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ABSTRACT.Objective. To ascertain current diagnostic and treatment practices for suspected late-onset sepsis in infants in neonatal intensive care units (NICUs) and identify areas that may benefit from clinical practice guidelines.Methods. During June 2000, we conducted a multicenter survey of neonatologists and infection control professionals regarding practices related to late-onset sepsis in NICUs at children's hospitals participating in the Pediatric Prevention Network.Results. Personnel at 35 hospitals with NICUs completed surveys; 34 were infection control professionals, and 278 were neonatology clinicians, primarily attending neonatologists or neonatology fellows. At these facilities, coagulase-negative staphylococci (CoNS) were the most frequent blood culture isolate from infants with lateonset sepsis accounting for 54% of bloodstream infections. When late-onset sepsis was suspected, 83% of clinicians drew only 1 blood culture when no central venous catheter was present or when a central vascular was present with no blood return. Thirty-two percent obtained 1 or more C-reactive protein concentration determinations. Sixty percent of clinicians prescribed a vancomycin-containing regimen for a 900 g, 3-week-old infant with suspected late-onset sepsis. The presence of a central venous catheter or shock increased empiric vancomycin use. The presence of methicillin-resistant Staphylococcus aureus in the NICU did not increase vancomycin use, but a vancomycin restriction policy decreased empiric vancomycin use. Clinicians at an individual NICU tended to have similar empiric antibiotic-prescribing practices: in 29 (83%) of 35 centers >75% of respondents had similar practice with regard to prescribing a vancomycin-containing regimen for empiric therapy. Forty-seven percent to 85% completed a full course of antimicrobials when a single blood culture was obtained and grew CoNS, but a significantly lower percentage of respondents (22%-47%) completed a full course when 1 of 2 blood cultures obtained grew CoNS. Eleven percent of respondents removed an umbilical catheter at the time of suspected sepsis, but fewer than 5% removed a nonumbilical central venous catheter for suspected sepsis. L ate-onset sepsis-invasive infection occurring in neonates older than 3 days-occurs in approximately 10% of all neonates and in Ͼ25% of very low birth weight infants (Յ1500 g) who are hospitalized in neonatal intensive care units (NICUs). 1 In NICUs, these infections are often associated with vascular catheters, and coagulase-negative staphylococci (CoNS) are the most commonly reported pathogens, accounting for Ͼ50% of bloodstream infections. 2,3 In this setting, the vast majority of CoNS are resistant to methicillin. NICU infants with suspected late-onset sepsis are typically treated with empiric antimicrobial therapy that often includes vancomycin. However, there are national recommendations that vancomycin use in hospitals be restricted because exposure of patients to vancomycin is a risk factor for emergence of vancomycinresistant ...

This is the first U.S. national multicenter description of antimicrobial use in NICUs and PICUs and demonstrates the high prevalence of antimicrobial use among these patients. Assessment strategies targeting antimicrobial use in pediatrics are needed.

The safety, immunogenicity, and efficacy of DNA and modified vaccinia virus Ankara (MVA) prime-boost regimes were assessed by using either thrombospondin-related adhesion protein (TRAP) with a multipleepitope string ME (ME-TRAP) or the circumsporozoite protein (CS) of Plasmodium falciparum. Sixteen healthy subjects who never had malaria (malaria-naive subjects) received two priming vaccinations with DNA, followed by one boosting immunization with MVA, with either ME-TRAP or CS as the antigen. Immunogenicity was assessed by ex vivo gamma interferon (IFN-␥) enzyme-linked immunospot assay (ELISPOT) and antibody assay. Two weeks after the final vaccination, the subjects underwent P. falciparum sporozoite challenge, with six unvaccinated controls. The vaccines were well tolerated and immunogenic, with the DDM-ME TRAP regimen producing stronger ex vivo IFN-␥ ELISPOT responses than DDM-CS. One of eight subjects receiving the DDM-ME TRAP regimen was completely protected against malaria challenge, with this group as a whole showing significant delay to parasitemia compared to controls (P ‫؍‬ 0.045). The peak ex vivo IFN-␥ ELISPOT response in this group correlated strongly with the number of days to parasitemia (P ‫؍‬ 0.033). No protection was observed in the DDM-CS group. Prime-boost vaccination with DNA and MVA encoding ME-TRAP but not CS resulted in partial protection against P. falciparum sporozoite challenge in the present study.Malaria remains one of the world's major killers of children (26), and a vaccine is urgently required. There are several lines of evidence that implicate T cells in the control of pre-erythrocytic malaria infection in mice (18, 38) and humans (16,17). Recent years have seen the development of vaccine strategies aiming to induce significant levels of cellular responses.DNA vaccines alone have shown efficacy in both murine (15, 40) and nonhuman primate (6, 52) studies in controlling malaria, many other infectious diseases, cancers, and autoimmune diseases (10). Clinical trials have confirmed the safety of DNA vaccines used alone encoding either the pre-erythrocytic malaria circumsporozoite (CS) protein (13, 24) or the thrombospondin-related adhesion protein (TRAP) (30), but the magnitude of the cellular response induced in humans by DNA vaccines alone has been considerably lower than in animal studies (52, 53) and insufficient to be protective against experimental malaria challenge. Heterologous prime-boost immunization strategies, using sequential administration of different antigen delivery systems encoding the same epitopes or antigen, have been shown to induce enhanced and persistent levels of CD8 ϩ T cells and Th1-type CD4 ϩ T cells, which are protective against murine models of malaria (25,38,41). This approach has also been applied to animal models for a range of intracellular diseases including human immunodeficiency virus infection (1, 4, 21), Ebola virus infection (47), hepatitis B (33), and tuberculosis (28). The aim of the present study was to evaluate two DNA-MVA heterologous prime...

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BackgroundA protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge.Methodology/Principal FindingsNMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected.SignificanceThe NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection.Trial Registration ClinicalTrials.gov NCT00392015

BackgroundThe Comprehensive T Cell Vaccine Immune Monitoring Consortium (CTC-VIMC) was created to provide standardized immunogenicity monitoring services for HIV vaccine trials. The ex vivo interferon-gamma (IFN-γ) ELISpot is used extensively as a primary immunogenicity assay to assess T cell-based vaccine candidates in trials for infectious diseases and cancer. Two independent, GCLP-accredited central laboratories of CTC-VIMC routinely use their own standard operating procedures (SOPs) for ELISpot within two major networks of HIV vaccine trials. Studies are imperatively needed to assess the comparability of ELISpot measurements across laboratories to benefit optimal advancement of vaccine candidates.MethodsWe describe an equivalence study of the two independently qualified IFN-g ELISpot SOPs. The study design, data collection and subsequent analysis were managed by independent statisticians to avoid subjectivity. The equivalence of both response rates and positivity calls to a given stimulus was assessed based on pre-specified acceptance criteria derived from a separate pilot study.FindingsDetection of positive responses was found to be equivalent between both laboratories. The 95% C.I. on the difference in response rates, for CMV (−1.5%, 1.5%) and CEF (−0.4%, 7.8%) responses, were both contained in the pre-specified equivalence margin of interval [−15%, 15%]. The lower bound of the 95% C.I. on the proportion of concordant positivity calls for CMV (97.2%) and CEF (89.5%) were both greater than the pre-specified margin of 70%. A third CTC-VIMC central laboratory already using one of the two SOPs also showed comparability when tested in a smaller sub-study.InterpretationThe described study procedure provides a prototypical example for the comparison of bioanalytical methods in HIV vaccine and other disease fields. This study also provides valuable and unprecedented information for future vaccine candidate evaluations on the comparison and pooling of ELISpot results generated by the CTC-VIMC central core laboratories.