each in the SAR150 + 26W and PBO + 26W taper groups, and 9 patients in the PBO + 52W taper group). | PMC10577982 |
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Outcome assessments | PMC10577982 |
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Secondary efficacy endpoints | PMC10577982 |
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Pharmacodynamics | From week 12 through week 52, CRP levels in the sarilumab groups were maintained at < 10 mg/L and were lower than that observed in the PBO groups (Additional file Mean changes in IL-6 and sIL-6R levels over time from baseline through week 52 are depicted in Fig. Change from baseline in IL-6 and sIL-6R levels during the 52W treatment period — safety population: | PMC10577982 |
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Pharmacokinetics | The PK analysis set comprised 26 patients in the SAR200 + 26W taper group and 14 patients in the SAR150 + 26W taper group. All pre-dose concentrations of functional sarilumab in serum at week 0 were below the lower limit of quantification (312.5 ng/mL). After multiple SC administrations of sarilumab, the observed trough concentrations of functional sarilumab increased over time from week 0 through week 52 in sarilumab groups. At week 24, the mean trough concentration of functional sarilumab increased 2.7-fold with a 1.3-fold increase in dose. There was an accumulation of sarilumab following SC administrations of sarilumab 150 and 200 mg, with the accumulation ratio of ~ 9-fold based on the mean trough concentrations (Additional file | PMC10577982 |
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Discussion | ’ disease, neutropenia, retinal artery occlusion, PD, RA | NEUTROPENIA, UNILATERAL BLINDNESS, DISEASE, RECRUITMENT, RETINAL ARTERY OCCLUSION, REMISSION, GCA, INFLAMMATORY RESPONSE | This study was designed to evaluate the efficacy and safety of sarilumab in patients with GCA; however, it was prematurely terminated, resulting in low enrollment and a limited dataset for statistical analyses. Due to the decision to discontinue all patients from the study, the interpretation of the study results was severely impeded. The decision to prematurely terminate the study was not driven by any safety issues with the administration of sarilumab.In this study, both CRP and ESR were used as a part of inclusion criteria as these are the usual inflammatory markers that correlate with disease activity and are used in general clinical practice for the monitoring of patients’ disease activity. Further, higher historical cutoff values were used for these inflammatory markers (CRP > 25 mg/L or ESR ≥ 50 mm/h) as per the study protocol eligibility criteria, to ensure a greater likelihood that the patients enrolled in the study truly had active GCA. Similar CRP and ESR levels have been required in previous trials investigating other IL-6R inhibitors for including patients [In this study, almost half of the patients in the SAR200 + 26W and SAR150 + 26W taper groups achieved SR at week 52 and week 24, which was numerically higher than that observed in the placebo groups; CRP was included as a part of the definition for disease remission, along with its normalization value of < 10 mg/L, consistent with the GiACTA trial [Unlike the GiACTA study of TCZ [In this study, there was some suggestion of a GC-sparing effect of 200 mg sarilumab, as shown by the reduced cumulative GC dose in the SAR200 + 26W taper group, but this result was not consistently observed for the lower sarilumab dose (150 mg).A majority of patients in all treatment groups experienced TEAEs, with neutropenia more frequently reported in patients who received sarilumab, as expected due to the known PD effect of IL-6R inhibition on neutrophil counts. One patient had SAEs of retinal artery occlusion and unilateral blindness, which were deemed by the investigator to be unrelated to the study drug. Overall, sarilumab was tolerable with a safety profile consistent with the previous studies in RA [Although the CRP levels varied among the study groups, they were maintained at < 10 mg/L in the sarilumab groups and were lower than those observed in the placebo groups. This aligns with the previously published data of sarilumab in patients with RA, and attributes to the blockade of IL-6 signaling pathway and subsequent inhibition of the inflammatory response by sarilumab [The main limitation of the study was its small sample size due to the early termination of the study with protracted recruitment timelines, exacerbated by the COVID-19 pandemic. | PMC10577982 |
Conclusions | RECRUITMENT, GCA | The planned recruitment of this study was not achieved, as it was stopped early by the sponsor due to slow recruitment and the COVID-19 pandemic. Therefore, it is difficult to draw clear conclusions regarding the efficacy of sarilumab in GCA. | PMC10577982 |
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Acknowledgements | Medical writing support for this manuscript was provided by Vasudha Chachra, MPharm of Sanofi. | PMC10577982 |
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Authors’ contributions | RS | WAS, BD, JS, AG, SHU, SLM, MAG, RS, KJW, PMV, MCN, BA, YL, FB, and JHS substantially contributed to the conception or design of the work. YX was involved in data analysis. All authors were involved in the interpretation of data for the work, reviewed the manuscript for important intellectual content, and approved the final version for publication. All authors agreed to be accountable for all aspects of the work related to the accuracy or integrity of the manuscript. | PMC10577982 |
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Authors’ information | Angeliki Giannelou’s Affiliation at the time of the conduct of study. | PMC10577982 |
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Funding | This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc. | PMC10577982 |
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Availability of data and materials | Qualified researchers may request access to patient-level data and related documents (including, e.g., the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications). Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at | PMC10577982 |
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Declarations | PMC10577982 |
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Ethics approval and consent to participate | The study was conducted according to the principles defined in the Declaration of Helsinki and Good Clinical Practices. All participating investigators obtained full ethics or institutional review board approval according to their local regulations. The Ethik-Kommission des Landes Berlin, Landesamt für Gesundheit und Soziales, Berlin, provided approval for the lead site in Germany (reference# 18/0339 – EK 12/15). Written informed consent was obtained from all participating patients. | PMC10577982 |
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Consent for publication | Not applicable. | PMC10577982 |
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Competing interests | RS, MCN | CORBUS | WAS: Received consulting fees and grants from AbbVie, GSK, Novartis, Roche, and Sanofi; speakers bureau for AbbVie, Chugai, GSK, Novartis, Roche, and Sanofi; has been an investigator on clinical trials for AbbVie, GSK, Novartis, and Sanofi. BD: Consultant for Sanofi and Roche Chugai; speakers bureau for Roche Chugai and Cipla; received grant/research support from Sanofi, Roche, and AbbVie. JS, YX, and YL: Employees of Sanofi and may hold stocks or stock options in the company. AG: Employee and shareholder of Regeneron Pharmaceuticals, Inc at the time of the conduct of study. MCN and BA: Employees and shareholders of Regeneron Pharmaceuticals, Inc. SHU: Consultant for Sanofi, Kiniksa, and Janssen; received grant/research support from Genentech. SLM: Consultant on behalf of her institution for Roche/Chugai, Sanofi, AbbVie, and AstraZeneca; received speaker fees for her institution from Pfizer and Vifor; received grant/research support from Vifor – all outside the submitted work; received support from Roche/Chugai to attend EULAR 2019 and from Pfizer to attend ACR Convergence 2021; SLM is supported by the NIHR Biomedical Research Centre. MAG: Received grant/research support from AbbVie, MSD, Janssen, and Roche; received consultation fees/participation from company-sponsored speakers bureaus tied to AbbVie, Pfizer, Roche, Sanofi, Eli Lilly, Celgene, and MSD. RS: Consultant for Sanofi, GSK, Novartis, ChemoCentryx, Roche-Genentech, and AbbVie; received grant/research support from GSK, ChemoCentryx, Corbus, InflaRx, and Boehringer Ingelheim. KJW: Paid instructor for ChemoCentryx; received grant/research support from Eli Lilly, Kiniksa, and GSK; received consulting fees from Sanofi. PMV: Received speaker, advisory fees, and/or research support from Roche, MSD, AbbVie, Sanofi, Grünenthal, Amgen, Chugai, BMS, Janssen, and Drossapharm. FB: Received grants and personal fees from Horizon Therapeutics, AbbVie, and Sanofi; received grants from Mundipharma; received grants, personal fees, and non-financial support from Roche; received personal fees from Galapagos outside the submitted work. JHS: Consultant for and received research funds from Roche. | PMC10577982 |
References | PMC10577982 |
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Introduction | Postural orientation requires the integration of vestibular, visual, and somatosensory information. Perception of the body in space also enables postural control and body movements [The effect of NMV on postural orientation differs during and after stimulation [The subjective straight ahead (SSA), a measurement that indicates the error between the objective midline of the body and subjective midline of perception, has been used as an index of midline perception in the horizontal plane [The effect of NMV is enhanced by increasing the amplitude [Thus, this study aimed to clarify the effects of NMV on standing postural orientation and spatial perception in the same healthy participants, depending on differences in stimulation duration and simultaneous stimulation of trunk muscles. | PMC9879387 |
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Materials and methods | PMC9879387 |
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Study design and participants | RECRUITMENT | This was an interventional study with a cross-over design. Approval was obtained from the Research Safety Ethics Review Committee of the Tokyo Metropolitan University Arakawa Campus (approval number: 20021) and the Tokyo Metropolitan Rehabilitation Hospital (approval number: 2021–10). All participants were informed, both orally and in writing, about the content of the research, and a letter of informed consent was obtained from each participant before their enrolment. A participant in this study (This study was conducted in a quiet laboratory environment in Tokyo Metropolitan Rehabilitation Hospital and Tokyo Metropolitan University. The period of study, including recruitment period was from 1 April 2021 to 31 March 2022.The following criteria were established to exclude a possible reduced response to NMV: (1) healthy participants under 65 years of age [ | PMC9879387 |
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Vibration settings | Vibratory stimulation was performed using a speaker-type stimulator [ | PMC9879387 |
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Speaker-type stimulator. | PMC9879387 |
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Location of vibratory stimulators. | The vibratory stimulators are fixed in two circular positions in the sitting position. | PMC9879387 |
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Outcome measures | Standing COP was measured using a COP platform (SR Vision by Sumitomo Riko Co. Ltd, Nagoya, Japan) to assess standing postural orientation. The frequency of signals was recorded at a sampling rate of 20 Hz to generate the COP data, which is valid and reliable for quantifying standing balance [To assess spatial perception, SSA was measured using a 32” (1375 × 767 pixels) touch panel (NEWCOM Inc., Saitama, Japan) [ | PMC9879387 |
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Procedures | The participants sat on a stable seat 40-cm high with both feet on the COP platform. Measurements were performed before and after stimulation. First, SSA was measured during the sitting position. Next, the participants stood up with their eyes open, and standing COP was measured with eyes closed for 30 s, and then with open eyes for 30 s. We tested four conditions: (1) no vibratory stimulation (control), (2) vibratory stimulation of the left neck for 30 s, (3) vibratory stimulation of the left neck for 10 min, and (4) vibratory stimulation of the left neck and left lumbar back for 10 min. Stimulation was performed with the eyes closed while in a resting, sitting position. Measurements in the four conditions were conducted with random cross-over using a random number table. There was a 5-min resting period between the conditions, and all procedures were conducted in approximately 90 minutes. | PMC9879387 |
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Statistical analysis | Measurements of COP and SSA values were subtracted before and after each condition for standardized variation. Statistical analysis was conducted using one-way analysis of variance with repeated measures or Greenhouse–Geisser correction [The sample size was calculated using G*Power version 3.1 [ | PMC9879387 |
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Results | The study included 24 participants (all right-handed; 12 males; 25.7±3.7 years; WBL with closed eyes 50.2±2.3%; WBL with open eyes: 50.4±2.8%), and they performed all four conditions, and a total of 96 trials was conducted.A one-way analysis of variance with repeated measures showed that the left lower limb loading rate, ML-COP, AP-COP, and pathlength of COP in closed eyes were significant ( | PMC9879387 |
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Differences in the mean position of COP before and after vibration (n = 24). | POSITIVE | Error bars indicate the standard error. A. The results of Dunnett’s test on the mean position of ML-COP with closed eyes. Positive values indicate a rightward deviation, whereas negative values indicate a leftward deviation on the mediolateral plane. B. The results of Dunnett’s test on the mean position of AP-COP with closed eyes. Positive values indicate an anterior deviation, whereas negative values indicate a posterior deviation on the anteroposterior plane. Asterisks indicate significant differences compared with the control condition, Dunnett’s test: p < 0.05. ML-COP, mediolateral-center of pressure; AP-COP, anteroposterior-center of pressure. | PMC9879387 |
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The results of one-way analysis of variance with repeated measures. | WBL, percentage of weight on the left limb; ML, mediolateral; AP, anteroposterior; CE, closed eyes; OE, open eyes: COP, center of pressure; SSA, subjective straight aheada, p < 0.05b, Greenhouse–Geisser p < 0.05. | PMC9879387 |
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Discussion | visual illusions, closed-eye, Proprioceptive sensations | This study aimed to clarify the effects of NMV on standing postural orientation and spatial perception in healthy participants, depending on differences in stimulation duration and simultaneous stimulation of trunk muscles. The results of this study showed that compared to the control condition, ML-COP was biased to the stimulus side and AP-COP was to the anterior side immediately following NMV and trunk muscle vibration for 10 min. There were no significant differences between 30 s and 10 min of NMV with the control condition, and SSA showed no significant differences. Thus, the results suggest that combining NMV with vibratory stimulation of the trunk muscles intensifies the effect on the standing postural orientation.Proprioceptive sensations from cervical muscles contribute to body representations, including the position and hierarchical arrangement of limbs and the organization of segments in space [In healthy participants, the trajectory of gait is modulated by vibration stimulation of the trunk muscles [SSA is ipsilateral to the stimulus after the end of vibratory stimulation in healthy participants [This study was conducted in young individuals, mainly in their 20s, which is a limitation of this study. Whether similar results occur in other age groups is unclear. The effects of sex differences have also not been taken into consideration.In conclusion, the findings suggest that proprioceptive input to the trunk muscles would amplify the central nervous system’s modulator effect of NMV in the standing position. It is also possible that SSA based on proprioceptive sensation is not biased under closed-eye measurement conditions where visual illusions are not produced. Combining NMV with vibratory stimulation of the trunk muscles may be a new method for intensifying an effect in the standing postural orientation. | PMC9879387 |
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1. Introduction | dysbiosis, asthma/allergic disease | LATE PREGNANCY, ASTHMA, VITAMIN D DEFICIENCY, REGRESSIONS | Shifts in the maternal gut microbiome and vitamin D deficiency during pregnancy have been associated, separately, with health problems for both the mother and the child. Yet, they have rarely been studied simultaneously. Here, we analyzed the gut microbiome (from stool samples obtained in late pregnancy) and vitamin D level (from blood samples obtained both in early and late pregnancy) data of pregnant women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized controlled trial of vitamin D supplementation during pregnancy, to investigate the association of vitamin D status on the pregnant women’s microbiome. To find associations, we ran linear regressions on alpha diversity measures, PERMANOVA tests on beta diversity distances, and used the ANCOM-BC and Maaslin2 algorithms to find differentially abundant taxa. Analyses were deemed significant using a cut-off Vitamin D has been strongly associated with many conditions of human health. Initially, it was discovered to promote bone health [The gut microbiome is composed of trillions of microbes that collectively influence the health of its host [The gut microbiome composition changes with age and is naturally modified during several stages of life. During pregnancy, the microbiome shift often resembles diseased states or dysbiosis that, surprisingly, instead of leading to a decline in fitness, promotes homeostasis [The impact on the offspring of the maternal vitamin D level in serum and of vitamin D consumption during pregnancy has been studied several times, establishing associations with the children’s microbiome and with outcomes such as changes in the immune system modulation, asthma/allergic disease incidence, likelihood of Here, we analyze the 16S rRNA data generated from stool samples of 114 pregnant women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a multi-site randomized, double-blind, placebo-controlled trial of vitamin D supplementation during pregnancy, to look for associations between the participants’ vitamin D status and their gut microbiome during the third trimester of pregnancy. We use three different measures for the vitamin D status: (1) baseline vitamin D level, (2) treatment assignment, and (3) change in vitamin D level over the trial period. In the following, we present three key findings. First, the baseline vitamin D level is associated with the gut microbiome composition. Second, the gut microbiome is robust enough such that the vitamin D supplementation (even with up to 4400 IU cholecalciferol daily) during pregnancy does not significantly modify it. Third, | PMC10181263 |
2. Materials and Methods | PMC10181263 |
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2.1. Vitamin D Antenatal Asthma Reduction Trial (VDAART) | asthma | ASTHMA | VDAART was a randomized controlled trial of Vitamin D supplementation during pregnancy to prevent asthma in offspring conducted in the United States (St. Louis, Boston, and San Diego; NCT00920621). Eight hundred and seventy women were enrolled at 10–18 weeks of gestation and randomized to receive either a high dose of vitamin D oral supplements (4400 IU cholecalciferol daily, called the treatment or high-dose treatment hereafter) or a placebo dose of vitamin D oral supplements (400 IU cholecalciferol daily) between enrollment and delivery. The study protocol was approved by the institutional review boards at each participating institution and at Brigham and Women’s Hospital. All participants provided written informed consent [ | PMC10181263 |
2.2. Stool Sample Collection and Processing | During the third trimester of pregnancy (weeks 32–38 gestation), 120 participants of the VDAART trial provided a stool sample. Subjects were asked to collect a 0.5 teaspoon-sized sample 1 to 2 days before a study visit and store the sample in a home freezer before transport with a freezer pack to the study site. Stool was not collected if participants had used antibiotics in the previous 7 days. After delivery to the study site, stool samples were immediately stored at −80 °C. Microbiome profiling was performed by sequencing the 16S rRNA hypervariable region 4 (V4 515F/816R region) on the Illumina MiSeq platform at Partners Personalized Medicine (Boston, MA, USA). Of the 120 stool samples collected, 2 with fewer than 1000 reads measured were excluded from the analysis, leaving 118 samples. | PMC10181263 |
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2.3. Blood Sample Collection and Processing | LATE PREGNANCIES | Maternal blood samples were collected at two time points: at enrollment at 10–18 weeks of gestation and at 32–38 weeks of gestation. The serum 25-hydroxyvitamin D 25(OH)D level (termed as the vitamin D level hereafter) was measured in both samples using the DiaSorin LIAISON method (a chemiluminescence assay) at the Channing Division of Network Medicine, Brigham and Women’s Hospital (Boston, MA, USA). All the 118 women who provided a stool sample in the third trimester of pregnancy provided a blood sample at the first time point (yielding a baseline vitamin D level), and 114 of them also provided one at the second time point (yielding a final vitamin D level). Therefore, we have blood samples to analyze the change in vitamin D level between the early and late pregnancies of 114 women; 59 of them were in the treatment group, and the remaining 55 were in the placebo group. | PMC10181263 |
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2.4. Serum Vitamin D Level | For the 114 women with baseline and final measurements ( | PMC10181263 |
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2.5. Mothers’ Characteristics | asthma | HAY FEVER, ASTHMA | The stool and blood samples were collected at three different sites: Boston, MA; San Diego, CA; and St. Louis, MO. The available subjects’ characteristics from the initial enrollment questionnaire are the mothers’ age, race, education, household income, and history of asthma and hay fever. Mothers were categorized into groups for each factor, except for their age, which was kept as a continuous variable. Race and ethnicity information was collected, because they are determinants of the circulating 25-hydroxyvitamin D levels; the race and ethnicity of every participant was self-reported. Participants were asked to first categorize themselves as either Hispanic or non-Hispanic, then to categorize their race into prespecified categories. Race/ethnicity (called race hereafter) groups were collapsed into 3 groups for the analysis: Black or African American mothers (called Black mothers hereafter), White, non-Hispanic mothers (called White mothers hereafter), and Hispanic mothers and mothers of other races ( | PMC10181263 |
2.6. Statistical Analyses | For the statistical analyses, we measured the vitamin D status in three different ways: baseline vitamin D level (measured at enrollment), randomized treatment assignment (treatment or placebo supplementation), and vitamin D level change between the baseline and final measurements (high or low change). Unless specifically noted, we used a cut-off | PMC10181263 |
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2.6.1. Alpha Diversity | Alpha diversity measures are estimates of an individual sample’s taxonomic diversity. We computed the observed richness, Shannon, and Simpson indices using the Phyloseq package in R [ | PMC10181263 |
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2.6.2. Beta Diversity | Beta diversity measures quantify the dissimilarity in taxonomic composition between two samples. We computed the following measures: Bray–Curtis dissimilarity, Jaccard distance, Unifrac distance, and Weighted-Unifrac distance using the Phyloseq package in R. We used the adonis2 algorithm in the R package vegan [ | PMC10181263 |
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2.6.3. Abundance Association Analysis | To ensure robustness of the identified associations, we used two different methods and their corresponding R packages, which look for associations between the subject variables and the abundance of specific taxa: ANCOM-BC [ | PMC10181263 |
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3. Results | PMC10181263 |
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3.2. Microbiome Composition Is Associated with Baseline Vitamin D Level | We found a small but not statistically significant positive correlation between the baseline vitamin D level and gut microbiome richness or for the three alpha diversity indices analyzed ( | PMC10181263 |
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3.3. Gut Microbiome Is Robust to Vitamin D Supplementation during Pregnancy | In an intention-to-treat analysis, we found no significant associations between the participants’ treatment assignment and any of the alpha diversity indices that we calculated ( | PMC10181263 |
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3.4. Change in Vitamin D Level Does Not Impact Microbiome Diversity | Comparing participants by the change in their vitamin D level allows for an assessment of the impact of vitamin D over a relatively short period (between weeks 10–18 and weeks 32–38 of pregnancy) on the microbiome and accounts for potential lack of adherence to the vitamin D supplementation treatment assignment. All the vitamin D level change analyses were adjusted for the participants’ baseline vitamin D level, in addition to their race and education. We found no significant associations between the participants’ vitamin D change and their microbiome richness for any of the alpha diversity indices that we analyzed. We also found no significant associations with the women’s microbiome composition for any of the analyzed beta diversity measurements. This suggests that the microbiome richness and composition are robust to changes in the vitamin D level during pregnancy. | PMC10181263 |
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3.5. Desulfovibrio Is Enriched in Pregnant Women with Low Change of Vitamin D Level | Next, we looked at differentially abundant taxa between the change groups at the genus level. We found that two genera were enriched in the low change group (Interestingly, we found that the presence of | PMC10181263 |
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Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10181263 |
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Author Contributions | Conceptualization, S.T.W., K.L.-S. and Y.-Y.L.; methodology, K.L.-S., Y.-Y.L. and A.A.; software, A.A.; validation, K.L.-S.; formal analysis, A.A.; investigation, A.A.; data curation and essential databases, D.R.G. and A.A.L.; writing—original draft preparation, A.A.; writing—review and editing, all authors; visualization, A.A.; and supervision, K.L.-S. and Y.-Y.L. All authors have read and agreed to the published version of the manuscript. | PMC10181263 |
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Institutional Review Board Statement | The study protocol was approved by the institutional review boards at each participating institution and at Brigham and Women’s Hospital. The study was conducted in accordance with the Declaration of Helsinki. | PMC10181263 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10181263 |
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Data Availability Statement | Microbiome sequencing data from VDAART are part of the ECHO consortium, and ECHO consortium members can obtain the data directly from the ECHO DCC or for those not part of ECHO directly from the authors. All other relevant data are available from the authors upon reasonable requests. | PMC10181263 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC10181263 |
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References | Vitamin D status was measured in three different ways: baseline vitamin D level (serum 25-hydroxyvitamin D 25(OH)D (ng/mL) measured in a blood sample at enrollment), treatment assignment (treatment or placebo vitamin D supplementation), and vitamin D level change over the trial period (high change or an increase of at least 10 ng/mL between the enrollment and third trimester and low change or a difference of less than 10 ng/mL). (The baseline vitamin D is associated with the microbiome composition but not with its richness; the microbiome is robust for vitamin D supplementation. (The sulfate−reducing bacteria Summary of the participants’ characteristics with respect to their measurement of the serum 25−hydroxyvitamin D 25(OH)D level at enrollment (baseline vitamin D level).Summary of the participants’ characteristics with respect to the treatment group that they were assigned. | PMC10181263 |
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Background | Flavivirus infections, TBEV, tick-borne encephalitis, YFV, yellow fever | VIRUS, JAPANESE ENCEPHALITIS, TICK-BORNE ENCEPHALITIS, YELLOW FEVER, FLAVIVIRUS INFECTION | The authors have declared that no competing interests exist.‡ These authors are joint senior authors on this work.Flavivirus infections pose a significant global health burden underscoring the need for the development of safe and effective vaccination strategies. Available flavivirus vaccines are from time to time concomitantly delivered to individuals. Co-administration of different vaccines saves time and visits to health care units and vaccine clinics. It serves to provide protection against multiple pathogens in a shorter time-span; e.g., for individuals travelling to different endemic areas. However, safety and immunogenicity-related responses have not been appropriately evaluated upon concomitant delivery of these vaccines. Therefore, we performed an open label, non-randomized clinical trial studying the safety and immunogenicity following concomitant delivery of the yellow fever virus (YFV) vaccine with tick-borne encephalitis virus (TBEV) and Japanese encephalitis virus (JE) virus vaccines. | PMC9946270 |
Methods and findings | YFV, TBEV | ADVERSE EVENTS, ADVERSE EFFECTS, ADVERSE EVENT | Following screening, healthy study participants were enrolled into different cohorts receiving either TBEV and YFV vaccines, JEV and YFV vaccines, or in control groups receiving only the TBEV, JEV, or YFV vaccine. Concomitant delivery was given in the same or different upper arms for comparison in the co-vaccination cohorts. Adverse effects were recorded throughout the study period and blood samples were taken before and at multiple time-points following vaccination to evaluate immunological responses to the vaccines. Adverse events were predominantly mild in the study groups. Four serious adverse events (SAE) were reported, none of them deemed related to vaccination. The development of neutralizing antibodies (nAbs) against TBEV, JEV, or YFV was not affected by the concomitant vaccination strategy. Concomitant vaccination in the same or different upper arms did not significantly affect safety or immunogenicity-related outcomes. Exploratory studies on immunological effects were additionally performed and included studies of lymphocyte activation, correlates associated with germinal center activation, and plasmablast expansion. | PMC9946270 |
Conclusions | YFV, TBEV | ADVERSE EVENTS | Inactivated TBEV or JEV vaccines can be co-administered with the live attenuated YFV vaccine without an increased risk of adverse events and without reduced development of nAbs to the respective viruses. The vaccines can be delivered in the same upper arm without negative outcome. In a broader perspective, the results add valuable information for simultaneous administration of live and inactivated flavivirus vaccines in general. | PMC9946270 |
Trial registration | Eudra | PMC9946270 |
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Author summary | PMC9946270 |
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Why was this study done? | YFV, yellow fever, TBEV | VIRUS, JAPANESE ENCEPHALITIS, TICK-BORNE ENCEPHALITIS, YELLOW FEVER, FLAVIVIRUS INFECTION | Flavivirus infections pose a significant global health burden, underscoring the need for the development of safe and effective vaccination strategiesCo-administration of different vaccines, including flavivirus vaccines, saves time and visits to health care units and vaccine clinics. It serves to provide protection against multiple pathogens in a shorter time-span; e.g., for individuals travelling to different endemic areasSafety and immunogenicity-related responses have not been appropriately evaluated upon co-administration of many vaccines including currently used flavivirus vaccines, such as yellow fever virus (YFV), tick-borne encephalitis virus (TBEV), and Japanese encephalitis virus (JE) virus vaccinesBecause of this, we performed an open label, non-randomized clinical trial studying the safety and immunogenicity following co-administration of YFV vaccine with TBEV and JEV vaccines | PMC9946270 |
What did the researchers find? | ADVERSE EVENT | Adverse events, neutralizing antibodies (nAbs) and other related immunological parameters were not detrimentally affected by concomitant delivery of the vaccinesConcomitant vaccination in the same versus different upper arms of study participants did not significantly affect safety or immunogenicity outcomes | PMC9946270 |
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What do these findings mean? | YFV, TBEV | ADVERSE EVENTS | Co-administration of YFV vaccine and TBEV or JEV vaccines is feasible without increased risk of adverse events or reduced development of nAbs against the respective viruses. | PMC9946270 |
Data Availability | All relevant data are within the manuscript and its | PMC9946270 |
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Introduction | YFV, JEV infections, TBEV, Yellow fever | VIRUS, YELLOW FEVER, JAPANESE ENCEPHALITIS, TICK-BORNE ENCEPHALITIS, BLOOD | Yellow fever virus (YFV), tick-borne encephalitis virus (TBEV), and Japanese encephalitis virus (JEV) all belong to the The vaccine regimen and outcome of vaccinations against YFV, TBEV, and JEV infections differ significantly. After a single dose, the live attenuated YFV 17D vaccine provides at least 10 years, and possibly life-long, immunity [Safe and effective vaccine administration strategies are of significant importance [While the major endemic flaviviruses do not generally overlap in the world, they may affect travelers visiting these areas with need for protection. Accordingly, simultaneous vaccination with different vaccines including flavivirus not seldom vaccines occurs. It saves time and visits to health care units and vaccine clinics. It provides protection against multiple pathogens in a shorter time-span. Vaccinations prior to travelling to endemic areas has been further emphasized more recently given that many present flavivirus endemic areas are increasing, in part due to changes in climate change and other possible factors [To this end, we carried out an open label, non-randomized clinical trial assessing the safety and immunogenicity of concomitant vaccination with different commonly used flavivirus vaccines. The clinical trial included healthy adult volunteers who were concomitantly vaccinated with TBEV and YFV vaccines, JEV and YFV vaccines, or with only one of the three respective vaccines. Half of the concomitantly vaccinated study participants received both vaccines in the same upper arm while the other half received the vaccines in different upper arms. Blood samples were taken before and at multiple time-points following vaccinations. Safety and immunological responses including nAbs were evaluated. Collectively, the study provides safety and immunogenicity outcomes following concomitant vaccination with different types of flavivirus vaccines. The studies can be used for forming guidelines for more flexible immunization regimens for pathogenic flaviviruses. | PMC9946270 |
Methods | PMC9946270 |
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Ethical and regulatory approval | The study was approved by the Stockholm Local Regional Ethical Committee (2017/1433-31/1) and the Swedish Medical Products Agency (5.1-2017-52376). It is registered in the European database (Eudra CT 2017-002137-32). All study volunteers signed informed consent documents in line with the ethical approval and clinical trial protocol. | PMC9946270 |
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Clinical trial design | non-Pharma | An open label, non-randomized academic (non-Pharma sponsored) clinical trial was conducted in order to assess safety and immunological responses of concomitant vaccination with three currently licensed flavivirus vaccines. The trial was conducted at the Karolinska University Hospital, Stockholm, Sweden. An independent data monitoring process was setup by the Karolinska Trial Alliance (KTA) support organization (KTA Support) in order to review safety data and the progress of the study according to the clinical trial protocol. The monitoring process also included review of the trial’s conductance in accordance with principles of good clinical practice (ICH-GCP) [ | PMC9946270 |
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Vaccines | YFV | The following vaccines were used in the trial: Stamaril (Sanofi), live, attenuated YFV 17D strain produced in pathogen-free chick embryo cells, 0.5 ml, not less than 1,000 IU. The vaccine was provided in freeze dried powder form and reconstituted with provided saline solution and was administered subcutaneously. IXIARO (Valneva), inactivated, alum-adjuvanted, Vero cell-derived vaccine based on JEV strain SA | PMC9946270 |
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Study participants and cohorts | YFV, TBEV | The study was initially designed to include a total of 140 healthy volunteers. Forty study participants were to receive both TBEV and YFV vaccines (cohort A). Twenty of these participants were to receive the vaccines in different upper arms (sub-cohort A1) and the other 20 in the same upper arm (sub-cohort A2). The next 40 study participants were to receive both JEV and YFV vaccines (cohort B). Similarly, 20 of these participants were to receive the vaccines in different upper arms (sub-cohort B1) and the other 20 in the same upper arm (sub-cohort B2). The remaining three cohorts of 20 study participants per cohort, were aimed to serve as study controls and were to receive either, the TBEV vaccine (cohort C), JEV vaccine (cohort D), or YFV vaccine (cohort E). Information on sample size calculations are outlined in the Study Protocol (available upon request). With respect to sample size, one emphasis of the present study was to study immunological reactivity over a longer period with multiple frequent samplings of peripheral blood. Study groups were recruited one at a time, and initiated in the order (A1, A2, C, B1, B2, D, and E).Upon initiation of the clinical trial, a total of 161 healthy volunteers were screened for enrollment ( | PMC9946270 |
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Clinical trial layout for study participants and vaccination strategy with sampling timeline. | ( | PMC9946270 |
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Procedures | BLOOD | Vaccinations were given in accordance with the clinical trial protocol and good clinical practice (GCP), with intervals for primary vaccinations as recommended in FASS (Pharmaceutical Specialties in Sweden): FSME IMMUN, three doses 0-, 1- and 5-month intervals; IXIARO, two doses, 0- and 1-month interval; Stamaril, one dose. For cohorts A1, A2, B1, B2, C, and D, blood and serum were set to be sampled before each vaccination, and then at day 7 (+/- 1 day) and at day 14 after each vaccination. Blood and serum were also set to be sampled 30 days after the last vaccination. For cohort E, blood and serum were sampled before the vaccination, and then after vaccination at day 7 (+/- 1 day), at day 14, at day 30 (+/-2 days), day 37 (+/- 1 day), day 44 (+5 days) and day 60 (+14 days). This schedule led to the following approximate time allocations in terms of days for blood and serum samplings: cohorts A and C, days 0 (first vaccination), 7, 14, 30 (second vaccination), 37, 44, 180 (third vaccination), 187, 194, and 210; cohorts B and D, days 0 (first vaccination), 7, 14, 30 (second vaccination), 37, 44, and 60; cohort E, days 0 (vaccination), 7, 14, 30, 37, 44, and 60 ( | PMC9946270 |
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Safety assessment | ADVERSE EVENTS, ADVERSE EVENT, EVENTS | Results from physical examination, including vital signs and body temperature, pulse, and blood pressure was recorded at each time-point for vaccination. Adverse events (AEs) following vaccinations were self-reported by the study participants at each study visit. Briefly, upon each 30 min visit (up to 10 visits per study subject pending vaccination group), study participants described all events during the period since last visit to the responsible study nurse. Information was registered by the study nurse, and then AEs were graded by the responsible physician at the Karolinska Clinical Trial Alliance unit classifying them as mild, moderate, or severe, and ultimately recorded in the eCRF. This followed a pre-set, standard procedure used for clinical trials at this unit. Severe adverse events were, when so deemed, further classified, and reported as serious adverse events (SAEs). AEs and SAEs recorded for all study participants were deemed unlikely, possible, or probably related to the vaccinations. | PMC9946270 |
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Determination of YFV RNA in serum | YFV | YFV-specific real-time PCR was used to determine the viral RNA in serum of study participants. RNA was isolated from 150 μL of serum using a NucleoSpin RNA Virus Kit (Machery-Nagel). One step real-time PCR was performed using TaqMan Fast Virus 1-Step Master Mix (Applied Biosystems), a FAM-TAMRA-labeled probe and primers (Fisher Biotechnology) according to the manufacturer’s instructions. The primers and probe were all specific for the highly conserved NS5 gene of YFV [ | PMC9946270 |
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Clinical chemistry | C-reactive protein (CRP), albumin (ALB), creatinine, bilirubin, aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT) were analyzed at the Karolinska University Hospital accredited clinical chemistry laboratory at the first three time-points (days 0, 7, and 14). Results were interpreted within the frame of normal values (range) provided by the Karolinska University Laboratory. | PMC9946270 |
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Absolute cell counts | LYSING | Absolute numbers of cells expressing CD45, CD3, CD4, and CD8 in peripheral blood were measured using BD TruCount tubes (BD Biosciences) according to the manufacturer’s instructions. Briefly, 50 μL of anticoagulated blood was added to TruCount tubes within three hours after extraction and thereafter fluorescently stained for CD45, CD3, CD4, and CD8 for 15 minutes at RT in the dark. Samples were then fixed with 1X BD FACS lysing solution before acquiring data on a BD Accuri flow cytometer (BD Biosciences). | PMC9946270 |
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Multiplex measurement of cytokine secretion | GM-CSF, IFN-ɣ, IL-2, IL-4, IL-6, IL-8, IL-10, TNF, IFN-ɑ2, MIP-1β, IL-12, IL-15 and IL-18 were measured in serum, diluted 1:4, from the first four time-points (days 0, 7, 14, and 30) from each study participant using a pre-designed 8-plex assay with a custom-designed 5 single-plex assay Bio-Plex Pro Human Cytokine Assay (Bio-Rad), according to the manufacturer’s instructions. | PMC9946270 |
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Antibody analyses | YFV, TBEV | VIRUS | Assessment of virus-specific IgG levels and nAbs against TBEV, JEV and/or YFV was performed on day 0, day 30, and at the final time-point of the clinical trial (day 210 for cohort A and cohort C, day 60 for B, D, and E). TBEV-specific IgG antibodies were assessed using an anti-TBE virus ELISA “Vienna” (IgG) kit (Euroimmun) and JEV-specific IgG antibodies were assessed using an anti-JEV ELISA (IgG) kit (Euroimmun) according to the manufacturer’s instructions. Both assays included complete virus lysates as coating antigen. Antibody levels equal to, or greater than, 120 were considered seropositive for TBEV-specific IgG and levels equal to, or greater than, 20 were considered seropositive of JEV-specific IgG, both as determined by the ELISA kit manufacturer. TBEV-specific IgG levels ≥1,000 Vienna units were recorded as 1,000 Vienna units and likewise, JEV-specific IgG levels ≥200 RU/ml were recorded as 200 RU/ml.Virus neutralization was measured by rapid fluorescent focus inhibition test (RFFIT) as previously described [ | PMC9946270 |
Flow cytometry | APC | Freshly isolated PBMCs were used for phenotypical analysis using the following antibodies: Live/Dead cell marker Near IR (Life Sciences), anti-CD19 (clone SIJ25C1) BUV 395, anti-CD4 (clone SK3) BUV 737, anti-CD16 (clone 3GB) Pacific Blue, anti-CD14 (clone MφP9) AmCyan, anti-Ki67 (clone B56) AF700 (BD Biosciences), anti-CD20 (clone 2H7) FITC, anti-CD123 (clone 6H6) AmCyan, anti-CD27 (clone O323) BV650, anti-CD38 (clone HIT2) BV785, anti-IgD (clone IA6-2) PE-Cy7, anti-IgG (clone HP6017) PE (BioLegend), anti-CD56 (clone N901) ECD, anti-CD3 (clone UCHt1) PE-Cy5 (Beckman Coulter), anti-CD8 (clone 3B5) Qdot 605 (Invitrogen) and anti-IgA (clone IS11-8E10) APC (Miltenyi Biotech). Cells were incubated with 50 μL of surface staining antibody mix diluted in PBS for 30 minutes at 4°C in the dark. Following incubation, the cells were washed twice in FACS buffer (2% FCS and 2 mM EDTA in PBS) and then fixed and permeabilized using Foxp3/Transcription Factor Staining kit (eBioscience) for 30 minutes at 4°C. Cells were then washed twice in permeabilization buffer (eBioscience) followed by intracellular staining. Antibodies against Ki67 and IgG in permeabilization buffer were added to the cells and incubated in the dark for 30 minutes at 4°C. Cells were finally washed with FACS buffer and data acquired on a BD LSR Fortessa (BD Bioscience). Analysis of acquired data was done with FlowJo software version 10 (FlowJo Inc). | PMC9946270 |
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CXCL13 ELISA | Undiluted serum was thawed at room temperature and analyzed using a Quantikine Human CXCL13/BLC/BCA-1 ELISA (R&D Systems) according to the manufacturer’s instructions. Limit of detection of the assay ranged between 7.8 and 500 pg/mL. | PMC9946270 |
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Statistics | Statistical analyses were performed using GraphPad Prism (GraphPad Software). Data sets were analyzed using non-parametric Wilcoxon matched-pairs signed rank test, Kruskal-Wallis, Friedman tests, or Fisher’s exact test. Dunn’s multiple comparisons test was used to correct for multiple comparisons where applicable. Handling of missing values due to missed visits (13 out of 1,150 visits) were determined before analysis according to the study protocol. In line with this, missing values were imputed in Figs using median values from the specific time-point in each cohort. All | PMC9946270 |
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Results | PMC9946270 |
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Study participants and vaccination schedule | 140 study participants were planned for the present clinical trial. Over the course of 17 months, 161 volunteers were screened, 145 of whom were found to be eligible for the clinical trial and enrolled into one of the seven cohorts (A1, A2, B1, B2, C, D, and E). All but six study participants completed the trial, leaving the clinical trial with a final 139 study participants ( | PMC9946270 |
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Cohort characteristics. | PMC9946270 |
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Adverse events | 69.8% of the 139 included study participants reported one or more AEs during the course of the clinical trial ( | PMC9946270 |
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Summary of registered adverse events over the entire study period. | pneumonitis, hip dysplasia, depression, TBEV | PNEUMONITIS | Briefly, cohorts A1, A2 and C, all of which received TBEV vaccinations, had a greater number of total registered AEs compared to the other cohorts, ascribed to multiple (n = 3) TBEV vaccinations. Cohorts B1, B2, and D, all of which received JEV vaccinations, had greater number of total registered AEs compared to the E cohort, concordantly ascribed to multiple (n = 2) JEV vaccinations. At total of four AEs were deemed severe, all of which were determined SAEs. These SAEs included one case with hip dysplasia in a newborn child of a study participant, one case with pneumonitis, one case with depression, and one case with a fall, all four of which were determined to be unrelated to vaccination. These SAEs were all, in accordance with regulatory rules, reported to the Swedish Medical Product Agency. | PMC9946270 |
Viral RNA levels, clinical chemistry, and immunology | YFV, infection | INFECTION, VIRUS | The YFV vaccine causes a mild infection, often with detectable virus in circulation. As a safety-related assessment, we measured serum YFV NS5-RNA levels in all cohorts vaccinated with the YFV vaccine in order to assess if concomitant vaccination had any effects on YFV viral replication. Across all study cohorts, most study participants receiving the YFV vaccine had detectable levels of YFV NS5-RNA seven days after vaccination ( | PMC9946270 |
Virus specific IgG levels | TBEV | VIRUS | As part of the primary endpoint, TBEV and JEV specific IgG levels were measured before vaccination and at days 30 (30 days after dose 1) and 210 (30 days after dose 3) for the TBEV vaccine cohorts, and at days 30 (30 days after dose 1) and 60 (30 days after dose 2) for the JEV vaccine cohorts. Study participants with detectable virus nAbs at day 0 were excluded from ELISA and RFFIT analyses.Study participants from cohorts A1, A2, and C all developed IgG antibodies against TBEV by the end of the trial ( | PMC9946270 |
Virus neutralization | YFV, TBEV | Apart from the assessment of antigen-binding IgG responses, rapid fluorescence focus inhibition tests (RFFIT) were performed to measure nAb titers against TBEV, JEV, and YFV to compare the effect of concomitant vaccinations with respective single vaccination outcomes. All study participants were screened at day 0 for nAbs against the three flaviviruses. Two study participants had nAbs against TBEV at day 0 (one each from cohorts A1 and A2, respectively). These were excluded from subsequent analyses. No study participants had preexisting nAbs against JEV or YFV at day 0.Few study participants developed TBEV nAbs by day 30, however, the majority developed nAb titers by day 210 (30 days after third dose) (A1: 84%, A2: 95%, and C: 80%) (No statistical differences were observed in terms of nAb titers were observed when concomitant vaccinated study participants had received their respective vaccine in the same upper arm versus in different upper arms. A trend towards higher titers (mean value) of nAb was noted in the groups where vaccines were given in the same upper arm (cohorts A2 and B2) versus different upper arms (cohorts A1 and B1) (The design of the clinical trial also allowed us to divide the enrolled study participants based on gender. No statistically significant differences were observed between males and females in terms of final nAb titers against TBEV, JEV, or YFV (In summary, concomitant TBEV or JEV vaccination with YFV vaccine did not affect the development of virus-specific nAbs towards TBEV or JEV. Likewise, YFV nAb titers did not differ between the cohorts, whether the YFV vaccine was administered alone or together with the TBEV or JEV vaccines ( | PMC9946270 |
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Activation of B cells, T cells and NK cells | In addition to the virus-specific binding IgG antibody responses and nAbs we, we expanded the analyses in exploratory studies to investigate specific cellular responses following vaccination of the different cohorts. Freshly isolated PBMCs from each time-point were used to assess the effects of concomitant vaccinations on lymphocyte activation. Co-expression of CD38 and Ki67 in B cells, CD4 | PMC9946270 |
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Germinal center activation and plasmablast responses | YFV | The observed activation of lymphocyte subsets indicates induction of innate and adaptive immune responses, likely linked to the development of protective immunity (nAbs). We therefore further explored parameters related to induction of humoral immunity such as germinal center activity and plasmablast expansion following vaccination.First, CXCL13 levels in serum were measured as a proxy to germinal center activity. Elevated levels of serum CXCL13 were observed at days 7 and/or 14 following each vaccination in all cohorts, with the most marked changes seen amongst vaccine cohorts receiving the YFV vaccine (cohorts A1, A2, B1, B2, and E) ( | PMC9946270 |
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Discussion | YFV, TBEV | COLD SYMPTOMS | Here, we report the results of an open label, non-randomized, academic clinical trial assessing the safety and immunogenicity upon concomitant vaccination with different commonly used flavivirus vaccines. Healthy study participants were enrolled into cohorts receiving vaccines against TBEV and YFV in different or the same upper arm, JEV and YFV in different or the same upper arm, and in control cohorts receiving vaccines against TBEV, JEV, or YFV. Co-administration of the TBEV or JEV vaccine with the YFV vaccine was well tolerated with respect to reported AEs. Clinical virology, chemistry, and immunological assessments supported these conclusions with no markedly unexpected responses observed. Serological responses including virus-specific IgG levels and virus-specific nAb titers towards individual viruses were not adversely affected by concomitant vaccination. Additional immunological studies added deeper immunological insights into vaccine responses in concomitantly vaccinated study participants and controls.Of the AEs reported following vaccination, the majority were mild, dominated by common cold symptoms followed by classical reactogenicity-related responses. The majority of the reported AEs were deemed unrelated to vaccination. AEs related to vaccination (deemed possible or probable) were in line with previous safety data of single vaccination studies and the manufacturer’s reported known side effects [Earlier studies have shown the possible enhancement of cross-reactive flavivirus cellular and humoral immunity after flavivirus vaccinations [In addition to assessing the effect of concomitant vaccination on serological outcomes, we also assessed effects on lymphocyte activation and, in more detail, germinal center and plasmablast responses. As expected, NK cell, T cell, and B cell activation was observed in the cohorts receiving the live attenuated YFV vaccine (cohorts A1, A2, B1, B2 and E) in line with previous research [Co-administration of vaccines into the same or different upper arms allowed for comparative studies between these different strategies of administering two different vaccines. One advantage with administrating vaccines in the same upper arm (or at the same site in general) is that the other upper arm is not affected in terms of local reactogenicity responses. That may save the dominant arm from possible functional impairment over the first days following vaccination. As mentioned, no statistically significant differences between the study and control cohorts’ TNF or IL-18 serum comparing cohorts A1 with A2 or B1 with B2 were observed. Similarly, no statistical differences were found in terms of the development of virus-specific nAbs between the A1 and A2 or B1 and B2 cohorts as well as other B cell-related responses including activation and plasmablasts expansion. The only observed statistically significant difference noted between the same arm (A2 and B2) and different arm (A1 and B1) concomitant vaccine cohorts was the frequency of activated CD4The relative strength of the present study is that data were collected from a Concomitant vaccine administration strategies have been used in child vaccination programs [In conclusion, this clinical trial showed that concomitant TBEV or JEV vaccination with the live attenuated YFV vaccine is associated with little risk of SAE and, additionally, does not associated with any impairment on the development of nAbs to the respective viruses. Finally, the vaccines can readily be administered in the same upper arm. The present findings may be relevant for simultaneous administration of live and inactivated flavivirus vaccines in general, and also in context of the shared antigenic relationships of these agents. | PMC9946270 |
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