Integrating Electronic Medical Records and Claims Data for Influenza Vaccine Research.

Real-world evidence (RWE) increasingly informs public health and healthcare decisions worldwide. A large database has been created (“Integrated Dataset”) that integrates primary care electronic medical records with pharmacy and medical claims data on >123 million US patients since 2014. This article describes the components of the Integrated Dataset and evaluates its representativeness to the US population and its potential use in evaluating influenza vaccine effectiveness.

Pivotal Vaccine Efficacy Trials-Study Design Considerations from a Vaccine Trial Design Working Group.

Vaccine candidates for are approaching phase 3 clinical trials in the target population of young children living in low- and middle-income countries. Key study design decisions will need to be made to maximize the success of such trials and minimize the time to licensure and implementation. We convened an ad hoc working group to identify the key aspects of trial design that would meet the regulatory requirements to achieve the desired indication of prevention of moderate or severe shigellosis due to strains included in the vaccine.

Immunogenicity of aIIV3, MF59-adjuvanted seasonal trivalent influenza vaccine, in older adults ≥65 years of age: Meta-analysis of cumulative clinical experience.

Objective: Compare the immunogenicity of MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3; Fluad™) versus conventional trivalent inactivated influenza vaccine (IIV3) in an integrated dataset using a meta-analysis.

Methods: In a meta-analysis, the immunogenicity of aIIV3 in subjects ≥65 years of age was compared with IIV3 immunogenicity using hemagglutination inhibition assay results from 23 phase I through III randomized controlled trials, including 16 first-dose vaccination studies and 7 revaccination studies assessing immunogenicity after second or third annual vaccination.

Results: The full analysis set consisted of 11,105 subjects (5869 aIIV3 and 5236 IIV3).

Analysis of the Risks and Benefits of New Chemical Entities Approved by the US Food and Drug Administration (FDA) and Subsequently Withdrawn From the US Market.

Benefit-risk evaluations of drugs have been conducted since the introduction of modern regulatory systems more than 50 years ago. Such judgments are typically made on the basis of qualitative or semiquantitative approaches, often without the aid of quantitative assessment methods, the latter having often been applied asymmetrically to place emphasis on benefit more so than harm. In an effort to preliminarily evaluate the utility of lives lost or saved, or quality-adjusted life-years (QALY) lost and gained as a means of quantitatively assessing the potential benefits and risks of a new chemical entity, we focused our attention on the unique scenario in which a drug was initially approved based on one set of data, but later withdrawn from the market based on a second set of data.

Safety and Immunogenicity of a Recombinant Influenza Vaccine: A Randomized Trial.

Objectives: The recombinant influenza vaccine is well established in adults ≥18 years of age for preventing seasonal influenza disease. In this randomized controlled trial, we compared the safety and immunogenicity of the quadrivalent, recombinant influenza vaccine (RIV4) versus the inactivated influenza vaccine in children and adolescents 6 to 17 years of age.

Methods: Two age cohorts were enrolled sequentially: 159 subjects aged 9 to 17 years and, after reviewing for safety, 60 children aged 6 to 8 years.

Randomized Comparison of Immunogenicity and Safety of Quadrivalent Recombinant Versus Inactivated Influenza Vaccine in Healthy Adults 18-49 Years of Age.

Background: Seasonal influenza vaccines are transitioning to quadrivalent formulations including the hemagglutinins of influenza A subtypes H1N1 and H3N2 and B lineages Yamagata and Victoria.

Methods: A new quadrivalent recombinant influenza vaccine (RIV4) was compared directly with a standard-dose, egg-grown, quadrivalent-inactivated influenza vaccine (IIV4) for immunogenicity and safety in adults 18-49 years of age. The coprimary endpoints for noninferiority were hemagglutination inhibition seroconversion rates and postvaccination geometric mean titer ratios for each antigen using US regulatory criteria.

Efficacy of Recombinant Influenza Vaccine in Adults 50 Years of Age or Older.

Background: Improved influenza vaccines are needed to control seasonal epidemics. This trial compared the protective efficacy in older adults of a quadrivalent, recombinant influenza vaccine (RIV4) with a standard-dose, egg-grown, quadrivalent, inactivated influenza vaccine (IIV4) during the A/H3N2-predominant 2014-2015 influenza season, when antigenic mismatch between circulating and vaccine influenza strains resulted in the reduced effectiveness of many licensed vaccines.

Methods: We conducted a randomized, double-blind, multicenter trial of RIV4 (45 μg of recombinant hemagglutinin [HA] per strain, 180 μg of protein per dose) versus standard-dose IIV4 (15 μg of HA per strain, 60 μg of protein per dose) to compare the relative vaccine efficacy against reverse-transcriptase polymerase-chain-reaction (RT-PCR)-confirmed, protocol-defined, influenza-like illness caused by any influenza strain starting 14 days or more after vaccination in adults who were 50 years of age or older.

Stable emulsion (SE) alone is an effective adjuvant for a recombinant, baculovirus-expressed H5 influenza vaccine in healthy adults: A Phase 2 trial.

Background: Influenza A viruses of the H5 subtype have been identified as important targets for development of vaccines. Achievement of potentially protective antibody responses against pandemic strains has usually required the use of adjuvants.

Objectives: We evaluated a candidate A/Indonesia/05/2005 (H5) vaccine generated by baculovirus expression of recombinant hemagglutinin (HA) protein with or without stable emulsion (SE) as an adjuvant.

Randomized comparison of the safety of Flublok(®) versus licensed inactivated influenza vaccine in healthy, medically stable adults ≥ 50 years of age.

Background: The safety and tolerability of Flublok(®), a purified recombinant hemagglutinin seasonal influenza vaccine, was compared to AFLURIA(®) in a randomized, blinded clinical trial in adults ≥ 50 years of age with attention to hypersensitivity reactions.

Methods: This blinded, randomized trial of healthy adults ≥ 50 years of age compared safety of Flublok vs. AFLURIA with respect to pre-specified possible hypersensitivity: "rash," "urticaria," "swelling" and "non-dependent edema;" solicited reactogenicity and unsolicited adverse events.

Characterisation of a wild-type influenza (A/H1N1) virus strain as an experimental challenge agent in humans.

Background: Human challenge models using respiratory viruses such as influenza are increasingly utilised in the development of novel vaccines and anti-viral modalities and can provide preliminary evidence of protection before evaluation in field trials. We describe the results of a clinical study characterising an A/H1N1 influenza challenge virus in humans.

Methods: The challenge agent, influenza A/California/2009 (H1N1), was manufactured under cGMP conditions and characterised in accordance with regulatory guidelines.

Evaluation of safety and immunogenicity of recombinant influenza hemagglutinin (H5/Indonesia/05/2005) formulated with and without a stable oil-in-water emulsion containing glucopyranosyl-lipid A (SE+GLA) adjuvant.

Background: Expression of recombinant hemagglutinin (rHA) in insect cells represents a technology with proven efficacy in seasonal influenza and with the potential for a rapid response to the emergence of new, pandemic strains. We evaluated the safety and immunogenicity of rHA vaccine (H5/Indonesia/5/05) produced in SF+ insect cells using a baculovirus expression vector system (BEVS). The rHA vaccine was tested with and without the adjuvant glucopyranosyl lipid A/stable emulsion (GLA/SE).

Review and assessment of poliovirus immunity and transmission: synthesis of knowledge gaps and identification of research needs.

With the intensifying global efforts to eradicate wild polioviruses, policymakers face complex decisions related to achieving eradication and managing posteradication risks. These decisions and the expanding use of inactivated poliovirus vaccine (IPV) trigger renewed interest in poliovirus immunity, particularly the role of mucosal immunity in the transmission of polioviruses. Sustained high population immunity to poliovirus transmission represents a key prerequisite to eradication, but poliovirus immunity and transmission remain poorly understood despite decades of studies.

Expert review on poliovirus immunity and transmission.

Successfully managing risks to achieve wild polioviruses (WPVs) eradication and address the complexities of oral poliovirus vaccine (OPV) cessation to stop all cases of paralytic poliomyelitis depends strongly on our collective understanding of poliovirus immunity and transmission. With increased shifting from OPV to inactivated poliovirus vaccine (IPV), numerous risk management choices motivate the need to understand the tradeoffs and uncertainties and to develop models to help inform decisions. The U.

Protective efficacy of a trivalent recombinant hemagglutinin protein vaccine (FluBlok®) against influenza in healthy adults: a randomized, placebo-controlled trial.

Background: Development of influenza vaccines that do not use embryonated eggs as the substrate for vaccine production is a high priority. We conducted this study to determine the protective efficacy a recombinant, baculovirus-expressed seasonal trivalent influenza virus hemagglutinin (rHA0) vaccine (FluBlok(®)).

Methods: Healthy adult subjects at 24 centers across the US were randomly assigned to receive a single injection of saline placebo (2304 subjects), or trivalent FluBlok containing 45 mcg of each rHA0 component (2344 subjects).

Evaluation of the safety, reactogenicity and immunogenicity of FluBlok® trivalent recombinant baculovirus-expressed hemagglutinin influenza vaccine administered intramuscularly to healthy adults 50-64 years of age.

Background: Alternative methods for influenza vaccine production are needed to ensure adequate supplies.

Methods: Healthy adults 50-64 years were assigned randomly to receive one intramuscular injection of trivalent recombinant hemagglutinin (rHA) or U.S.

Comparative immunogenicity of recombinant influenza hemagglutinin (rHA) and trivalent inactivated vaccine (TIV) among persons > or =65 years old.

Alternative substrates for influenza vaccine production are needed to ensure adequate supplies. We evaluated the relative safety and immunogenicity of recombinant hemagglutinin (rHA) or trivalent inactivated vaccine (TIV) among 869 > or =65-year-old subjects in a randomized clinical trial. Virologic surveillance for influenza-like illness (ILI) was conducted during the 2006-2007 epidemic.

Evaluation of the safety, reactogenicity and immunogenicity of FluBlok trivalent recombinant baculovirus-expressed hemagglutinin influenza vaccine administered intramuscularly to healthy children aged 6-59 months.

Background: Recombinant baculovirus-expressed hemagglutinin (rHA [FluBlok]) influenza vaccine is unique in avoiding production in eggs and its rapid production capability.

Objective: Compare the safety and immunogenicity of trivalent FluBlok to egg-grown trivalent influenza vaccine (TIV) in children.

Methods: Healthy children were randomized to receive two doses of study vaccines.

FluBlok, a recombinant hemagglutinin influenza vaccine.

FluBlok, a recombinant trivalent hemagglutinin (HA) vaccine produced in insect cell culture using the baculovirus expression system, provides an attractive alternative to the current egg-based trivalent inactivated influenza vaccine (TIV) manufacturing process. FluBlok contains three times more HA than TIV and does not contain egg-protein or preservatives. This review discusses the four main clinical studies that were used to support licensure of FluBlok under the 'Accelerated Approval' mechanism in the United States.

Common methodology is inadequate for studies on the microbicidal activity of neutrophils.

Microbicidal activity of neutrophils is usually measured by colony-counting techniques after cell lysis in distilled water. While studying the effect of the reduced nicotinamide adenine dinucleotide phosphate-oxidase inhibitor diphenyleneiodonium (DPI) on the staphylocidal activity of neutrophils, we obtained inconsistent results: various degrees of inhibition in some experiments and no effect in others. The lysis step, i.

Genetic studies on myeloperoxidase deficiency in Italy.

Hereditary myeloperoxidase (MPO) deficiency is the most common neutrophil biochemical defect characterized by the lack of peroxidase activity. In order to extend the epidemiological studies on hereditary MPO deficiency in Italy, approximately 40,000 individuals were analyzed and 7 partial and 8 total MPO deficient subjects were identified. The genetic characterization of the subjects showed the presence of 3 already-known mutations (c.

Genetic characterization of myeloperoxidase deficiency in Italy.

Hereditary myeloperoxidase (MPO) deficiency (MPOD) is the most common neutrophil biochemical defect, and is characterized by a lack of peroxidase activity. In order to extend the epidemiological studies on hereditary MPOD in Italy, a population screening was carried out to detect mutations in the MPO gene. Of approximately 40,000 individuals analyzed, seven partial and eight total MPO-deficient subjects were identified.

A single-step, sensitive flow cytofluorometric assay for the simultaneous assessment of membrane-bound and ingested Candida albicans in phagocytosing neutrophils.

Background: Distinguishing ingested particles from those attached to the cell surface is an essential requirement when performing quantitative studies of phagocytosis. In the present report, we describe a simple, sensitive and reliable flow cytofluorometric method that achieves this goal in a Candida albicans-human neutrophils (PMN) system.

Methods: The assay is based on the observation that the vital dye trypan blue (TB), while quenching the green fluorescence of fluorescein-labeled C.

Evidence that elastase is the TNF-R75 shedding enzyme in resting human polymorphonuclear leukocytes.

We previously showed that a metalloprotease and a serine protease mediate shedding of the TNF-R75 (75-kDa tumor necrosis factor receptor) in neutrophils. Here we show that elastase is the TNF-R75 solubilizing serine protease. Release of the TNF-R75 by resting cells was almost totally inhibited by the serine protease inhibitor diisopropylfluorophosphate (DFP), by two synthetic, chemically unrelated, elastase-specific inhibitors and by alpha1-protease inhibitor.