4-fold Rise Research Articles

Infectivity and Immunogenicity of Live-Attenuated Respiratory Syncytial Virus Vaccines in Human Immunodeficiency Virus-Exposed Uninfected Children.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory illness among young children. Human immunodeficiency virus (HIV)-exposed, uninfected (HEU) children experience a higher burden of RSV disease and have immune abnormalities that may influence their responses to live-attenuated RSV vaccines. In a pooled analysis of clinical trials of 7 live-attenuated, intranasal RSV vaccines conducted by the IMPAACT Network among children 6 to <25 months of age with serum RSV-neutralizing titers of <1:40, the infectivity and immunogenicity of these vaccines were compared among HEU and HIV-unexposed, uninfected (HUU) children. Nasal washes were collected during the first 28 days after vaccination. Serum RSV-neutralizing and anti-RSV F glycoprotein immunoglobulin G (IgG) antibodies were measured prior to and 56 days after vaccination, and before and after the following winter season. Of 156 children, 90 (58%) were HUU and 66 (42%) were HEU. Seventy-six (84%) HUU and 63 (95%) HEU participants were infected with vaccine (shed vaccine virus and/or had a ≥4-fold rise in serum RSV antibodies at 56 days after vaccination). HUU children had higher serum RSV-neutralizing and anti-RSV F IgG titers prior to vaccination. Compared to HEU children, lower percentages of HUU children had ≥4-fold rises in RSV-neutralizing (67% vs 88%) and anti-RSV F IgG (70% vs 89%) titers at 56 days after vaccination. Live-attenuated RSV vaccines are highly immunogenic in HEU children. Given their increased burden of RSV disease and higher early childhood mortality in some settings, HEU children should be prioritized for vaccination against RSV as these vaccines become available.

Perinatal bisphenol A exposure has an age- and dose-dependent association with thyroid allostasis adaptive response, as well as anxiogenic-depressive-like and asocial behaviors in juvenile and adult male rats

Thyroid hormones are essential for brain development, and a shortage throughout the fetal and postnatal periods can result in mood disorders. Perinatal exposure to bisphenol A (BPA) affects thyroid activity and dependent processes indirectly during pregnancy or early postnatal life. This is particularly important because it may cause changes in tissue ontogeny, increasing the risk of developing disorders later in life. The study aimed to investigate the consequences of thyroid hormone deficiency on anxiety, social, and depressive behaviors, as well as disruption in thyroid peroxidase (TPO) gene expression, which influences the NF-κB/Nrf-2/HO-1/iNOS signaling pathway, leading to oxidative stress, inflammation, and DNA fragmentation in perinatal BPA exposure (PND18), and whether these effects can be observed in juvenile (PND60) and adult (PND95) male offspring rats. BPA increased anxiety-like behavior while decreasing sucrose preference and sociability on a choice task between novel conspecific male rats and enhanced immobility on the forced swim test. Perinatal exposure to BPA causes thyroid insult by overproducing ROS, increasing iNOS, and NF-κB levels—these effects, in turn, down-regulate Nrf-2/HO-1 signaling, resulting in DNA fragmentation within thyroid tissues. Furthermore, perinatal BPA exposure for 60 and 95 days resulted in a significant fold decrease in TPO mRNA levels in the thyroid tissues, with an insignificant fold rise in TPO expression levels in BPA 50–60. In conclusion, the present study found that perinatal BPA exposure induced thyroid allostasis-adaptive response by inhibiting the NF-κB/Nrf-2/HO-1/iNOS signaling pathway and altering the transcriptional expression of TPO, where TSH reinforced a possible association with TPO activity, disrupting thyroid hormone synthesis in juvenile rats and gradual deterioration reaching the adult stage.

Telemedicine through social media to enhance guideline-directed revascularization in STEMI: a five-year analysis in a developing nation

Abstract Background Timely reperfusion reduces mortality in ST segment Elevation Myocardial infarction (STEMI). Telemedicine and social media have been variably used to improve STEMI care in community settings. We established a new care system for STEMI in a public health setting serving a population of over 80 million, in a state with from a developing nation. Purpose To enhance guideline directed revascularisation (GDR) in STEMI by networking non-percutaneous coronary intervention (PCI) capable hospitals to PCI capable hospitals in a hub-and-spoke model and implementing telemedicine via social media platforms (Whatsapp) over five years(2019-2023). Methods Eighteen Government medical college hospitals were identified as hubs and were provided with cardiac catheterisation laboratories and empowered to provide either round the clock (Phase I hubs) or office hour primary PCI (Phase II hubs). They were linked to 188 Taluk or District-level, non-PCI capable Government hospitals identified as spokes to form 18 STEMI clusters. Separate social media groups on WhatsApp were created for each of the clusters, facilitating the sharing of de-identified ECGs and clinical data from spokes for guidance on diagnosis and management by hub hospital cardiologists. Transfer to hub hospitals for catheter based therapies were coordinated through prior intimation in the cluster WhatsApp group to ensure timely arrival and treatment. A customised uniform protocol for STEMI management was developed and health care personnel were trained accordingly. Human resource support was provided to collect and submit cumulative daily data on the number of STEMIs, the revascularisation provided and mortality through online free web forms. Annual cumulative data on STEMI volumes and GDR were analysed. Results 71,907 STEMI patients were treated from 2019 to 2023. We observed a 67% increase in STEMIs treated per year from over five years (11,363 in 2019 to 18565 in 2023). Use of pharmaco-invasive therapy increased from 7.9% to 31.7% (Figure-1). There was a marginal increase in use of primary PCI. The count of patients without GDR decreased by 20%. There was a 6.7 fold (672 in 2019 to 4,535 in 2023) rise in patients referred from spoke to hub hospitals for catheter-based revascularization. Over five years, there was an increase in the proportion of patients receiving GDR. This increase was more evident in Phase II hubs (52% in 2019 to 87.1% in 2023). Commensurate with the increase in GDR, phase II hubs demonstrated a tangible decrease in mortality (Figure-2). Conclusion We have shown that networking of non-PCI-capable hospitals with PCI-capable hospitals in a hub and spoke model using social media groups, facilitates telemedicine, leading to improved GDR in STEMI. This innovative approach not only enhances connectivity but also contributes to more efficient and timely cardiac care in resource-constrained settings.Figure 1. Revascularisation in STEMIFigure 2.Mortality Trends in STEMI (hubs)

The added value of serologic testing: A comparison of influenza incidence among pregnant persons based on molecular-based surveillance versus serologic testing

BackgroundWe examined the added value of serologic testing for estimating influenza virus infection incidence based on illness surveillance with molecular testing versus periodic serologic testing. MethodsPregnant persons unvaccinated against influenza at <28 weeks gestation were enrolled before the 2017 and 2018 influenza seasons in Peru and Thailand. Blood specimens were collected at enrollment and ≤14 days postpartum for testing by hemagglutination inhibition assay for antibodies against influenza reference viruses. Seroconversion was defined as a ≥4-fold rise in antibody titers from enrollment to postpartum with the second specimen's titer of ≥40. Throughout pregnancy, participants responded to twice weekly surveillance contacts asking about influenza vaccination and influenza-like symptoms (ILS). A mid-turbinate swab was collected with each ILS episode for influenza real-time reverse transcription polymerase chain reaction (rRT-PCR). ResultsOf 1,466 participants without evidence of influenza vaccination during pregnancy, 296 (20.2%) had evidence of influenza virus infections. Fifteen (5.1%) were detected by rRT-PCR only, 250 (84.4%) by serologic testing only, and 31 (10.5%) by both methods. ConclusionsInfluenza virus infections during pregnancy occurred in 20% of cohort participants; >80% were not detected by a broad illness case definition coupled with rRT-PCR.

Establishment of Amblyomma maculatum Ticks and Rickettsia parkeri the Northeastern United States.

We document a case of Rickettsia parkeri rickettsiosis in a patient in Connecticut, USA, who became ill after a bite from a Gulf Coast tick (Amblyomma maculatum). We used PCR to amplify R. parkeri DNA from the detached tick. The patient showed a 4-fold rise in IgG reactive with R. parkeri antigens.

Exploring the viability of peracetic acid-mediated antibiotic degradation in wastewater through activation with electrogenerated HClO

Electrochemical advanced oxidation processes (EAOPs) face challenging conditions in chloride media, owing to the co-generation of undesirable Cl−disinfection byproducts (Cl−DBPs). Herein, the synergistic activation between in-situ electrogenerated HClO and peracetic acid (PAA)-based reactive species in actual wastewater is discussed. A metal-free graphene−modified graphite felt (graphene/GF) cathode is used for the first time to achieve the electrochemically-mediated activation of PAA. The PAA/Cl− system allowed a near−complete sulfamethoxazole (SMX) degradation (kobs =0.49 min−1) in only 5 min in a model solution, inducing 32.7− and 8.2−fold rise in kobs as compared to single PAA and Cl− systems, respectively. Such enhancement is attributed to the occurrence of 1O2 (25.5 μmol L−1 after 5 min of electrolysis) from the thermodynamically favored reaction between HClO and PAA-based reactive species. The antibiotic degradation in a complex water matrix was further considered. The SMX removal is slightly susceptible to the coexisting natural organic matter, with both the acute cytotoxicity (ACT) and the yield of 12 DBPs decreasing by 29.4 % and 37.3 %, respectively. According to calculations, HClO accumulation and organic Cl−addition reactions are thermodynamically unfavored. This study provides a scenario-oriented paradigm for PAA−based electrochemical treatment technology, being particularly appealing for treating wastewater rich in Cl− ion, which may derive in toxic Cl−DBPs.

Humoral Immunogenicity of mRNA-1345 RSV Vaccine in Older Adults.

The mRNA-1345 vaccine demonstrated efficacy against respiratory syncytial virus (RSV) disease with acceptable safety in adults aged ≥60 years in the ConquerRSV trial. Here, humoral immunogenicity results from the trial are presented. This phase 2/3 trial randomly assigned adults (≥60 years) to mRNA-1345 50-µg encoding prefusion F (preF) glycoprotein (n = 17 793) vaccine or placebo (n = 17 748). RSV-A and RSV-B neutralizing antibody (nAb) and preF binding antibody (bAb) levels at baseline and day 29 postvaccination were assessed in a per-protocol immunogenicity subset (PPIS; mRNA-1345, n = 1515; placebo, n = 333). Day 29 nAb geometric mean titers (GMTs) increased 8.4-fold against RSV-A and 5.1-fold against RSV-B from baseline. Seroresponses (4-fold rise from baseline) in the mRNA-1345 groups were 74.2% and 56.5% for RSV-A and RSV-B, respectively. Baseline GMTs were lower among participants who met the seroresponse criteria than those who did not. mRNA-1345 induced preF bAbs at day 29, with a pattern similar to nAbs. Day 29 antibody responses across demographic and risk subgroups were generally consistent with the overall PPIS. mRNA-1345 enhanced RSV-A and RSV-B nAbs and preF bAbs in adults (≥60 years) across various subgroups, including those at risk for severe disease, consistent with its demonstrated efficacy in the prevention of RSV disease. NCT05127434.

Preparation and impregnation of deep eutectic solvents containing zileuton onto adsorbents to elicit the biopharmaceutical attributes

Deep eutectic solvent (DES) is a contemporary and eco-friendly solvent recently exploited to modulate the solubility of drugs. Herein, we developed DESs for an increment of solubility and bioavailability of zileuton (ZLT). ZLT is an anti-inflammatory drug categorized as an inhibitor of the enzyme 5-lipoxygenase commonly prescribed for treating chronic bronchial asthma. However, its therapeutic uses are limited owing to its poor water solubility. Several stable DESs were developed and assessed for viscosity, pH, and solubility. The DES comprising ChCl: EG (1:3) exhibits an excellent ZLT solubility (57.27 ± 0.14 mg/mL). The molecular and electrostatic interaction was assessed through a conductor-like screening model for real solvents (COSMO-RS). Further, 1H NMR analysis, FTIR, and digital microscopy were used to investigate the molecular transition in the chosen DES-ZLT. The DES in a liquid state possesses several drawbacks, such as instability, volatility, and dose precision. Therefore, a wet impregnation approach utilizing inert carriers such as Aerosil-200 and Avicel PH-102 was performed for the solidification of liquid DES. The solidified DES-ZLT was characterized by DSC and PXRD techniques and indicated the existence of ZLT in a highly dissolved state. Furthermore, solid DES-ZLT showed a significant increment in the dissolution studies, resulting in a 2.91 fold rise in oral bioavailability of ZLT. Hence, the presented study proves a well-organized and proficient development of a solid DES system to ameliorate the solubility and stability aspects of ZLT, which could provide the template for promising drugs that lack therapeutic effectiveness owing to solubility issues.

Assessing the impact of agriculture, coal mining, and ecological restoration on water sustainability in the Mu Us Sandyland

Balancing water demand for socio–economic development and ecosystem stability presents a challenge for regional sustainable management, especially in drylands. Previous studies have indicated that large–scale ecological restoration projects (ERPs) lead to a decline in terrestrial water storage (TWS) in the Mu Us Sandyland (MUS). However, the effects of other human activities (e.g., cropland reclamation, coal mining) on water resources remain unclear, raising concerns regarding water crisis and human–natural system sustainability. Through the utilization of coal mine location data, we found that the impact of coal mass loss on the Gravity Recovery and Climate Experiment (GRACE) products cannot be ignored in MUS, especially in the coal–rich northeastern part. Combining these data with auxiliary datasets, we observed a significant (p < 0.05) decrease in TWS (−0.85 cm yr−1) and groundwater storage (GWS, −0.95 cm yr−1) in the MUS, with human activities accounting for 79.23 % of TWS and 90.45 % of GWS reductions, primarily due to increased agricultural and industrial water consumption. Agricultural water consumption increased 2.23 times from 2001 to 2020, attributed to enhanced water use intensity (62.6 %) and cropland expansion (37.4 %). Industrial water consumption in Shenmu, a representative coal county, experienced a 4.16–fold rise between 2001 and 2020. Despite these challenges, local governments have alleviated water stress, ensured food security, and increased household income by comprehensive management strategies, such as enhancing water–saving technology and enforcing stringent policies. Previous studies have overestimated the amount of water resources consumed by ERPs. However, ERPs has played a critical role in stabilizing the regional ecological environment and ensuring the region as a vital food and energy supplier. Our findings can guide for socio-economic development and water management policies in similar regions.

Direct and indirect responses of the Arabidopsis transcriptome to an induced increase in trehalose 6-phosphate.

Trehalose 6-phosphate (Tre6P) is an essential signal metabolite that regulates the level of sucrose, linking growth and development to the metabolic status. We hypothesized that Tre6P plays a role in mediating the regulation of gene expression by sucrose. To test this, we performed transcriptomic profiling on Arabidopsis (Arabidopsis thaliana) plants that expressed a bacterial TREHALOSE 6-PHOSPHATE SYNTHASE (TPS) under the control of an ethanol-inducible promoter. Induction led to a 4-fold rise in Tre6P levels, a concomitant decrease in sucrose, significant changes (FDR ≤ 0.05) of over 13,000 transcripts, and 2-fold or larger changes of over 5,000 transcripts. Comparison with nine published responses to sugar availability allowed some of these changes to be linked to the rise in Tre6P, while others were probably due to lower sucrose or other indirect effects. Changes linked to Tre6P included repression of photosynthesis-related gene expression and induction of many growth-related processes including ribosome biogenesis. About 500 starvation-related genes are known to be induced by SUCROSE-NON-FERMENTING-1-RELATED KINASE 1 (SnRK1). They were largely repressed by Tre6P in a manner consistent with SnRK1 inhibition by Tre6P. SnRK1 also represses many genes that are involved in biosynthesis and growth. These responded to Tre6P in a more complex manner, pointing toward Tre6P interacting with other C-signaling pathways. Additionally, elevated Tre6P modified the expression of genes encoding regulatory subunits of the SnRK1 complex and TPS class II and FCS-LIKE ZINC FINGER proteins that are thought to modulate SnRK1 function and genes involved in circadian, TARGET OF RAPAMYCIN, light, abscisic acid, and other hormone signaling.

Prevalence and risk factors for Q fever, spotted fever group rickettsioses, and typhus group rickettsioses in a pastoralist community of northern Tanzania, 2016-2017.

In northern Tanzania, Q fever, spotted fever group (SFG) rickettsioses, and typhus group (TG) rickettsioses are common causes of febrile illness. We sought to describe the prevalence and risk factors for these zoonoses in a pastoralist community. Febrile patients ≥2 years old presenting to Endulen Hospital in the Ngorongoro Conservation Area were enrolled from August 2016 through October 2017. Acute and convalescent blood samples were collected, and a questionnaire was administered. Sera were tested by immunofluorescent antibody (IFA) IgG assays using Coxiella burnetii (Phase II), Rickettsia africae, and Rickettsia typhi antigens. Serologic evidence of exposure was defined by an IFA titre ≥1:64; probable cases by an acute IFA titre ≥1:128; and confirmed cases by a ≥4-fold rise in titre between samples. Risk factors for exposure and acute case status were evaluated. Of 228 participants, 99 (43.4%) were male and the median (interquartile range) age was 27 (16-41) years. Among these, 117 (51.3%) had C. burnetii exposure, 74 (32.5%) had probable Q fever, 176 (77.2%) had SFG Rickettsia exposure, 134 (58.8%) had probable SFG rickettsioses, 11 (4.8%) had TG Rickettsia exposure, and 4 (1.8%) had probable TG rickettsioses. Of 146 participants with paired sera, 1 (0.5%) had confirmed Q fever, 8 (5.5%) had confirmed SFG rickettsioses, and none had confirmed TG rickettsioses. Livestock slaughter was associated with acute Q fever (adjusted odds ratio [OR] 2.54, 95% confidence interval [CI] 1.38-4.76) and sheep slaughter with SFG rickettsioses case (OR 4.63, 95% CI 1.08-23.50). Acute Q fever and SFG rickettsioses were detected in participants with febrile illness. Exposures to C. burnetii and to SFG Rickettsia were highly prevalent, and interactions with livestock were associated with increased odds of illness with both pathogens. Further characterisation of the burden and risks for these diseases is warranted.

Immune responses to typhoid conjugate vaccine in a two dose schedule among Nepalese children

BackgroundPreviously, the Vi-typhoid conjugate vaccine (Vi-TT) was found to be highly efficacious in Nepalese children under 16 years of age. We assessed the immunogenicity of Vi-TT at 9 and 12 months of age and response to a booster dose at 15 months of age. MethodsInfants were recruited at Patan Hospital, Kathmandu and received an initial dose of Vi-TT at 9 or 12 months of age with a booster dose at 15 months of age. Blood was taken at four timepoints, and antibody titres were measured using a commercial ELISA kit. The primary study outcome was seroconversion (4-fold rise in antibody titre) of IgG one month after both the doses. FindingsFifty children were recruited to each study group.Some visits were disrupted by the COVID19 pandemic and occurred out of protocol windows.Both the study groups attained 100 % IgG seroconversion after the initial dose. IgG seroconversion in the 9-month group was significantly higher than in the 12-month group (68.42 % vs 25.8 %, p < 0.001). Among individuals who attended visits per protocol, IgG seroconversion after the first dose occurred in 100 % of individuals (n = 27/27 in 9-month and n = 32/32 in 12-month group). However, seroconversion rates after the second dose were 80 % in the 9-month and 0 % in the shorter dose-interval 12-month group (p < 0.001) (n = 16/20 and n = 0/8, respectively). InterpretationVi-TT is highly immunogenic at both 9 and 12 months of age. Stronger response to a booster in the 9-month group is likely due to the longer interval between doses.

Longitudinal phase 2 clinical trials of live, attenuated tularemia vaccine in healthy research laboratory workers

BackgroundTularemia is caused by the intracellular bacterium Francisella tularensis (Ft). It was weaponized historically due to low infectious aerosol dose, high morbidity, and mortality rates for pneumonic disease. The US Army developed the attenuated Live Vaccine Strain (LVS) from stocks provided by the former Soviet Union in the 1950s. The vaccine has been safe and immunogenic over the ensuing decades in multiple clinical trials including human challenge studies.MethodsTwo sequential FDA-regulated, non-randomized, single-arm LVS trials enrolled at-risk laboratory personnel working on tularemia in bio-containment laboratories under IND#157. Volunteers received a single dose of LVS manufactured in 1962 by scarification. Positive immunization was based on local scarification site “take reaction,” and either a &amp;gt;1:20 tularemia antigen microagglutination (MA) titer (protocol FY03-24; 2004-8) or &amp;gt;4-fold rise in MA titer (protocol FY07-15; 2009-2017). Those still negative by week 4 were offered a second dose.ResultsThe LVS vaccine was safe, well tolerated, and highly immunogenic. Between the two studies, all recipients (100%) had positive “take reactions,” with 95.5% of those in study FY03-24 having a positive response following initial vaccination. All but three subjects (98%) in protocol FY03-24 had positive MA titer results defined as &amp;gt;1:20, most within 28–35 days. In protocol FY07-15, 95% of subjects had a 4-fold or greater rise in MA titer, the primary immunogenicity endpoint for that study.DiscussionLVS vaccine administered to laboratory workers at risk for tularemia exposure over 12 years was safe and highly immunogenic. Response rates remained robust despite the vaccine lots employed having been manufactured 42–55 years prior to vaccination. The results and historical comparator data presented here serve as a benchmark for future studies. LVS remains unlicensed due to instability in culture and the potential for reversion to the wild-type pathogen. Despite the threat, there are no FDA-approved vaccines. In the absence of a clinical-stage commercial development effort, an ongoing LVS vaccine protocol under investigational new drug (IND) application for at-risk laboratory workers to prevent occupationally acquired disease should be considered based on extensive favorable data for this vaccine.Clinical trial registrationClinicalTrials.gov, identifiers NCT00584844 (trial FY03-24) and NCT00787826 (trial FY07-15).

P21 A Phase 3 randomized, double-blind, active comparator-controlled study to evaluate the safety, tolerability and immunogenicity of a 21-valent PCV, V116, in pneumococcal vaccine-naive adults (STRIDE-3)

Abstract Background Pneumococcal disease (PD) prevention remains an unmet medical need in adults. V116 is an investigational pneumococcal conjugate vaccine (PCV) containing the most prevalent serotypes associated with PD in adults in regions with established paediatric vaccination programmes. This Phase 3 study evaluated safety, tolerability, and immunogenicity of V116 compared with PCV20 in adults. Methods Pneumococcal vaccine-naive adults ≥18 years were eligible. Cohort 1 (≥50 years, n=2362) was stratified by age (50–64, 65–74, 75–84 and ≥85) and randomized 1:1 to receive 1 dose of V116 or PCV20, and cohort 2 (18–49 years, n=301) was randomized 2:1 to receive 1 dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured at baseline (Day 1) and 30 days post vaccination (Day 30). Primary objectives included assessment of (i) non-inferiority of immune responses for the serotypes common to V116 and PCV20 in cohort 1; (ii) superiority of serotypes unique to V116 compared with PCV20 in cohort 1; and (iii) immunobridging from adults 18–49 to adults 50–64 for all 21 serotypes in V116. Safety was evaluated by the proportion of participants with adverse events (AEs). Results V116 is non-inferior to PCV20 for the 10 serotypes common to both vaccines as measured by serotype-specific OPA geometric mean titres (GMTs) at Day 30. V116 is superior to PCV20 for 10 of 11 unique serotypes as measured by OPA GMTs at Day 30 as well as based on the proportions of participants with a ≥4-fold rise in OPA from Day 1 to Day 30. V116 elicits comparable immune responses in participants 18–49 years compared with participants 50–64 years for the 21 serotypes in V116 as assessed by serotype-specific OPA GMTs at Day 30, successfully demonstrating immunobridging. In total, 61.7% and 67.2% of participants vaccinated with V116 and PCV20, respectively, had ≥1 AE. There were no vaccine-related serious AEs or vaccine-related deaths. Conclusions V116 elicits immune responses that are non-inferior to PCV20 for the common serotypes and superior to PCV20 for 10 of 11 unique serotypes in V116 and has a safety profile comparable to PCV20. This pivotal study supports V116 as a novel population-specific vaccine for the prevention of PD in adults.

Femoral nailing associated with bone marrow emboli in pigs induced a specific increase in blood IL-6 and broad inflammatory responses in the heart and lungs.

Bone marrow embolization may complicate orthopedic surgery, potentially causing fat embolism syndrome. The inflammatory potential of bone marrow emboli is unclear. We aimed to investigate the inflammatory response to femoral intramedullary nailing, specifically the systemic inflammatory effects in plasma, and local tissue responses. Additionally, the plasma response was compared to that following intravenous injection of autologous bone marrow. Twelve pigs underwent femoral nailing (previously shown to have fat emboli in lung and heart), four received intravenous bone marrow, and four served as sham controls. Blood samples were collected hourly and tissue samples postmortem. Additionally, we incubated bone marrow and blood, separately and in combination, from six pigs in vitro. Complement activation was detected by C3a and the terminal C5b-9 complement complex (TCC), and the cytokines TNF, IL-1β, IL-6 and IL-10 as well as the thrombin-antithrombin complexes (TAT) were all measured using enzyme-immunoassays. After nailing, plasma IL-6 rose 21-fold, compared to a 4-fold rise in sham (p=0.0004). No plasma differences in the rest of the inflammatory markers were noted across groups. However, nailing yielded 2-3-times higher C3a, TCC, TNF, IL-1β and IL-10 in lung tissue compared to sham (p<0.0001-0.03). Similarly, heart tissue exhibited 2-times higher TCC and IL-1β compared to sham (p<0.0001-0.03). Intravenous bone marrow yielded 8-times higher TAT than sham at 30 minutes (p<0.0001). In vitro, incubation of bone marrow for four hours resulted in 95-times higher IL-6 compared to whole blood (p=0.03). A selective increase in plasma IL-6 was observed following femoral nailing, whereas lung and heart tissues revealed a broad local inflammatory response not reflected systemically. In vitro experiments may imply bone marrow to be the primary IL-6 source.

Immunogenicity and safety of SARS-CoV-2 recombinant protein nanoparticle vaccine GBP510 adjuvanted with AS03: interim results of a randomised, active-controlled, observer-blinded, phase 3 trial

GBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) in healthy adults aged ≥18 years, up to 6 months after the second dose. This was a randomised, active-controlled, observer-blinded, parallel group, phase 3 study, conducted at 38 sites across six countries (South Korea, Philippines, Thailand, Vietnam, Ukraine and New Zealand). Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination) was randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety), while Cohort 2 (regardless of baseline serostatus) was randomised 5:1 (safety). Primary objectives were to demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; ≥4-fold rise from baseline) of GBP510/AS03 vs. ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity (long-term 6 months cut-off date: 09 August 2022). This study was registered on ClinicalTrials.gov (NCT05007951). Between 30 August 2021 and 11 January 2022, a total of 4913 participants were screened and 4036 participants (1956 in Cohort 1 and 2080 in Cohort 2) who met eligibility criteria were enrolled and randomised to receive 2 doses of GBP510/AS03 (n=3039) or ChAdOx1-S (n=997). Most participants were Southeast Asian (81.5%) and aged 18-64 years (94.7%). The primary objectives assessed in per-protocol set included 877 participants in GBP510/AS03 and 441 in ChAdOx1-S group: at 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03/ChAdOx1-S) in per-protocol set was 2.93 (95% CI 2.63-3.27), demonstrating superiority (95% CI lower limit >1) of GBP510/AS03; the between-group SCR difference of 10.8% (95% CI 7.68-14.32) also satisfied the non-inferiority criterion (95% CI lower limit >-5%). Neutralizing antibody titres sustained higher for the GBP510/AS03 group compared to the ChAdOx1-S group through 6 months after the second vaccination. In Safety analysis (Cohort 1 & 2), the proportion of participants with adverse events (AEs) after any vaccination was higher with GBP510/AS03 vs. ChAdOx1-S for solicited local AEs (56.7% vs. 49.2%), but was similar for solicited systemic AEs (51.2% vs. 53.5%) and unsolicited AEs (13.3% vs. 14.6%) up to 28 days after the second vaccination. No safety concerns were identified during follow-up for 6 months after the second vaccination. Our interim findings suggested that GBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile. This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

A Comparative Study of Immunogenicity, Antibody Persistence, and Safety of Three Different COVID-19 Boosters between Individuals with Comorbidities and the Normal Population.

Data on immunogenicity, immune response persistency, and safety of COVID-19 boosters in patients with comorbidities are limited. Therefore, we aimed to evaluate three different boosters' immunogenicity and safety in individuals with at least one underlying disease (UD) (obesity, hypertension, and diabetes mellitus) with healthy ones (HC) who were primed with two doses of the BBIBP-CorV vaccine and received a booster shot of the same priming vaccine or protein subunit vaccines, PastoCovac Plus or PastoCovac. One hundred and forty subjects including sixty-three ones with a comorbidity and seventy-seven healthy ones were enrolled. The presence of SARS-CoV-2 antibodies was assessed before the booster injection and 28, 60, 90, and 180 days after it. Moreover, the adverse events (AEs) were recorded on days 7 and 21 postbooster shot for evaluating safety outcomes. Significantly increased titers of antispike, antiRBD, and neutralizing antibodies were observed in both UD and HC groups 28 days after the booster dose. Nevertheless, the titer of antispike IgG and anti-RBD IgG was lower in the UD group compared to the HC group. The long-term assessment regarding persistence of humoral immune responses showed that the induced antibodies were detectable up to 180 days postbooster shots though with a declined titer in both groups with no significant differences (p > 0.05). Furthermore, no significant difference in antibody levels was observed between each UD subgroup and the HC group, except for neutralizing antibodies in the hypertension subgroup. PastoCovac Plus and PastoCovac boosters induced a higher fold rise in antibodies in UD individuals than BBIBP-CorV booster recipients. No serious AEs after the booster injection were recorded. The overall incidence of AEs after the booster injection was higher in the UD group than the HC group among whom the highest systemic rate of AEs was seen in the BBIBP-CorV booster recipients. In conclusion, administration of COVID-19 boosters could similarly induce robust and persistent humoral immune responses in individuals with or without UD primarily vaccinated with two doses of the BBIBP-CorV. Protein-based boosters with higher a higher fold rise in antibodies and lower AEs in individuals with comorbidities might be considered a better choice for these individuals.

Group 1 and group 2 hemagglutinin stalk antibody response according to age.

Antibodies elicited by seasonal influenza vaccines mainly target the head of hemagglutinin (HA). However, antibodies against the stalk domain are cross-reactive and have been proven to play a role in reducing influenza disease severity. We investigated the induction of HA stalk-specific antibodies after seasonal influenza vaccination, considering the age of the cohorts. A total of 166 individuals were recruited during the 2018 influenza vaccine campaign (IVC) and divided into groups: <50 (n = 14), 50-64 (n = 34), 65-79 (n = 61), and ≥80 (n = 57) years old. Stalk-specific antibodies were quantified by ELISA at day 0 and day 28 using recombinant viruses (cH6/1 and cH14/3) containing an HA head domain (H6 or H14) from wild bird origin with a stalk domain from human H1 or H3, respectively. The geometric mean titer (GMT) and the fold rise (GMFR) were calculated, and differences were assessed using ANOVA adjusted by the false discovery rate (FDR) and the Wilcoxon tests (p <0.05). All age groups elicited some level of increase in anti-stalk antibodies after receiving the influenza vaccine, except for the ≥80-year-old cohort. Additionally, <65-year-old vaccinees had higher group 1 antibody titers versus group 2 before and after vaccination. Similarly, vaccinees within the <50-year-old group showed a higher increase in anti-stalk antibody titers when compared to older individuals (≥80 years old), especially for group 1 anti-stalk antibodies. Seasonal influenza vaccines can the induction of cross-reactive anti-stalk antibodies against group 1 and group 2 HAs. However, low responses were observed in older groups, highlighting the impact of immunosenescence in adequate humoral immune responses.

Acute kidney injury among preterm infants receiving nonsteroidal anti-inflammatory drugs: A pilot study.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a frequently prescribed class of medications in the neonatal intensive care unit (NICU). We aimed to reveal acute kidney injury (AKI) epidemiology in NSAID-exposed premature infants admitted to the NICU using a standardized definition and determine the percentage of NSAID-exposed patients with adequate serum creatinine (SCr) monitoring. This retrospective study compared infants born at ≤34 weeks gestational age who received NSAID for intraventricular hemorrhage prophylaxis (prophylaxis group) or symptomatic treatment for patent ductus arteriosus (PDA; treatment group) between January and December 2014at a tertiary NICU. All available SCr and 12-h urine output (UO) values were recorded from admission until day seven post-NSAID exposure. AKI incidence was determined using the neonatal modified Kidney Disease Improving Global Outcomes classification, defined as an increase in SCr (i.e., 1.5 fold rise from previous SCr measurement within seven days or 26.5mmol/L increase within 48h) or UO<1mL/kg/hour, excluding the first 24h of life. We identified 70 eligible subjects; 32 received prophylactic NSAIDs, and 38 received indomethacin or ibuprofen for treating symptomatic PDA. AKI incidence for the entire cohort was 23% (16/70). The prophylaxis group had a significantly lower AKI rate than the treatment group (9% vs. 34%; p=0.014). The treatment group had a higher proportion of infants with adequate SCr monitoring during NSAID treatment than the prophylaxis group (87% vs. 13%, p<0.001). NSAID-associated AKI occurred in approximately one-quarter of premature infants overall, and the AKI incidence was higher in infants treated with NSAIDs for the symptomatic treatment of PDA than in those receiving prophylactic treatment during the first day of life. Standardized protocols for monitoring daily SCr and UO after exposure should be implemented for all neonates with NSAID exposure to improve early AKI recognition and management.

The propositive study: Immunogenicity and safety of a four-component recombinant protein-based vaccine against MenB and a quadrivalent conjugate MenACWY vaccine in people living with HIV.

People living with HIV have been shown to have an increased risk of invasive meningococcal disease. In some countries, meningococcal vaccines are now routinely recommended to all people living with HIV, but no study has yet assessed the immunogenicity and safety of a meningococcal serogroup B vaccine or the co-administration of a MenB and MenACWY vaccine in people living with HIV. This phase IV open-label clinical trial investigated the immunogenicity and safety of two doses of a four-component recombinant protein-based MenB vaccine (4CMenB) and a quadrivalent conjugate polysaccharide MenACWY vaccine (MenACWY-CRM197) given 1 month apart in a population of people living with HIV. Immunogenicity analysis was performed before vaccination and 1 month after the second doses of 4CMenB and MenACWY. Primary outcome measures were serum bactericidal assay geometric mean titres against three MenB reference strains at baseline and 1 month post vaccination, the proportion of participants achieving a putative protective titre of ≥4, and the proportion of participants with a ≥4-fold rise in titre from baseline. Secondary outcome measures were serum bactericidal assay geometric mean titres against MenA, C, W, and Y reference strains at baseline and 1 month post vaccination, the proportion achieving a putative protective titre of ≥8, and the proportion with a ≥4-fold rise in titre from baseline. Safety outcomes were solicited and unsolicited adverse events in the 7 days following vaccination. The trial was registered with clinicaltrials.gov (NCT03682939). In total, 55 participants aged 20-45 years were enrolled. All participants (100%; 95% confidence interval [CI] 93-100) achieved putative protective titres for two of the three MenB strains and for MenA, W, and Y. A total of 98% (95% CI 89-100) achieved a protective titre for the third MenB strain and 94% (95% CI 83-99) for MenC. No serious adverse events were reported. 4CMenB and MenACWY were immunogenic and well-tolerated in a population of people living with HIV 1 month after two doses.