bluuebunny/crossref_metadata_2025_split huggingface dataset:
2718. Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine in US Adults Hospitalized with Pneumonia, 2014–2017
Authors: Lessa Fernanda C , Spiller Michael , Wu Xiyuan , Wang Rongrong , Chillarige Yoganand , Wernecke Michael , MaCurdy Thomas E , Kelman Jeffrey A , Shang Nong , Pilishvili Tamara 
Published: October 2019

Abstract

Background
Efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) against pneumococcal pneumonia in adults aged &gt;65 years was shown in a 2014 clinical trial. However, its benefits in countries with a mature PCV infant program remain unclear. In August 2014, PCV13 was recommended for all US adults aged &gt;65 years. We evaluated the direct effect of this recommendation on pneumonia hospitalizations among the elderly.

Methods
We analyzed claims data from US Medicare beneficiaries aged &gt;65 years enrolled in part A/B during September 1, 2014 through December 31, 2017. Participants were followed until they died, left part A/B, or developed a study outcome: community-acquired pneumonia (CAP), non-healthcare-associated CAP (non-HA CAP) or lobar pneumonia (LP). We identified outcomes using inpatient diagnosis codes, and vaccination status using procedure codes. We used discrete-time survival models, stratified by influenza season (October–April) and influenza vaccination status, to estimate incidence rate ratios (IRR) by pneumococcal vaccination status (PCV13-only vs. no pneumococcal vaccination). We adjusted for demographic factors, healthcare utilization, month/year of hospital discharge, and underlying conditions. We derived vaccine effectiveness (VE) and number of hospitalizations averted by PCV13 from the IRRs.

Results
Of 26.6 million beneficiaries in September 2014, 43.4% were male, 54.2% were aged 65–74 years, and 28.9% had a Charlson comorbidity score &gt;3. PCV13 coverage increased from 0.8% in September 2014 to 41.5% in December 2017. Annual incidence of CAP, non-HA CAP, and LP are shown in the figure. PCV13-vaccinated persons were more likely to be older, sicker, and have received flu vaccine than unvaccinated persons. VE estimates for CAP, non-HA CAP, and LP ranged from 6.0–11.4%, 5.0–11.0%, and 1.3–11.0%, respectively. From September 2014 to December 2017, an estimated 28,600 (95% CI: 21,000–36,000) CAP, 18,700 (12,000–25,800) non-HA CAP and 1,100 (190–1,900) LP hospitalizations were averted.

Conclusion
Within 40 months after implementation of the adult PCV13 program, 2.0% (28,600) of US CAP hospitalizations were averted. Despite PCV13 effectiveness against adult CAP, only a small fraction of CAP hospitalizations was prevented.

Disclosures
All authors: No reported disclosures.
2730. Estimating Deaths Attributable to Influenza Mortality Using Traditional and Novel Forecasting Methods
Authors: McConeghy Kevin , Zullo Andrew R , Van Aalst Robertus , Bosco Elliott , Gravenstein Stefan 
Published: October 2019

Abstract

Background
Seasonally-adjusted linear models (‘Serfling’ models) serve as an important surveillance measure to estimate influenza (flu) attributable deaths for resource allocation to public health programs (e.g., vaccination campaigns). We compared performance of traditional time-series and viral activity-based models to a novel open-source R-package ‘Prophet’ for estimating the number of deaths attributable to influenza per season.

Methods
We evaluated deaths from the 122-Cities Mortality Reporting System which reports the total number of death certificates where pneumonia or flu was listed as a contributing cause of death. Models were fitted to 2010–2015 influenza seasons. The first Serfling model (M1) used baseline periods of low-endemicity (summer months) to estimate attributable deaths during a flu season (OCT-MAY), the second Serfling model (M2) incorporated both baseline and virology data (count laboratory proven flu cases in a given period). The Prophet model (M3) uses generalized additive models incorporating annual, seasonal terms and viral activity data. The difference between observed deaths, and those predicted by each model in the absence of flu were ‘attributable death.” Epidemic weeks exceeded the 95% upper prediction interval. Model performance was assessed by Root Mean Square Error (RMSE).

Results
From 2010 to 2015, the average deaths due to pneumonia and influenza per season numbered 824 per week (total 198,692). Compared with the traditional Serfling model (M1), the Prophet model estimated 52% more influenza-attributable deaths (13,443 vs. 8,800) and more epidemic weeks (25 vs. 10) with lower RMSE (75.9 vs. 95.3 [lower is better]). Compared with the viral activity-based model (M2), the Prophet model estimated 6% fewer attributable deaths (13,443 vs. 14,326), with more epidemic weeks (25 vs. 19) and lower RMSE (RMSE 75.9 vs. 92.6).

Conclusion
Generalized additive models, implemented through the R-package Prophet, are superior in terms of reducing model prediction error for influenza mortality vs. traditional models. Based on superior model performance, the attributable mortality estimated by these novel models may be preferred over traditional regression models. This study was funded by Sanofi Pasteur.

Disclosures
All authors: No reported disclosures.
166. Comparison of Oral Fluoroquinolones to Alternative Oral Agents for Definitive Step-Down Therapy in Gram-Negative Bloodstream Infections
Authors: Cho Christian Y , Dillon Caroline , Carr Dustin R , Walsh Thomas L , Moffa Matthew , Bremmer Derek N 
Published: October 2019

Abstract

Background
During the management of Gram-negative bloodstream infections (GN BSIs), definitive oral step-down therapy is often utilized. Fluoroquinolones (FQs) are commonly utilized due to excellent bioavailability; however, comparative evidence to oral trimethoprim/sulfamethoxazole (TMP/SMX) or β-lactams (BLs) are limited.

Methods
This multicenter, retrospective cohort included patients ≥18 years of age who had a GN BSI and received oral FQ, BL, or TMP/SMX as definitive oral step-down therapy for >33% of their total treatment duration. Patients were excluded if received ˂7 days or >17 days of total therapy, or had polymicrobial bacteremia. The primary outcome was treatment failure within 90 days. Treatment failure was a composite endpoint including both all-cause mortality and recurrence of infection. Secondary outcomes included all-cause and infection-related readmissions at 30 days.

Results
A total of 220 patients were included (FQ n = 106, BL n = 96, SMX/TMP n = 18). Patients were elderly (median age 70 years; IQR 59–79) and had a median Pitt bacteremia score of 1 (IQR 0–2). The most common pathogens were E. coli (58.2%) and K. pneumoniae (17.3%) and the primary source of infection was urinary (70%). Majority of BL use consisted of cephalexin (44.7%) and cefuroxime (21.3%) while FQ use was mostly ciprofloxacin (69.8%). Infectious diseases consultations were associated with 52.8%, 39.6%, and 72.2% of the prescribed FQ, BL, and SMX/TMP, respectively. Overall median intravenous, oral, and total effective antibiotic durations were 3.9, 9, and 13 days, respectively, and were similar between each group. Ninety day treatment failure rates were 9.5% in the FQ group vs. 14.6% in the BL group (P = 0.27) and 0% in the TMP/SMX group (P = 0.35). All-cause and infection-related readmissions were similar between FQ, BL, and TMP/SMX: (25.5%, 27.1%, 16.7%; P = 0.73) and (4.7%, 5.2%, 5.6%; P = 1.0), respectively.

Conclusion
We identified similar treatment failure rates between oral FQs, BLs, and TMP/SMX. Oral step-down therapy with BLs may be a promising FQ-sparing option for the definitive treatment of GN BSIs. Limitations to TMP/SMX efficacy should be interpreted with caution due to the small sample size. Further investigations into optimal and tolerable oral dosing of such agents are needed.

Disclosures
All authors: No reported disclosures.
2738. Influenza Vaccination During Pregnancy Among Mothers of Infants with Acute Respiratory Illness, United States, 2016–2018
Authors: Ogokeh Constance E , Patel Manish , Lively Joana Y , Staat Mary A , Weinberg Geoffrey A , Boom Julie A , Englund Janet A , Williams John V , Halasa Natasha B , Selvarangan Rangaraj , Harrison Christopher J , Klein Eileen J , Schlaudecker Elizabeth P , Michaels Marian G , Sahni Leila C , Szilagyi Peter G , Stewart Laura S , Rha Brian , Beacham Lauren , Bardenheier Barbara , Payne Daniel C , Fry Alicia M , Campbell Angela P 
Published: October 2019

Abstract

Background
Influenza vaccination has been shown to reduce influenza risk in pregnant women and their infants who are not yet age-eligible for vaccine. Ascertainment of vaccination history is important for vaccine safety and effectiveness evaluations. Our goals were to (a) determine coverage, location, and timing of maternal influenza vaccination and (b) compare a subset of self-reported influenza vaccinations with documented vaccine records.

Methods
We enrolled children < 18 years. with acute respiratory illness in 7 pediatric hospitals and emergency departments in the New Vaccine Surveillance Network from December 1, 2016 to October 31, 2018. We interviewed all mothers of enrolled infants < 1 year, and obtained mother’s influenza vaccine information while pregnant. As an option, sites obtained maternal influenza vaccine records from reported sources (e.g., registries, provider records, pharmacies).

Results
Among 5,458 mothers, 2,944 (54%) self-reported receiving influenza vaccine during pregnancy (57% in 2016–2017; 51% in 2017–2018), varying from 49% to 74% by site. Among self-reported vaccinees, 17%, 36%, and 47% received vaccine during their first, second, and third trimester, respectively. Most women (76%) were vaccinated at their OB/GYN or midwife office, 7% at their primary care provider, 7% at their workplace, and 5% at a retail pharmacy. Among 1,338 infants < 6 months. during early influenza season (i.e., born from June to August) and thus ineligible for vaccination, only 46% of mothers reported receiving vaccine during pregnancy (42% reported not receiving it, 12% were unsure). Of 2,242 women for whom vaccine verification was attempted, 1,491 (67%) self-reported receiving influenza vaccine during pregnancy; of those, documentation of vaccine receipt was found for 901 (60%).

Conclusion
Influenza vaccination coverage among pregnant women was suboptimal, potentially increasing the risk of influenza in unvaccinated pregnant women. Infants born to unvaccinated women, particularly those born from June to August, may also be at higher risk since they are not age-eligible to receive vaccine before influenza season. The optimal approach to ascertainment of maternal vaccination history with accuracy and completeness merits further investigation.

Disclosures
All authors: No reported disclosures.
2744. A Phase I Randomized, Observer-Blind, Controlled, Dose Escalation Trial of the Safety and Tolerability of a Single Intramuscular Dose of a PAL Adjuvant (Laboratory Code, FB-631) Co-administered with Seasonal TIV (2013–2014) to Healthy Adults ≥18–50 Years of Age
Authors: Langley Joanne Marie , Pastural Elodie , Halperin Scott , Halperin Scott , McNeil Shelly , ElSherif May , MacKinnon-Cameron Donna , Ye Lingyun , Lapointe Rejean , McElhaney Janet , Martin Luis , Bolduc Marilène , Laliberté-Gagné Marie-Ève , LeClerc Denis , Savard Pierre 
Published: October 2019

Abstract

Background
Inactivated influenza vaccines (IV) efficacy is variable and sometimes poor. In this phase 1 trial the safety and immunogenicity of a novel nanoparticle adjuvant (Papaya Mosaic Virus (PapMV or PAL) at different dose levels combined with inactivated trivalent IV (TIV; FLUVIRAL® 2013–2014, GSK, Kirkland PQ) was assessed. Nonpathogenic in mammals, PAL is recognized as a pathogen-associated molecular pattern (PAMP) which stimulates innate, cell-mediated immunity (CMI) and adaptive immunity in naïve mice through activation of toll like receptor 7 and 8.

Methods
Healthy persons 18–50 years of age were randomized to one of 6 study groups: 30 µg, 60 µg, 120 µg or 240 µg of PAL with 0.25 mL TIV, 240 µg of PAL with 0.125 mL TIV, or control (0.5 mL TIV). Solicited local and general adverse events (AE) were collected Day (D)0 to 6, unsolicited AE to D28, and serious AE to D1095. Hemagglutination-inhibition assays (HI), antibody to Influenza A virus nucleoprotein (NP), and peripheral blood mononuclear cells (PBMC) for measurement of interferon-gamma (IFNg) ELISPOT (response to PepMix influenza A H2N2 Ann Arbour NP, MP1, and an influenza peptide pool), granzyme B, and IFNg:IL:10 ratio were collected on D0, 7, 28, 120, and 180.

Results
The most common solicited AEs were transient mild-to-moderate local pain (62.5%–87.5% of participants/group), drowsiness (≤37.5% of participants/group) and generalized muscle aches (12.5–50% of participants/group). There was one unrelated SAE. All participants had HI and anti-NP titers at baseline. HI GMTs increased at D28 post vaccine in most groups (Figure 1) and waned over time. HI fold Ab (Far) responses to TIV strains were poor in all groups (≤37.5% of participants/group had 4-Far to any strain). CMI results were consistent with humoral responses.

Conclusion
The PAL adjuvant in doses of 30 to 240µg combined with reduced TIV dosages was safe with no signals up to 3 years after vaccine. Reduced doses of TIV co-presented with 240 µg PAL had similar HI GMTs as TIV. The CMI results suggest that the assessment of PAL efficacy on TIV immunization would have to be conducted in an influenza naïve population.

Disclosures
Scott Halperin, MD, GlaxoSmithKline: Ad hoc advisory boards, Other Financial or Material Support, Research Grant; Janssen Pharm: Research Grant; sanofi pasteur: Ad hoc advisory boards, Other Financial or Material Support, Research Grant.
2750. Sequential Influenza A H1N1 and Influenza A H3N2 Challenge Infections in Healthy Volunteers
Authors: Han Alison , Giurgea Luca , Cervantes-Medina Adriana , Edwards Kristina , Rosas Luz Angela , Czajkowski Lindsay , Baus Holly Ann , Athota Rani , Reed Susan , Taubenberger Jeffery , Memoli Matthew 
Published: October 2019

Abstract

Background
Seasonal influenza causes significant annual morbidity and mortality. The effects of yearly exposures on immunity are not clear and recent observations have demonstrated that long lasting protection against a matched strain may not naturally occur. The 2018–2019 influenza season consisted of an initial peak of H1N1 infections followed by a wave of H3N2 infections. These consecutive waves raise questions about how influenza immunity is affected by sequential exposure to different influenza strains. Challenge studies provide a unique opportunity to study this phenomenon. Here we describe a subset of participants who were sequentially infected in two separate challenge studies with wild-type H1N1 and H3N2 viruses.

Methods
Healthy volunteers completed two sequential influenza challenge studies at the NIH Clinical Center. Participants were inoculated with reverse genetics, cell-based, GMP wild-type influenza viruses, A(H1N1)pdm09 and A(H3N2) strains. Participants remained isolated in the hospital for a minimum of 9 days and were monitored daily for viral shedding and clinical symptoms. After discharge, participants were followed for 2 months.

Results
Between 2014 and 2017, 14 healthy volunteers were exposed to Influenza A(H1N1) and Influenza A(H3N2). Time between infections ranged from 2 months to 2 years. Thirteen (93%) participants developed confirmed influenza infection after H1N1 challenge and 9 (64%) after H3N2 challenge. Eight (57%) participants developed confirmed infections after both exposures. Variable degrees of symptoms, shedding, and disease severity were observed. Systemic antibody responses to the HA and NA of both H1N1 and H3N2 varied over time during these sequential infections.

Conclusion
More than half of all participants who completed 2 sequential H1N1 and H3N2 challenge studies demonstrated confirmed infection to both viruses. These sequential infections had varying effects on the disease experienced and the immunity that developed after infection. These observations are important in understanding the impact of sequential exposures on influenza immunity.

Disclosures
All authors: No reported disclosures.
2755. Phase 1/2, First-in-Human Study of the Safety, Tolerability, and Immunogenicity of an RSV Prefusion F-Based Subunit Vaccine Candidate
Authors: Schmoele-Thoma Beate , Falsey Ann R , Walsh Edward E , Swanson Kena , Zareba Agnieszka , Cooper David , Gruber William C , Jansen Kathrin U , Radley David , Scott Daniel , Dormitzer Philip R 
Published: October 2019

Abstract

Background
The respiratory syncytial virus (RSV) fusion glycoprotein (F) is a molecule that fuses the viral and host cell membranes during virus entry as it rearranges from a meta-stable prefusion to a stable postfusion conformation. Using structure-guided design, Pfizer engineered a prefusion RSV F subunit vaccine antigen with stable and well-characterized conformational homogeneity.

Methods
We report results of a 1,182 subject, first-in-human, phase 1/2, placebo-controlled, randomized, observer-blind, dose-finding study to describe the safety, tolerability, and immunogenicity of the Pfizer RSV vaccine candidate in healthy men and non-pregnant women from 18 to 85 years of age. The study compares three dosages of the vaccine candidate, with and without aluminum hydroxide, and also compares immunization with the RSV vaccine candidate alone or concomitantly with influenza vaccine. The study is ongoing to collect antibody persistence and additional safety data.

Results
The data, which are currently available for the 18- to 49-year-old subgroup, demonstrate an excellent safety and tolerability profile. Immunization with the various formulations of the vaccine candidate elicited RSV 50% neutralization titer geometric mean fold rises (GMFRs) of 10.6–17.2 for subgroup A and 10.4–19.8 for subgroup B, measured one month after immunization, with evidence of a dose–response.

Conclusion
The 10- to 20-fold increases in neutralizing antibody titers elicited by this vaccine with a stable prefusion F antigen represent a step change relative to the historical performance of vaccine candidates, such as Wyeth’s PFP, with F antigens that were not stabilized in the prefusion conformation (Simoes et al., Vaccine 20:954–60, 2002). The data strongly support development of this vaccine candidate to prevent RSV disease in infants, by immunizing pregnant women, and to prevent RSV disease in older adults, by direct immunization.

Disclosures
All authors: No reported disclosures.
2761. Interventions to Improve Influenza Vaccination Coverage in Children with Medical Comorbidities: A Meta-Analysis
Authors: Norman Daniel , Barnes Rosanne , Danchin Margie , Seale Holly , Moore Hannah C , Blyth Christopher C 
Published: October 2019

Abstract

Background
Influenza vaccination is the most effective influenza prevention tool for children with medical comorbidities. Despite this, coverage remains inadequate. Numerous interventions to improve vaccination coverage have been assessed, yet there remains a paucity of data comparing the relative efficacy and effectiveness of different interventions.

Methods
We searched MEDLINE, PubMed, Scopus, Embase, CINAHL, CENTRAL, and Web of Science (1980 to March 2019) for studies evaluating interventions which sought to improve influenza vaccine coverage in children with medical comorbidities. Interventions were divided into those targeting parents, targeting vaccination providers, and targeting the hospital, clinic or ward. Screening and data extraction from publications meeting inclusion criteria was performed by two reviewers. Results were pooled and meta-analyses were performed using Mantel–Haenszel random-effects models in Review Manager 5.

Results
35 articles met inclusion criteria; 14 cross-sectional, 12 randomized trials, and 9 cohort studies, 25 articles had sufficient data for pooled analysis. Of the included interventions, 17 were based within primary care or community-based settings, 17 were based in hospitals or tertiary clinics, and 1 intervention was conducted across both primary and tertiary settings. Interventions overall increased influenza vaccination likelihood by 33% (RR = 1.33: 95% CI 1.31, 1.35). Interventions targeting providers’ influenza vaccine knowledge increased vaccine coverage (RR = 1.42: 95% CI 1.36, 1.49) greater than those targeting parental knowledge (RR = 1.23: 95% CI 1.21, 1.26). Conversely, vaccination reminders targeting parents increased vaccine coverage (RR = 1.53: 95% CI 1.49, 1.58) greater than reminders targeting providers (RR = 1.23: 95% CI 1.20, 1.27). Interventions targeting hospitals, clinics or ward processes had the weakest impact on coverage (RR = 1.15: 95% CI 1.13, 1.17).

Conclusion
Interventions targeting parents, providers, and places individually have all shown to improve influenza vaccination in children with medical comorbidities. However, specifically targeting providers’ vaccine knowledge and parental reminders appear to have the greatest impact on vaccine uptake.

Disclosures
All authors: No reported disclosures.
2763. Uptake and Safety of Measles-Mumps-Rubella (MMR) Vaccine in Adolescents and Adults in the Vaccine Safety Datalink
Authors: Hanson Kayla E , McLean Huong , Marin Mona , Panagiotakopoulos Lakshmi , Weintraub Eric , Daley Matthew F , Groom Holly , Jackson Lisa , Jacobsen Steven J , Klein Nicola , Nordin James D , Belongia Edward 
Published: October 2019

Abstract

Background
MMR vaccine is given routinely to young children but may be given at other ages. We described MMR use in adolescent and adult populations in the Vaccine Safety Datalink (VSD) and estimated the incidence of medically-attended outcomes after MMR to inform future studies estimating vaccine-associated risk.

Methods
The study population included adolescents (9–17 years) and adults (≥18 years) in VSD who received at least one MMR vaccine from 2010 through 2016. Outcomes were pre-specified based on previous vaccine safety studies and categorized as clinically serious (anaphylaxis, encephalitis/myelitis, GBS, meningitis, seizure) or non-serious (allergic reaction, arthropathy, fever, injection site reaction, lymphadenopathy, nonspecific reaction, parotitis, rash, syncope). Outcomes were identified by searching for ICD-9 and ICD-10 diagnosis codes in post-vaccination exposure windows. Medical records were reviewed for all serious outcomes to verify incident diagnoses. Incidence and 95% confidence intervals were calculated for validated serious and all non-serious outcomes.

Results
146,503 adolescents and adults received 162,992 MMR vaccines during the study period. The mean age at vaccination was 33.7 years, 65% were female, and 53% received at least one other vaccine simultaneously. Demographic and vaccination characteristics varied across age groups (Table 1). The analysis of post-vaccination outcomes included 162,053 MMR vaccinations. The incidence of validated serious outcomes was low, ranging from 0 to 6.8 per 100,000 vaccinations. Only one serious outcome (anaphylaxis) was noted to be vaccine-associated in the medical record. Incidence of clinically non-serious outcomes varied from 0.4 to 56.0 per 10,000 vaccinations. Injection site reactions were more common among adolescents (118.1 per 10,000 vaccinations), who also had a higher frequency of simultaneous vaccination (80%).

Conclusion
Clinically serious outcomes were rare following MMR vaccination. Rates of clinically non-serious outcomes varied but were similar to or lower than previous reports in children. This descriptive analysis did not evaluate the association between MMR and adverse events. Future analysis with an appropriate comparison group is needed for risk estimation.

Disclosures
All authors: No reported disclosures.