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Importance: Chikungunya virus (CHIKV) is a mosquito-borne Alphavirus prevalent worldwide. There are currently no licensed vaccines or therapies.Objective: To evaluate the safety and tolerability of an investigational CHIKV virus-like particle (VLP) vaccine in endemic regions.Design, Setting, and Participants: This was a randomized, placebo-controlled, double-blind, phase 2 clinical trial to assess the vaccine VRC-CHKVLP059-00-VP (CHIKV VLP). The trial was conducted at 6 outpatient clinical research sites located in Haiti, Dominican Republic, Martinique, Guadeloupe, and Puerto Rico. A total of 400 healthy adults aged 18 through 60 years were enrolled after meeting eligibility criteria. The first study enrollment occurred on November 18, 2015; the final study visit, March 6, 2018.Interventions: Participants were randomized 1:1 to receive 2 intramuscular injections 28 days apart (20 µg, n = 201) or placebo (n = 199) and were followed up for 72 weeks.Main Outcomes and Measures: The primary outcome was the safety (laboratory parameters, adverse events, and CHIKV infection) and tolerability (local and systemic reactogenicity) of the vaccine, and the secondary outcome was immune response by neutralization assay 4 weeks after second vaccination.Results: Of the 400 randomized participants (mean age, 35 years; 199 [50%] women), 393 (98%) completed the primary safety analysis. All injections were well tolerated. Of the 16 serious adverse events unrelated to the study drugs, 4 (25%) occurred among 4 patients in the vaccine group and 12 (75%) occurred among 11 patients in the placebo group. Of the 16 mild to moderate unsolicited adverse events that were potentially related to the drug, 12 (75%) occurred among 8 patients in the vaccine group and 4 (25%) occurred among 3 patients in the placebo group. All potentially related adverse events resolved without clinical sequelae. At baseline, there was no significant difference between the effective concentration (EC50)-which is the dilution of sera that inhibits 50% infection in viral neutralization assay-geometric mean titers (GMTs) of neutralizing antibodies of the vaccine group (46; 95% CI, 34-63) and the placebo group (43; 95% CI, 32-57). Eight weeks following the first administration, the EC50 GMT in the vaccine group was 2005 (95% CI, 1680-2392) vs 43 (95% CI, 32-58; P < .001) in the placebo group. Durability of the immune response was demonstrated through 72 weeks after vaccination.Conclusions and Relevance: Among healthy adults in a chikungunya endemic population, a virus-like particle vaccine compared with placebo demonstrated safety and tolerability. Phase 3 trials are needed to assess clinical efficacy.Trial Registration: ClinicalTrials.gov Identifier: NCT02562482. [ABSTRACT FROM AUTHOR]

Background: Seasonal influenza results in significant morbidity and mortality worldwide, but the currently licensed inactivated vaccines generally have low vaccine efficacies and could be improved. In this phase 1 clinical trial, we compared seasonal influenza vaccine regimens with different priming strategies, prime-boost intervals, and administration routes to determine the impact of these variables on the resulting antibody response. Methods: Between August 17, 2012 and January 25, 2013, four sites enrolled healthy adults 18–70 years of age. Subjects were randomized to receive one of the following vaccination regimens: trivalent hemagglutinin (HA) DNA prime followed by trivalent inactivated influenza vaccine (IIV3) boost with a 3.5 month interval (DNA-IIV3), IIV3 prime followed by IIV3 boost with a 10 month interval (IIV3-IIV3), or concurrent DNA and IIV3 prime followed by IIV3 boost with a 10 month interval (DNA/IIV3-IIV3). Each regimen was additionally stratified by an IIV3 administration route of either intramuscular (IM) or intradermal (ID). DNA vaccines were administered by a needle-free jet injector (Biojector). Study objectives included evaluating the safety and tolerability of each regimen and measuring the antibody response by hemagglutination inhibition (HAI). Results: Three hundred and sixteen subjects enrolled. Local reactogenicity was mild to moderate in severity, with higher frequencies recorded following DNA vaccine administered by Biojector compared to IIV3 by either route (p <0.02 for pain, swelling, and redness) and following IIV3 by ID route compared to IM route (p <0.001 for swelling and redness). Systemic reactogenicity was similar between regimens. Though no overall differences were observed between regimens, the highest titers post boost were observed in the DNA-IIV3 group by ID route and in the IIV3-IIV3 group by IM route. Conclusions: All vaccination regimens were found to be safe and tolerable. While there were no overall differences between regimens, the DNA-IIV3 group by ID route, and the IIV3-IIV3 group by IM route, showed higher responses compared to the other same-route regimens. [ABSTRACT FROM AUTHOR]

Background: mAb114 is a single monoclonal antibody that targets the receptor-binding domain of Ebola virus glycoprotein, which prevents mortality in rhesus macaques treated after lethal challenge with Zaire ebolavirus. Here we present expedited data from VRC 608, a phase 1 study to evaluate mAb114 safety, tolerability, pharmacokinetics, and immunogenicity.Methods: In this phase 1, dose-escalation study (VRC 608), conducted at the US National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA), healthy adults aged 18-60 years were sequentially enrolled into three mAb114 dose groups of 5 mg/kg, 25 mg/kg, and 50 mg/kg. The drug was given to participants intravenously over 30 min, and participants were followed for 24 weeks. Participants were only enrolled into increased dosing groups after interim safety assessments. Our primary endpoints were safety and tolerability, with pharmacokinetic and anti-drug antibody assessments as secondary endpoints. We assessed safety and tolerability in all participants who received study drug by monitoring clinical laboratory data and self-report and direct clinician assessment of prespecified infusion-site symptoms 3 days after infusion and systemic symptoms 7 days after infusion. Unsolicited adverse events were recorded for 28 days. Pharmacokinetic and anti-drug antibody assessments were completed in participants with at least 56 days of data. This trial is registered with ClinicalTrials.gov, number NCT03478891, and is active but no longer recruiting.Findings: Between May 16, and Sept 27, 2018, 19 eligible individuals were enrolled. One (5%) participant was not infused because intravenous access was not adequate. Of 18 (95%) remaining participants, three (17%) were assigned to the 5 mg/kg group, five (28%) to the 25 mg/kg group, and ten (55%) to the 50 mg/kg group, each of whom received a single infusion of mAb114 at their assigned dose. All infusions were well tolerated and completed over 30-37 min with no infusion reactions or rate adjustments. All participants who received the study drug completed the safety assessment of local and systemic reactogenicity. No participants reported infusion-site symptoms. Systemic symptoms were all mild and present only in four (22%) of 18 participants across all dosing groups. No unsolicited adverse events occurred related to mAb114 and one serious adverse event occurred that was unrelated to mAb114. mAb114 has linear pharmacokinetics and a half-life of 24·2 days (standard error of measurement 0·2) with no evidence of anti-drug antibody development.Interpretation: mAb114 was well tolerated, showed linear pharmacokinetics, and was easily and rapidly infused, making it an attractive and deployable option for treatment in outbreak settings.Funding: Vaccine Research Center, US National Institute of Allergy and Infectious Diseases, and NIH. [ABSTRACT FROM AUTHOR]

BACKGROUNDBroadly neutralizing monoclonal antibodies (bNAbs) represent a promising strategy for HIV-1 immunoprophylaxis and treatment. 10E8VLS and VRC07-523LS are bNAbs that target the highly conserved membrane-proximal external region (MPER) and the CD4-binding site of the HIV-1 viral envelope glycoprotein, respectively.METHODSIn this phase 1, open-label trial, we evaluated the safety and pharmacokinetics of 5 mg/kg 10E8VLS administered alone, or concurrently with 5 mg/kg VRC07-523LS, via s.c. injection to healthy non-HIV-infected individuals.RESULTSEight participants received either 10E8VLS alone (n = 6) or 10E8VLS and VRC07-523LS in combination (n = 2). Five (n = 5 of 8, 62.5%) participants who received 10E8VLS experienced moderate local reactogenicity, and 1 participant (n = 1/8, 12.5%) experienced severe local reactogenicity. Further trial enrollment was stopped, and no participant received repeat dosing. All local reactogenicity resolved without sequelae. 10E8VLS retained its neutralizing capacity, and no functional anti-drug antibodies were detected; however, a serum t1/2 of 8.1 days was shorter than expected. Therefore, the trial was voluntarily stopped per sponsor decision (Vaccine Research Center, National Institute of Allergy and Infectious Diseases [NIAID], NIH). Mechanistic studies performed to investigate the underlying reason for the reactogenicity suggest that multiple mechanisms may have contributed, including antibody aggregation and upregulation of local inflammatory markers.CONCLUSION10E8VLS resulted in unexpected reactogenicity and a shorter t1/2 in comparison with previously tested bNAbs. These studies may facilitate identification of nonreactogenic second-generation MPER-targeting bNAbs, which could be an effective strategy for HIV-1 immunoprophylaxis and treatment.TRIAL REGISTRATIONClinicaltrials.gov, accession no. NCT03565315.FUNDINGDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.

Background: Human monoclonal antibodies that potently and broadly neutralise HIV-1 are under development to prevent and treat HIV-1 infection. In this phase 1 clinical trial we aimed to determine the safety, tolerability, and pharmacokinetic profile of the broadly neutralising monoclonal antibody VRC07-523LS, an engineered variant of VRC01 that targets the CD4 binding site of the HIV-1 envelope protein., Methods: This phase 1, open-label, dose-escalation clinical trial was done at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Individuals were recruited from the greater Washington, DC, area by IRB-approved written and electronic media. We enrolled healthy, HIV-1-negative adults aged 18-50 years. Inclusion criteria were good general health, measured through clinical laboratory tests, medical history, and physical examination. Participants self-selected into one of seven open groups during enrolment without randomisation. Four groups received a single intravenous dose of 1, 5, 20, or 40 mg/kg of VRC07-523LS, and one group received a single 5 mg/kg subcutaneous dose. Two groups received three doses of either 20 mg/kg intravenous VRC07-523LS, or 5 mg/kg subcutaneous VRC07-523LS at 12-week intervals. The primary outcome was the safety and tolerability of VRC07-523LS, assessed by dose, route, and number of administrations. This study is registered with ClinicalTrials.gov, NCT03015181., Findings: Between Feb 21, 2017, and September 13, 2017, we enrolled 26 participants, including 11 (42%) men and 15 (58%) women. Two (8%) participants withdrew from the study early: one participant in group 1 enrolled in the study but never received VRC07-523LS, and one participant in group 6 chose to withdraw after a single administration. One (4%) participant in group 7 received only one of the three scheduled administrations. 17 participants received intravenous administrations and 8 participants received subcutaneous administrations. VRC07-523LS was safe and well tolerated, we observed no serious adverse events or dose-limiting toxic effects. All reported local and systemic reactogenicity was mild to moderate in severity. The most commonly reported symptoms following intravenous administration were malaise or myalgia in three (18%) participants and headache or chills in two (12%) participants. The most commonly reported symptoms following subcutaneous administration were pain and tenderness in four participants (50%) and malaise or headache in three (38%) participants., Interpretation: Safe and well tolerated, VRC07-523LS is a strong and practical candidate for inclusion in HIV-1 prevention and therapeutic strategies. The results from this trial also indicate that an HIV-1 broadly neutralising monoclonal antibody engineered for improved pharmacokinetic and neutralisation properties can be safe for clinical use., Funding: National Institutes of Health., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: The Council on Medical Student Education in Pediatrics and Association of Pediatric Program Directors developed a Pediatric Subinternship (CAPS) curriculum for use with an individualized learning plan (ILP). The authors determined which learning objectives (LOs) pediatric subinterns selected when provided the CAPS curriculum, summarized students' self-reported progress, and determined feasibility of ILPs in subinternship., Methods: Students from 10 medical schools completed a standardized ILP during pediatric subinternship. Students listed ≥3 LOs using CAPS curriculum as a guide and self-assessed their progress. Students reviewed ILPs with faculty preceptors; preceptors completed questionnaires on time and effort spent. Authors mapped student LOs to CAPS curriculum objectives and grouped in Accreditation Council for Graduate Medical Education competency domains., Results: Two hundred four students documented 850 LOs. Authors mapped student LOs to 61 of the 69 CAPS objectives (88%). Students most commonly chose Patient Care LOs, with the top 3 related to oral presentations, time management, and management plans. Student LOs not in CAPS addressed nutrition, child development, test interpretation, and cost. No students chose LOs related to health disparities, shared decision making, informed consent, or patient safety. Students self-reported significant progress on most LOs (73%). Faculty met with students ≥1 time and 93% met for a total of ≤1 hour. According to faculty, students required little or no help completing ILPs., Conclusions: Students chose a wide range of LOs when provided the CAPS curriculum. Revision to include additional student-identified LOs would enhance CAPS curriculum's comprehensiveness. Using this curriculum with an ILP during subinternship is feasible, but gaps between educator-identified and student-identified objectives require further exploration., (Copyright © 2018 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Oral case presentations provide an opportunity for trainees to communicate diagnostic reasoning at the bedside. However, few tools exist to enable faculty to provide effective feedback. We developed a tool to assess diagnostic reasoning and communication during oral case presentations., (Published by Elsevier Inc.)