Designing the next generation of vaccines for global public health

Vaccine research and development are experiencing a renaissance of interest from the global scientific community. There are four major reasons for this: (1) the lack of efficacious treatment for many devastating infections; (2) the emergence of multidrug resistant bacteria; (3) the need for improving the safety of the more traditional licensed vaccines; and finally, (4) the great promise for innovative vaccine design and research with convergence of omics sciences, such as genomics, proteomics, immunomics, and vaccinology. Our first project based on omics was initiated in 2000 and was termed reverse vaccinology. At that time, antigen identification was mainly based on bioinformatic analysis of a singular genome. Since then, omics-guided approaches have been applied to its full potential in several proof-of-concept studies in the industry, with the first reverse vaccinology-derived vaccine now in late stage clinical trials and several vaccines developed by omics in preclinical studies. In the meantime, vaccine discovery and development has been further improved with the support of proteomics, functional genomics, comparative genomics, structural biology, and most recently vaccinomics. We illustrate in this review how omics biotechnologies and integrative biology are expected to accelerate the identification of vaccine candidates against difficult pathogens for which traditional vaccine development has thus far been failing, and how research will provide safer vaccines and improved formulations for immunocompromised patients in the near future. Finally, we present a discussion to situate omics-guided rational vaccine design in the broader context of global public health and how it can benefit citizens in both developed and developing countries.     

Peptide crosslinked micelles: a new strategy for the design and synthesis of peptide vaccines

This report presents a new and simple methodology for the synthesis of multicomponent peptide vaccines, named the peptide crosslinked micelles (PCMs). The PCMs are core shell micelles designed to deliver peptide antigens and immunostimulatory DNA to antigen-presenting cells (APCs). They are composed of immunostimulatory DNA, peptide antigen, and a thiopyridal derived poly(ethylene glycol)-polylysine block copolymer. The peptide antigen acts as a crosslinker in the PCM strategy, which allows the peptide antigen to be efficiently encapsulated into the PCMs and also stabilizes them against degradation by serum components. Cell culture studies demonstrated that the PCMs greatly enhance the uptake of peptide antigens into human dendritic cells.     

Monophosphoryl lipid A (MPL) formulations for the next generation of vaccines.

Many of the latest trends in vaccine development are dependent on immunological adjuvants that mediate and promote a wide variety of immune responses. One promising adjuvant candidate, monophosphoryl lipid A (MPL) immunostimulant, is being investigated with many of these new vaccine approaches in either preclinical or clinical trials. This is possible because different vehicle formulations can significantly influence the type of immunological response MPL promotes. Procedures are provided for formulating MPL in an aqueous vehicle or an oil-in-water emulsion. These two MPL formulations can be beneficial for most vaccine approaches being investigated today.     

靶向M细胞的抗原递送¾¾增强黏膜免疫应答的关键策略

黏膜是阻止病原入侵的第一道防线,黏膜免疫系统在抵抗感染方面起着至关重要的作用。通过黏膜途径接种疫苗可以同时诱导黏膜和全身免疫反应,因此,理论上针对黏膜的免疫策略是最合理和有效的。但黏膜免疫系统的复杂性和屏障作用造成抗原诱导的免疫应答水平低下,制约了黏膜疫苗的发展。M细胞(Microfoldcells)是黏膜免疫系统所独有的,其具有捕获腔内抗原和启动抗原特异性免疫应答的功能。M细胞摄取抗原的多少直接关系到黏膜疫苗的免疫效力,而利用M细胞配体可将抗原靶向递呈给M细胞,从而实现高效的黏膜免疫应答。靶向M细胞的抗原递送策略及其应用可以提高黏膜免疫应答水平,促进黏膜疫苗的研制。尽管如此,要成功研制安全高效的黏膜疫苗,今后依然有漫长的路要走,这可能有赖于进一步探究M细胞的特性和功能及黏膜免疫机制。     

Immunology for the next generation

Immunologists need to establish a vibrant dialogue with young people. This is not only important for the continuation and progress of biomedical research, but it can also contribute to the fight against diseases such as HIV/AIDS and can help young people to make informed decisions about lifestyle, medical treatment and ethical issues. Good communication skills are crucial to any scientific career, and the lessons learned from talking with non-scientists can also be useful when writing scientific papers and grants. This article is a personal account of one scientist's experience of communicating biomedical science to young people.     

Biotechnological perspectives on algae: a viable option for next generation biofuels

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Adaptation genomics: the next generation

Understanding the genetics of how organisms adapt to changing environments is a fundamental topic in modern evolutionary ecology. The field is currently progressing rapidly because of advances in genomics technologies, especially DNA sequencing. The aim of this review is to first briefly summarise how next generation sequencing (NGS) has transformed our ability to identify the genes underpinning adaptation. We then demonstrate how the application of these genomic tools to ecological model species means that we can start addressing some of the questions that have puzzled ecological geneticists for decades such as: How many genes are involved in adaptation? What types of genetic variation are responsible for adaptation? Does adaptation utilise pre-existing genetic variation or does it require new mutations to arise following an environmental change?     

Evolutionary ecology: next generation inference

Oak forests support a rich ecology of fellow travellers, but how do these fare when the forests move during glacial cycles? The answers revealed by a new study are important for ecology, but being able to get answers at all highlights a turning point in evolutionary inference.     

Structure-based design of a heptavalent anthrax toxin inhibitor

The design of polyvalent molecules, consisting of multiple copies of a biospecific ligand attached to a suitable scaffold, represents a promising approach to inhibit pathogens and oligomeric microbial toxins. Despite the increasing interest in structure-based drug design, few polyvalent inhibitors based on this approach have shown efficacy in vivo. Here we demonstrate the structure-based design of potent biospecific heptavalent inhibitors of anthrax lethal toxin. Specifically, we illustrate the ability to design potent polyvalent ligands by matching the pattern of binding sites on the biological target. We used a combination of experimental studies based on mutagenesis and computational docking studies to identify the binding site for an inhibitory peptide on the heptameric subunit of anthrax toxin. We developed an approach based on copper-catalyzed azide-alkyne cycloaddition (click-chemistry) to facilitate the attachment of seven copies of the inhibitory peptide to a β-cyclodextrin core via a polyethylene glycol linker of an appropriate length. The resulting heptavalent inhibitors neutralized anthrax lethal toxin both in vitro and in vivo and showed appreciable stability in serum. Given the inherent biocompatibility of cyclodextrin and polyethylene glycol, these potent well-defined heptavalent inhibitors show considerable promise as anthrax antitoxins.     

Polyvalency: a promising strategy for drug design

The simultaneous binding of multiple ligands on one entity to multiple receptors on another can result in an affinity that is significantly greater than that for the binding of a single ligand to a single receptor. This concept of "polyvalency" can be used to design molecules that are potent inhibitors of toxins and pathogens. We describe the design of potent polyvalent inhibitors that neutralize anthrax toxin in vivo as well as our attempts to elucidate the relationship between inhibitor structure and activity. We also highlight promising future avenues for research in polyvalent drug design.     

Structure-based design of a pathway-specific nuclear import inhibitor

Kapbeta2 (also called transportin) recognizes PY nuclear localization signal (NLS), a new class of NLS with a R/H/Kx((2-5))PY motif. Here we show that Kapbeta2 complexes containing hydrophobic and basic PY-NLSs, as classified by the composition of an additional N-terminal motif, converge in structure only at consensus motifs, which explains ligand diversity. On the basis of these data and complementary biochemical analyses, we designed a Kapbeta2-specific nuclear import inhibitor, M9M.     

Structure-based design of amidinophenylurea-derivatives for factor VIIa inhibition

The amidinophenylurea scaffold was earlier shown to provide an excellent template for the synthesis of novel and potent inhibitors of the blood coagulation factor VIIa. In this contribution we describe the structure-based design of potent ligands guided by X-ray crystallography, molecular modeling and docking studies. The design and synthetic efforts were directed towards novel modifications to explore the protease binding region close to the S4 subsite.     

Wake-promoting agents: search for next generation modafinil: part I

In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.