Universal Vaccines: Shifting to One for Many

Human vaccines, with their exquisite antigenic specificity, have greatly helped to eliminate or dramatically abate the incidence of a number of historical and current plagues, from smallpox to bacterial meningitis. Nonetheless, as new infectious agents emerge and the number of vaccine-preventable diseases increases, the practice and benefits of single-pathogen- or disease-targeted vaccination may be put at risk by constraints of timely production, formulation complexity, and regulatory hurdles. During the last influenza pandemic, extraordinary efforts by vaccine producers and health authorities have had little or no influence on disease prevention or mitigation. Recent research demonstrating the possibility of protecting against all influenza A virus types or even phylogenetically distant pathogens with vaccines based on highly conserved peptide or saccharide sequences is changing our paradigm. “Universal vaccine” strategies could be particularly advantageous to address protection from antibiotic-resistant bacteria and fungi for which no vaccine is currently available

A new dawn for monoclonal antibodies against antimicrobial resistant bacteria

Antimicrobial resistance (AMR) is a quickly advancing threat for human health worldwide and almost 5 million deaths are already attributable to this phenomenon every year. Since antibiotics are failing to treat AMR-bacteria, new tools are needed, and human monoclonal antibodies (mAbs) can fill this role. In almost 50 years since the introduction of the first technology that led to mAb discovery, enormous leaps forward have been made to identify and develop extremely potent human mAbs. While their usefulness has been extensively proved against viral pathogens, human mAbs have yet to find their space in treating and preventing infections from AMR-bacteria and fully conquer the field of infectious diseases. The novel and most innovative technologies herein reviewed can support this goal and add powerful tools in the arsenal of weapons against AMR

Novel approaches, including systems biology, to HIV vaccine research and development: Report from a Global HIV Vaccine Enterprise Working Group

The Global HIV Vaccine Enterprise convened a two-day workshop on August 10-11 2009, at the Fred Hutchison Cancer Research Center offices in Seattle, WA, to discuss the application of novel approaches,including systems biology, to HIV vaccine research and development. The goals of this Working Group were to identify key scientific issues and opportunities that have emerged since the Enterprise Scientific Strategic Plan1 was published in 2005, and to make recommendations to Enterprise stakeholders

Novel approaches, including systems biology, to HIV vaccine research and development: Report from a Global HIV Vaccine Enterprise Working Group

The Global HIV Vaccine Enterprise convened a two-day workshop on August 10-11 2009, at the Fred Hutchison Cancer Research Center offices in Seattle, WA, to discuss the application of novel approaches,including systems biology, to HIV vaccine research and development. The goals of this Working Group were to identify key scientific issues and opportunities that have emerged since the Enterprise Scientific Strategic Plan1 was published in 2005, and to make recommendations to Enterprise stakeholders

Histidine 21 is at the NAD+ binding site of diphtheria toxin.

Treatment of fragment A chain of diphtheria toxin (DT-A) with diethylpyrocarbonate modifies His-21, the single histidine residue present in the chain, without alteration of other residues. Parallel to histidine modification, NAD+ binding and the NAD-glycohydrolase and ADP-ribosyltransferase activities of DT-A are lost. Both NAD+ and adenosine are very effective in protecting DT-A from histidine modification and in preserving its biological properties, while adenine is ineffective. Reversal of histidine modification with hydroxylamine restores both NAD+ binding and enzymatic activities of the toxin. The possible role of His-21 in the activity of diphtheria toxin is discussed in relation to the available three-dimensional structure of the related toxin produced by Pseudomonas aeruginosa

Emerging Vaccine Informatics

Vaccine informatics is an emerging research area that focuses on development and applications of bioinformatics methods that can be used to facilitate every aspect of the preclinical, clinical, and postlicensure vaccine enterprises. Many immunoinformatics algorithms and resources have been developed to predict T- and B-cell immune epitopes for epitope vaccine development and protective immunity analysis. Vaccine protein candidates are predictable in silico from genome sequences using reverse vaccinology. Systematic transcriptomics and proteomics gene expression analyses facilitate rational vaccine design and identification of gene responses that are correlates of protection in vivo. Mathematical simulations have been used to model host-pathogen interactions and improve vaccine production and vaccination protocols. Computational methods have also been used for development of immunization registries or immunization information systems, assessment of vaccine safety and efficacy, and immunization modeling. Computational literature mining and databases effectively process, mine, and store large amounts of vaccine literature and data. Vaccine Ontology (VO) has been initiated to integrate various vaccine data and support automated reasoning

Tyrosine 65 is photolabeled by 8-azidoadenine and 8-azidoadenosine at the NAD binding site of diphtheria toxin.

8-Azidoadenine and 8-azidoadenosine, two photoactivatable derivatives of adenine and adenosine, are competitive inhibitors of diphtheria toxin of similar potency with respect to their parent compounds. On irradiation, the two tritium-labeled photoactivatable azidoadenines bind covalently and specifically to an enzymic fragment of diphtheria toxin that is known to bind to NAD. This photolabeling is protected by the enzyme substrate NAD. The radiolabeled protein was fragmented, and the radioactive fragments were sequenced. Tyr-65 is labeled specifically by both photoreagents, and its labeling was reduced strongly when NAD was present during irradiation. Labeling is also reduced strongly by adenine, adenosine, and nicotinamide. These results suggest that Tyr-65 is at the NAD binding site of diphtheria toxin and that the competitive inhibitors adenine, adenosine, and nicotinamide bind to the same portion of the catalytic center of the toxin

Effect of Helicobacter pylori Vacuolating Toxin on Maturation and Extracellular Release of Procathepsin D and on Epidermal Growth Factor Degradation

Abstract The effect of vacuolating toxin (VacA) fromHelicobacter pylori on endosomal and lysosomal functions was studied by following procathepsin D maturation and epidermal growth factor (EGF) degradation in HeLa cells exposed to the toxin. VacA inhibited the conversion of procathepsin D (53 kDa) into both the intermediate (47 kDa) and the mature (31 kDa) form. Nonprocessed cathepsin D was partly retained inside cells and partly secreted in the extracellular medium via the constitutive secretion pathway. Intracellular degradation of EGF was also inhibited by VacA with a similar dose-response curve. VacA did not alter endocytosis, cell surface recycling, and retrograde transport from plasma membrane totrans-Golgi network and endoplasmic reticulum, as estimated by using transferrin, diphtheria toxin, and ricin as tracers. Subcellular fractionation of intoxicated cells showed that procathepsin D and nondegraded EGF accumulate in lysosomes. Measurements of intracellular acidification with fluorescein isothiocyanate-dextran revealed a partial neutralization of the lumen of endosomes and lysosomes, sufficient to account for both mistargeting of procathepsin D outside the cell and the decreased activity of lysosomal proteases