Dengue is a pantropic public health problem. In children, dengue shock syndrome (DSS) is the most common life-threatening complication. The ability to predict which patients may develop DSS may improve triage and treatment. To this end, we conducted a nested case-control comparison of the early host transcriptional features in 24 DSS patients and 56 sex-, age-, and virus serotype-matched uncomplicated (UC) dengue patients. In the first instance, we defined the "early dengue" profile. The transcriptional signature in acute rather than convalescent samples (<72 h post-illness onset) was defined by an overabundance of interferoninducible transcripts (31% of the 551 overabundant transcripts) and canonical gene ontology terms that included the following: response to virus, immune response, innate immune response, and inflammatory response. Pathway and network analyses identified STAT1, STAT2, STAT3, IRF7, IRF9, IRF1, CEBPB, and SP1 as key transcriptional factors mediating the early response. Strikingly, the only difference in the transcriptional signatures of early DSS and UC dengue cases was the greater abundance of several neutrophilassociated transcripts in patients who progressed to DSS, a finding supported by higher plasma concentrations of several canonical proteins associated with neutrophil degranulation (bactericidal/permeability-increasing protein [BPI], elastase 2 [ELA2], and defensin 1 alpha [DEF1A]). Elevated levels of neutrophil-associated transcripts were independent of the neutrophil count and also of the genotype of the infecting virus, as genome-length sequences of dengue virus serotype 1 (DENV-1) (n ؍ 15) and DENV-2 (n ؍ 3) sampled from DSS patients were phylogenetically indistinguishable from those sampled from uncomplicated dengue patients (32 DENV-1 and 9 DENV-2 sequences). Collectively, these data suggest a hitherto unrecognized association between neutrophil activation, pathogenesis, and the development of DSS and point to future strategies for guiding prognosis.
Herpes simplex virus 2 is an important human pathogen as the causative agent of genital herpes, neonatal herpes, and increased risk of HIV acquisition and transmission. Nevertheless, the only genomic sequence that has been completed is the attenuated HSV-2 HG52 laboratory strain. In this study we defined the genomic sequence of the HSV-2 SD90e low passage clinical isolate and a plaque-purified derivative, SD90-3P. We found minimal sequence differences between SD90e and SD90-3P. However, in comparisons with the HSV-2 HG52 reference genome sequence, the SD90e genome ORFs contained numerous point mutations, 13 insertions/delections (indels), and 9 short compensatory frameshifts. The indels were true sequence differences, but the compensatory frameshifts were likely sequence errors in the original HG52 sequence. Because HG52 virus is less virulent than other HSV-2 strains and may not be representative of wildtype HSV-2 strains, we propose that the HSV-2 SD90e genome serve as the new HSV-2 reference genome.
BackgroundCDI is a 2-hit process requiring C. difficile spores and antibiotic-mediated dysbiosis, a low diversity state of the gut microbiome. Recurrent CDI (rCDI) is common and may be related to inadequate antibiotic concentrations (e.g., metronidazole; MET) or persistent dysbiosis (e.g., vancomycin; VAN). SER-262 is an oral investigational microbiome drug rationally designed to reduce rCDI by restoring colonization resistance.MethodsSERES-262-001 was a Phase 1b randomized placebo (PBO)-controlled single and multidose study. Subjects with primary CDI (n = 96) were enrolled in 8 cohorts (SER-262: PBO, 5:1). Subjects were dosed after MET (n = 57) or VAN (n = 39) per investigator discretion. Engraftment of SER-262 strains was evaluated using strain-specific molecular probes in fecal samples; microbial diversity was measured via whole metagenomic shotgun sequencing. Endpoints included safety and rCDI rates up to 8 weeks posttreatment and strain engraftment at 1, 4, 8, 12, and 24 weeks.ResultsSER-262 safety was comparable to PBO. Although overall rCDI rates were similar in SER-262 (n = 80) and PBO (n = 16) subjects (18.8% vs. 12.5%, respectively), in a post-hoc analysis we observed reduced rates of rCDI in the VAN+SER-262 arm compared with MET+SER-262 (6.3 vs. 27.1%, respectively, P = 0.02, Figure 1). Overall, 8 of 12 SER-262 strains showed significant engraftment relative to PBO. However, greater SER-262 strain engraftment was observed in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 2). To better understand the impact of dysbiosis on engraftment, we evaluated baseline microbial diversity by prior antibiotic received and observed that the diversity of Bacteroidetes and Firmicute species was lower in VAN-treated subjects compared with MET-treated subjects (P < 0.001, Figure 3).ConclusionIn this first phase 1b study of a fermented microbiome drug in subjects with primary CDI, SER-262 was safe and well-tolerated. The higher efficacy rates of SER-262 in reducing rCDI among VAN-treated subjects may be due to low baseline microbial diversity, which creates an ecologic niche for greater engraftment of dose species. Treatment of C. difficile with VAN, followed by restoration of colonization resistance with SER-262, is a promising 2-pronged therapeutic paradigm to reduce rCDI. Disclosures All authors: No reported disclosures.
Background The gastrointestinal microbiota is the first line of defense against colonization with antimicrobial resistant (AR) bacteria, particularly in vulnerable hosts with frequent antibiotic exposure. In a double-blind Phase 3 trial of rCDI patients, SER-109, an orally formulated consortia of purified Firmicutes spores, was superior to placebo in reducing CDI recurrence at week 8 post clinical resolution on standard-of-care (SoC) antibiotics. Overall recurrence rates were lower in SER-109 vs placebo (12.4% vs 39.8%, respectively) relative risk, 0.32 [95% CI, 0.18–0.58; p< 0.001 for RR< 1.0; p< 0.001 for RR< 0.833]. This is a post-hoc analysis examining the impact of SER-109 on antimicrobial resistance genes (ARGs) abundance in the intestinal microbiota compared to placebo. Methods Subjects with rCDI received SoC antibiotics, then were randomized 1:1 to SER-109 or placebo at baseline. Of 182 subjects, 140 who had paired stool samples at baseline and 1-week post-treatment were included in this analysis. ARG abundances and taxonomic profiles were generated from whole metagenomic shotgun sequencing. t-tests were used to compare changes in ARG abundance from baseline; mixed linear models were used to associate ARG and taxon abundances across time points. Results ARG abundance was reduced overall by week 1, with a significantly greater decrease in SER-109 subjects vs. placebo at week 1 (Fig. 1). Proteobacteria relative abundance were positively correlated with ARG abundance across all samples (Fig. 2), with the Enterobacteriaceae family associated with the abundance of 95 ARGs (all p < 0.05). Enterococcaceae relative abundance was associated with glycopeptide AR abundance (p < 0.001). At week 1, Proteobacteria relative abundance was significantly decreased from baseline in SER-109 subjects vs. placebo (p < 0.001). Enterobacteriaceae and Enterococcaceae relative abundances were also decreased from baseline in SER-109 subjects vs. placebo (p < 0.001 and p = 0.007, respectively). Figure 1. Significant reduction in ARG abundance at week 1 from baseline in SER-109 treatment compared to placebo. Figure 2. Total ARG abundance is associated with the relative abundance of Proteobacteria in SER-109 and placebo subjects at baseline and week 1. Conclusion SER-109 was associated with significantly greater reduction of ARGs and AR bacteria abundances compared to placebo at 1 week post treatment. These findings support a potential role of microbiome therapeutics in rapid decolonization of AR bacteria with implications for infection prevention. Disclosures Timothy J. Straub, MS, Seres Therapeutics (Employee) Liyang Diao, PhD, Seres Therapeutics (Employee) Christopher Ford, PhD, Seres Therapeutics (Employee, Shareholder) Matthew Sims, MD, PhD, Astra Zeneca (Independent Contractor)Diasorin Molecular (Independent Contractor)Epigenomics Inc (Independent Contractor)Finch (Independent Contractor)Genentech (Independent Contractor)Janssen Pharmaceuticals NV (Independent Contractor)Kinevant Sciences gmBH (Independent Contractor)Leonard-Meron Biosciences (Independent Contractor)Merck and Co (Independent Contractor)OpGen (Independent Contractor)Prenosis (Independent Contractor)Regeneron Pharmaceuticals Inc (Independent Contractor)Seres Therapeutics Inc (Independent Contractor)Shire (Independent Contractor)Summit Therapeutics (Independent Contractor) Thomas J. Louie, MD, Artugen (Advisor or Review Panel member)Crestone (Consultant, Grant/Research Support)Da Volterra (Advisor or Review Panel member)Finch Therapeutics (Grant/Research Support, Advisor or Review Panel member)MGB Biopharma (Grant/Research Support, Advisor or Review Panel member)Rebiotix (Consultant, Grant/Research Support)Seres Therapeutics (Consultant, Grant/Research Support)Summit PLC (Grant/Research Support)Vedanta (Grant/Research Support, Advisor or Review Panel member) Colleen S. Kraft, MD, MSc, Rebiotix (Individual(s) Involved: Self): Advisor or Review Panel member Stuart H. Cohen, MD, Seres (Research Grant or Support) Stuart H. Cohen, MD, Nothing to disclose Mary-Jane Lombardo, PhD, Seres Therapeutics (Employee, Shareholder) Barbara McGovern, MD, Seres Therapeutics (Employee, Shareholder) Lisa von Moltke, MD, Seres Therapeutics (Employee, Shareholder) Matt Henn, PhD, Seres Therapeutics (Employee, Shareholder)
Background During allogeneic hematopoietic stem cell transplant (HSCT), the diversity and stability of the GI microbiome is disrupted, increasing the risk of domination by pathogens associated with bacteremia, aGvHD, and mortality. SER-155 is an investigational, oral microbiome therapeutic composed of cultivated spores and vegetative bacterial strains rationally designed to reduce the risk of bacteremia and aGvHD in HSCT recipients by decolonizing potential pathogens and restoring GI colonization resistance. SER-155 was evaluated in vitro for key pharmacological properties associated with colonization resistance, and in vivo to assess its ability to restore colonization resistance by reducing Enterococcus and Enterobacteriaceae carriage. Methods The design of SER-155 leveraged genomic data from interventional and observational human datasets to include taxa associated with reduced risk of infection and aGvHD in HSCT. Strains of interest were phenotyped, and over 50 candidate consortia containing different combinations of over 150 species were designed and tested in vitro and in vivo. In vivo, candidate compositions were evaluated in mouse models of vancomycin-resistant Enterococcus faecium (VRE) and carbapenem-resistant Klebsiella pneumoniae (CRE) colonization. Results Oral administration of SER-155 led to a 2-3 Log10 reduction in VRE and CRE titers compared to untreated mice (Figure 1). In vitro, the carbon source utilization profile of VRE, CRE, and SER-155 strains were assessed using a panel of 85 carbon sources. All 56 carbon sources used by CRE or VRE for anaerobic growth were also utilized by SER-155 strains, supporting a model in which nutrient competition may contribute to reducing CRE and VRE carriage and restoring colonization resistance. Figure 1. SER-155 Efficacy in Mouse Models of VRE and CRE Colonization. The titers of VRE or CRE were quantified in fecal pellets by plating on selective agar at the indicated time-points. The median A) VRE and B) CRE CFU per gram of feces was calculated for each group and plotted on the line graph (n=6-10 per group). L.O.D., limit of detection. Data were analyzed using the Mann-Whitney t-test and significance was determined as a p-value of p< 0.05*, p<0.01**, p<0.001***, p<0.0001****. Conclusion SER-155 is an investigational cultivated microbiome therapeutic intended to reduce the risk of infection by engrafting human-commensal bacterial strains in adults undergoing allogeneic HSCT. Preclinical assessments in vitro and in vivo support the ability of SER-155 to reduce VRE and CRE carriage and restore colonization resistance in the gut. A Phase 1b study evaluating SER-155 in allogeneic HSCT patients is being planned. Disclosures Elizabeth Halvorsen, PhD, Seres Therapeutics (Employee, Shareholder) Marin Vulic, PhD, Seres Therapeutics (Employee) Edward J. O’Brien, PhD, Seres Therapeutics (Employee, Shareholder) Jessica Byrant, PhD, Seres Therapeutics (Employee, Shareholder) Mary-Jane Lombardo, PhD, Seres Therapeutics (Employee, Shareholder) Christopher Ford, PhD, Seres Therapeutics (Employee, Shareholder) Matt Henn, PhD, Seres Therapeutics (Employee, Shareholder)
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