bluuebunny/crossref_metadata_2025_split huggingface dataset:
2104. Cytomegalovirus DNAemia Patterns in Mismatched Solid Organ Transplant Recipients: A Retrospective Cohort Study.
Authors: Garcia Oscar A Fernandez , Kabbani Dima , Doucette Karen , Robbins Mark , Cervera Carlos 
Published: December 2022

Abstract

Background
Cytomegalovirus (CMV) seronegative solid organ transplant (SOT) recipients who receive grafts from seropositive donors are at high risk of CMV disease. Antiviral prophylaxis in usually given to this group of patients to prevent illness. Patients are still at risk of CMV after completion of prophylaxis. Surveillance after prophylaxis is used in some centres to prevent late CMV disease, but there is scant information of its efficacy. Finally, little is known on CMV kinetics post-prophylaxis in high-risk patients.

Methods
This was a retrospective cohort study including adult CMV mismatch (D+/R-) SOT recipients between 2003-2017 at a multiorgan transplant center in Canada. Post-prophylaxis CMV kinetics were classified into 3 patterns of DNAemia: no DNAemia, single episode of DNAemia and recurrent episodes of DNAemia. We calculated the cumulative incidence of each DNAemia pattern. We also compared 5-year mortality according to CMV DNAemia pattern by Cox-regression analysis. Patients were monitored weekly with CMV viral load for 12 weeks after completion of prophylaxis.

Results
Two-hundred and forty-five transplant patients were included (Table 1). Median follow up time was 9.2 years (7-12.7). Death occurred in 32 patients during the study period, the median time to death was 7.3 years (4.9-10). Pattern 1 (no CMV DNAemia) occurred in 38%, 27% had a single episode (pattern 2) of CMV DNAemia and 35% had recurrent (pattern 3) CMV DNAemia. Median time to DNAemia was 186 days. The first episode occurred at a significantly shorter interval in liver recipients when compared to non-liver recipients, 158 days (134-217) vs. 208 days (149-315), p=0.0164. Recurrent CMV DNAemia (pattern 3) was significantly more common in lung transplant recipients compared to non-lung transplant recipients. (63% vs. 32% p=0.003).
Mortality at 5 years was statistically not different between CMV patterns, adjusted by organ transplanted and age (Pattern 1 reference; pattern 2 HR 1.484 [0.24-9. Table 1.Population characteristics.* Includes 16 simultaneous kidney-pancreas, pancreas after kidney or pancreas alone, 1 combined liver-kidney, 1 multivisceral. ATG: Anti-thymocyte globulin.

Conclusion
A surveillanceafter prophylaxis strategy allowed us to characterize the CMV kinetics post-prophylaxis, with 35% of CMV mismatch patients having recurrent CMV episodes. CMV kinetic pattern was not associated with 5 years mortality in CMV high-risk patients.

Disclosures
Carlos Cervera, Associate Professor, Astra-Zeneca: Advisor/Consultant|AVIR Pharma: Grant/Research Support|AVIR Pharma: Honoraria|Lilly: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Sunovion: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Honoraria|VerityPharma: Advisor/Consultant.
97. A Cross-kingdom Vaccine Protects against Multiple Healthcare-associated Infections
Authors: Singh Shakti , Barbarino Ashley M , Youssef Eman , Ghbremariam Teklegiorgis , Nabeela Sunna , Alkhazraji Sondus , Ibrahim Ashraf S 
Published: December 2022

Abstract

Background
Rise in multi-drug-resistance (MDR) among pathogens and increasing populations at risk for these infections raises the threat of nearly untreatable infectious diseases. Thus, novel vaccine strategies to prevent and/or treat MDR pathogens would benefit global health immensely. Candida albicans (CA) cell wall proteins Als3p and Hyr1p protect against candidemia due to CA and MDR C. auris (CAU). Further, Hyr1p shares structural homology with conserved hemagglutinin (FhaB) and OmpA proteins in many Gram-negative bacteria (GNB) Acinetobacter baumannii (AB), Klebsiella pneumoniae (KP), and Pseudomonas aeruginosa (PA). Thus, Hyr1p antigen-based active and passive vaccinations protect against AB and KP pneumonia. We hypothesized that a dual Als3p/Hyr1p antigen vaccine formulated with CAF01 (a clinical stage adjuvant) that can promote a balanced Th1/Th2/Th17 immune response is likely to protect against multiple healthcare-associated infections caused by Candida species and MDR GNB.

Methods
To formulate Als3p/Hyr1p antigen, we mixed CAF01 with Als3p and Hyr1p antigens in the following ratios: 0/0, 10/10, 10/30, 30/10 and 30/3 µg for each dose. CD-1 mice with each dose subcutaneously, followed by booster immunization on day 21. For efficacy evaluation, vaccinated mice (n=20 mice/group) were immunosuppressed by administration of cyclophosphamide and cortisone acetate on day -2 and +3, relative to infection with either CAU, AB, KP or PA. Infection occurred two weeks following the booster immunization. For, CA infection, immunocompetent mice were infected intravenously two weeks following a primary booster or after a second booster given on day 35.

Results
All Als3p/Hyr1p formulations induced robust immunity against both antigens. For CA infection, two booster immunizations provide superior protection over one booster immunization. For CAU and GNB, one booster dose was enough to provide significant protection. Further, both 30/10 and 10/10 vaccine formulations protected significantly against all five infections. Specifically, for fungal infections, 30/10 and 10/10 formulations showed 30-40% and 40-50% survival efficacies (vs. 0% for placebo), respectively.
TABLE 1. Survival efficacy of Als3p/Hyr1p formulations against Candida species and Gram-negative bacterial infections.

Conclusion
Our study shows that the Als3p/Hyr1p induced a robust protective immunity against CA, MDR CAU and GNB.

Disclosures
All Authors: No reported disclosures.
2132. Placental histopathology and long-term outcomes of children with antenatal Zika virus exposure
Authors: Mulkey Sarah B , Puscasiu Elena , Corn Elizabeth , Ansusinha Emily , Arroyave-Wessel Margarita , Rossi Christopher T , Delaney Meghan , du Plessis Adre , Cure Carlos A , DeBiasi Roberta L 
Published: December 2022

Abstract

Background
It is unclear whether placental changes in ZIKV infection influence short- and long-term child outcomes. The objective of this study is to determine if placental histopathology findings in ZIKV correlate with offspring outcomes at birth and age 4-5 years for children with in utero ZIKV exposure without congenital Zika syndrome.

Methods
24 placentas collected from pregnant women with symptomatic ZIKV infection enrolled in a prospective ZIKV study in Colombia were formalin fixed and reviewed by a placental pathologist, blinded to child outcome. Children had neuroimaging as newborns and were longitudinally evaluated to age 4-5 years with the Bracken School Readiness Assessment (BSRA) and Pediatric Evaluation of Disability Inventory (PEDI-CAT). Scores were compared by presence of placental findings of perivillous fibrin deposition, calcifications, and increased syncytial knotting. T-test, fisher exact, and one way ANOVA were used for analysis; significance, p&lt; .05.

Results
All 24 placentas had at least one abnormal pathological finding (Table 1). 14 (58%) placentas had extensive ( &gt;30% coverage) and 7 (29%) had mild-moderate perivillous fibrin deposition (Fig. 1a). Placental calcifications were many ( &gt;10) in 10 (42%) cases, and mild in 7 (29%) cases (Fig. 1b). 14 (58%) placentas had increased syncytial knotting. Placentas stained positive with CD163 for Hofbauer macrophages (Fig. 1c). All infants were born at term with normal birth weight, height, and head circumference, and 22 had a normal ponderal index. There was no difference in measurements based on each placental finding. There was no relationship between placental findings and non-specific neuroimaging. 20 (83%) children with placentas were evaluated at age 4-5. Children without placental calcifications scored higher on BSRA than children with mild/severe calcifications (p = .031). Children with increased syncytial knotting had lower scores on PEDI-CAT social/cognitive ability (p = .024).

Conclusion
Placentas from ZIKV-infected pregnancies have pathological findings that indicate risk of impaired fetal perfusion, but these were not associated with preterm birth or growth. There may be associations between placental findings and long-term neurodevelopment in ZIKV-exposed children requiring additional studies.

Disclosures
All Authors: No reported disclosures.
2138. Evaluating the Safety and Immunogenicity of the rZIKV/D4Δ30-713 Live Attenuated Chimeric Zika Candidate Vaccine in Healthy Flavivirus-Naïve Adults
Authors: Zhong Diana , Kirkpatrick Beth , Pierce Kristen , Patel Urvi , Blunt Madeleine R , Durbin Anna 
Published: December 2022

Abstract

Background
Zika virus (ZIKV) is a flavivirus associated with a serious congenital Zika syndrome, with a recent epidemic originating in Brazil in 2015. Novel ZIKV vaccine candidates are in development. We report results of a phase I study of the first live attenuated ZIKV vaccine for use in humans. rZIKV/D4Δ30-713 is a chimeric Zika vaccine, expressing the premembrane (prM) and envelope (E) genes of a contemporary ZIKV strain within a dengue DEN4Δ30 background.

Methods
We conducted a phase I, randomized, placebo-controlled double-blind trial, evaluating two different doses, 103 PFU and 104 PFU, of rZIKV/D4Δ30 in healthy adult subjects 18 – 50. Between October 2018 and August 2021, 28 subjects were enrolled in each dose cohort (20 to vaccine; 8 to placebo) at the Johns Hopkins Center for Immunization Research and the University of Vermont Vaccine Testing Center. Subjects were followed 26 weeks post-vaccination. Primary outcomes included safety and reactogenicity (adverse events graded by severity) and immunogenicity assessed by seroconversion by day 90 post-vaccination (ZIKV peak titer ≥ 1:10). The study was IRB approved (WCG 20181303, UVM CHRMS 18-0566).

Results
Fifty-five of 56 enrolled subjects completed the study. One volunteer (104 PFU group) withdrew before study day 28 due to work conflicts. The most common adverse events were headache, fatigue, and myalgias. These events did not occur significantly more frequently in vaccine recipients compared with placebo recipients. One severe adverse event was deemed unrelated to study product (new breast cancer diagnosis). In the 103 PFU group, 9 of 20 (45%) seroconverted. In the 104 PFU group, 7 of 19 (37%) seroconverted (Figure 1). ZIKV could not be recovered by culture or PCR in the blood, saliva, or urine from any subject.

Conclusion
The vaccine appears to be safe and well-tolerated in healthy flavivirus-naïve adults. The seroconversion proportion was similar between the two dosing groups, with higher peak titers in the 104 PFU group. Given the lack of dose effect on seroconversion, further dose increases are unlikely to improve seroconversion. Chimerization can be highly attenuating to viruses. Our results suggest rZIKV/DEN4Δ30 is over-attenuated and thus will not be further developed as a candidate ZIKV vaccine.

Disclosures
Anna Durbin, MD, Merck & Co.: Advisor/Consultant.
2140. INO-4800, a DNA Plasmid Vaccine Encoding the Ancestral SARS-CoV-2 Spike Protein, Is Stable Over a Range of Temperatures Not Requiring Ultra-Cold Chain Storage
Authors: Juba Robert J , Samawova Anthony , Seals Katherine , Kinney Peggy , Brandreth E J 
Published: December 2022

Abstract

Background
Effective vaccines deployable globally are needed to control the COVID-19 pandemic. INO-4800, a plasmid DNA vaccine encoding the ancestral SARS-CoV-2 spike (S) protein, has demonstrated safety and immunogenicity. We report the stability of multiple INO-4800 lots used in Phase 3 clinical trials.

Methods
Lots of INO-4800 stored at the test temperatures (storage temperature [2–8°C] and accelerated temperature [25 ± 2°C]) were sampled every 3 months. Sample stability at each timepoint was assessed in terms of 2 parameters: i) purity as measured by DNA isoform homogeneity by capillary gel electrophoresis (CGE) to quantify relative proportions of different plasmid topologies (supercoiled, open circular, and linear), and ii) potency as measured by a cell-based assay for flow cytometric detection of fluorescently labeled S protein.

Results
At 2–8°C, all tested lots of INO-4800 retained structural homogeneity for ≥12 months (Fig. 1A). Proportions of circular and supercoiled plasmid isoforms were ≥96% and ≥89%, respectively, remaining above minimum regulatory authority-approved specifications (≥85% for circular and ≥80% for supercoiled isoforms). At 25 ± 2°C, all tested lots retained structural homogeneity within specifications for ≥6 months (Fig. 1B), with proportions of circular and supercoiled plasmid isoforms being ≥96% and ≥81%, respectively. Moreover, structural homogeneity of 1/2 (50%) lots was within specification at 9 months at 25 ± 2°C. Potency of all tested lots was ≥84% for ≥6 months at both 2–8°C and 25 ± 2°C, remaining above the regulatory authority-approved minimum of 77% (Figs. 1C and 1D). Moreover, 3/3 (100%) of tested lots were within potency specification at 12 months at 2–8°C and 2 lots and 1 lot, respectively, were within specification at 9 and 12 months at 25 ± 2°C. Data from additional timepoints are accruing and will be presented. Figure 1:Stability of INO-4800 lots used in Phase 3 trials as measured by isoform homogeneity (A and B) and potency (C and D). Shaded areas represent regulatory authority-approved specifications.

Conclusion
INO-4800 is stable across temperatures ranging from 2°C to 25 ± 2°C and does not require ultra-cold storage. This demonstrated stability confers upon INO-4800 the potential to be deployed globally even in resource-constrained settings lacking cold chain infrastructure, thereby contributing to pandemic preparedness and control.

Disclosures
Robert J. Juba, Jr., MS Chemical Engineering Practice, BS Chemical Engineering, Inovio Pharmaceuticals: Employee|Inovio Pharmaceuticals: Stocks/Bonds Katherine Seals, n/a, Inovio Pharmaceuticals: Employee|Inovio Pharmaceuticals: Stocks/Bonds Peggy Kinney, MS Quality Management, Inovio Pharmaceuticals: Employee|Inovio Pharmaceuticals: Stocks/Bonds.
2152. Types and Resistance Patterns of Gram-negative Bacteria (GNB) causing Bloodstream Infections (BSIs) in a Neonatal ICU (NICU), 2010-2019
Authors: Frantzis Irene , Paul Anshu , Gentzler Eliza , Solowey Kyra , Manickam Surya , Hill-Ricciuti Alexandra , Messina Maria , Alba Luis , Johnson Candace L , Brachio Sandhya S , Saiman Lisa 
Published: December 2022

Abstract

Background
BSIs caused by GNB, particularly with multidrug resistance, cause substantial morbidity and mortality in NICUs worldwide1. We previously reported low overall rates of gentamicin resistance in commonly isolated GNB, i.e., Escherichia coli and Klebsiella species, supporting gentamicin as empiric therapy in our NICU2. Over a decade later, we sought to assess GNB BSI rates and potential changes in GNB resistance patterns.
References:
&lt; ! 1.Dramowski A, et al. Paediatr Int Child Health. 2015;35:265-72.
2.Smith A, et al. Pediatr Infect Dis J 2010;29:831–35.

Methods
We retrospectively reviewed GNB BSIs that occurred in infants &gt; 3 days old admitted to a level IV academically affiliated NICU from 2010-2019. Pre-approval for broad spectrum antibiotics was in place throughout the study period. Post-prescription review began in 2017. We collected the types of GNB and resistance to gentamicin, 3rd/4th generation cephalosporin agents, and meropenem. Data analysis included frequency of GNB type per year, incidence per 1000 admissions, and regression analysis

Results
Admissions were generally stable during the study period (range 855-1057). The types of GNB causing BSIs each year and BSI incidence are shown (Figure 1). Incidence ranged from 8-26 per 1000 admissions and during the 10-year period, GNB BSI incidence decreased (p&lt; 0.001). The most common GNB were E. coli (n=21) and Klebsiella spp. (n=25) followed by Enterobacter spp. (n=15) and Serratia marcescens (n=12). GNB resistance trends are shown (Figure 2). Overall, resistance to gentamicin appeared stable (14.5%), while resistance to ceftriaxone increased (19.1%) and resistance to cefepime (3.8%) and meropenem (2.3%) was rare.

Conclusion
GNB BSIs have decreased in our NICU with low rates of gentamicin resistance, supporting the continued use of gentamicin for empiric antibiotic therapy. To maintain low resistance rates, antimicrobial stewardship efforts should continue. NICU-specific antibiograms should be considered to facilitate assessment of resistance trends.

Funding
IF supported by NIAID T32 AI007531.

Disclosures
Lisa Saiman, MD MPH, Merck & Co., Inc.: Advisor/Consultant|Merck & Co., Inc.: Grant/Research Support.
2172. Closing the CAP Gap: Improving the Management of Community Acquired Pneumonia (CAP)
Authors: Hoffman Paige A , Son Andrea H , Hoeprich Stephanie L , Hecker Michelle T 
Published: December 2022

Abstract

Background
In October 2019 updated community acquired pneumonia (CAP) guidelines were published, highlighting indications for empiric anti-MRSA and antipseudomonal antibiotics and use of MRSA nares screens. During a review of patients receiving vancomycin and piperacillin-tazobactam at our institution in 2020 we noted frequent use of anti-MRSA and antipseudomonal antibiotics and infrequent use of MRSA nares screens for CAP. In May 2020 we initiated a multifaceted intervention, including prospective audit and feedback, an updated pneumonia order set, and system-wide education. In this study we sought to describe gaps in the care of patients with CAP at our institution and to evaluate the impact of a multifaceted intervention on those gaps in care.

Methods
We performed a retrospective cohort study on a random sample of unique adult patients admitted with pneumonia from January 1, 2020 through June 30, 2021. Exclusion criteria included COVID infection within 4 weeks of admission, no antibiotics for pneumonia given during admission, immunocompromised condition, and diagnosis of hospital-acquired or ventilator-associated pneumonia. The primary objective was to describe the percentage of patients receiving appropriate anti-MRSA and antipseudomonal therapy and MRSA nares testing during the study period. The secondary objective was to compare appropriateness of these outcomes before and after the intervention.
Study groups

Results
For the 126 patients reviewed, 68.3% received the appropriate empiric spectrum of activity for MRSA and Pseudomonas aeruginosa, improving from 60% to 80% before and after the intervention respectively. The percentage of patients screened for MRSA increased from 6 to 34%; however, the percentage of appropriate MRSA screens decreased from 71 to 54% because screens were often collected despite absence of MRSA risk factors.
Results

Conclusion
The percentage of patients receiving appropriate anti-MRSA and antipseudomonal therapy for CAP improved after a multifaceted stewardship intervention. The percentage of patients for whom appropriate MRSA nares screens was performed worsened, mainly due to use of MRSA nares screens when not needed.

Disclosures
All Authors: No reported disclosures.
102. Efficacy and Effectiveness of High-Dose Influenza Vaccine in Older Adults by Age and Seasonal Characteristics: An Updated Systematic Review and Meta-Analysis
Authors: Lee Jason K , Lam Gary K , Vaisman Rolan , Yin Kevin J , Seet Bruce T , Loiacono Matthew M , Samson Sandrine I 
Published: December 2022

Abstract

Background
High-dose influenza vaccine (HD-IIV) has been used extensively in older adults since its approval in 2009. Studies comparing HD-IIV to standard-dose influenza vaccines (SD-IIV) have demonstrated protection beyond influenza, including reduction of outcomes like cardiorespiratory and all-cause hospitalizations. This study is an update of previously-conducted reviews of the relative vaccine efficacy/effectiveness (rVE) of HD-IIV vs. SD-IIV in adults ≥65 years against influenza-associated outcomes from 2009-2020, with sub-analyses by seasonal and recipient characteristics.

Methods
An updated systematic review and meta-analysis was conducted for studies assessing the rVE of HD-IIV against probable/laboratory-confirmed influenza-like illness (ILI), emergency department (ED) and/or hospital admissions in adults ≥65 years. Results from individual seasons – stratified by outcome, subject characteristics, and influenza season, were meta-analyzed to estimate pooled rVEs of HD-IIV.

Results
19 studies from 11 consecutive seasons with over 45 million HD-IIV or SD-IIV recipients were meta-analyzed. Overall, HD-IIV demonstrated improved protection vs. SD-IIV against ILI (rVE=14.3%, 95%CI:4.2-23.3%), HD-IIV was more effective at preventing hospital/ED visits due to influenza (rVE=10.4%, 95%CI:6.8-13.9%), and hospitalizations due to influenza (rVE=11.2%, 95%CI:7.4-14.8%), pneumonia (rVE=27.3%, 95%CI:15.3-37.6%); pneumonia and influenza (rVE=13.4%, 95%CI:7.3-19.2%); respiratory (rVE=14.3%, 95%CI:8.5-20.0%), cardiovascular (rVE=13.1%, 95%CI:10.5-15.7%), and cardiorespiratory events (rVE=17.9%, 95%CI:15.0-20.8%); and all-causes (rVE=8.4%, 95%CI:5.7-11.0%). Pooled rVEs were similar in sub-analyses by dominant strain, antigenic match, and study type/setting. While all adults 65+ benefited from the use of HD-IIV, age-stratified analyses of the rVE of HD-IIV suggested additional relative benefit with increasing age.

Conclusion
Evidence over 11 consecutive influenza seasons from both randomized and observational studies suggests HD-IIV was consistently more effective than SD-IIV at reducing influenza and associated serious outcomes irrespective of recipient age and characteristics of the influenza season.

Disclosures
Jason K. Lee, MS, MBiotech, Sanofi: Employee|Sanofi: Stocks/Bonds Gary K. Lam, PharmD, RPh, Sanofi: Employee Rolan Vaisman, PharmD, RPh, Sanofi: Employee Kevin J. Yin, MD, MPH, PhD, Sanofi: Employee|Sanofi: Stocks/Bonds Bruce T. Seet, PhD, MBA, Sanofi: Employee|Sanofi: Stocks/Bonds Matthew M. Loiacono, PhD, MSc, Sanofi: Employee|Sanofi: Stocks/Bonds Sandrine I. Samson, PhD, Sanofi: Employee|Sanofi: Stocks/Bonds.