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.     

Structure-based antigen design: a strategy for next generation vaccines

Vaccine design is progressing from empiricism towards the increasingly rational presentation of the targets of protective immunity. Nevertheless, most current vaccine antigens are essentially the native macromolecules of pathogens. These molecules are adapted to evade, not induce, immunity. High resolution structures reveal the electrostatic surfaces recognized by neutralizing antibodies and the architectures underlying these surfaces, thereby identifying which substructures must be left intact and which can be changed to optimize biochemical and immunologic performance. Armed with detailed structural information, we can engineer optimized antigens that are more stable, homogeneous, and efficiently produced, making immunization more practical and affordable. Understanding the structural basis for immunogenicity and immunodominance will allow us to improve vaccine efficacy and broaden the range of vaccine-preventable diseases.     

Mitochondria: the next (neurode)generation

Adult-onset neurodegenerative disorders are disabling and often fatal diseases of the nervous system whose underlying mechanisms of cell death remain unknown. Defects in mitochondrial respiration had previously been proposed to contribute to the occurrence of many, if not all, of the most common neurodegenerative disorders. However, the discovery of genes mutated in hereditary forms of these enigmatic diseases has additionally suggested defects in mitochondrial dynamics. Such disturbances can lead to changes in mitochondrial trafficking, in interorganellar communication, and in mitochondrial quality control. These new mechanisms by which mitochondria may also be linked to neurodegeneration will likely have far-reaching implications for our understanding of the pathophysiology and treatment of adult-onset neurodegenerative disorders.     

Evaluation of monophosphoryl lipid A (MPL) as an adjuvant. Enhancement of the serum antibody response in mice to polysaccharide-protein conjugates by concurrent injection with MPL

Concurrent injection of monophosphoryl lipid A (MPL) in saline or as an oil-in-water emulsion enhanced both the primary and secondary serum antibody responses to the capsular polysaccharide (CP) components of seven conjugates: the enhanced responses were Ag-specific. In contrast, MPL did not enhance the serum antibody response to five of the six unconjugated CP. MPL and trehalose dimycolate injected concurrently with the unconjugated Vi CP of Salmonella typhi (Vi) enhanced the serum antibody response to that Ag. MPL further enhanced the Vi antibody levels when injected with conjugates of this CP. The serum antibody responses to Pseudomonas aeruginosa exotoxin A, used as the carrier protein for the Staphylococcus aureus types 5 and 8 conjugates, were also enhanced by MPL. MPL in oil-in-water emulsion was generally more effective than when administered in saline.     

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.     

Moving towards the next generation.

In most organisms, primordial germ cells are set aside from the cells of the body early in development. To form an embryonic gonad, germ cells often have to migrate along complex routes through and along diverse tissues until they reach the somatic part of the gonad. Recent advances have been made in the genetic analysis of these early stages of germ line development. Here we review findings from Drosophila, zebrafish, and mouse; each organism provides unique insight into the mechanisms that determine germ cell fate and the cues that may guide their migration.     

Fluorescence in situ hybridisation (FISH)--the next generation

Fluorescence in situ hybridisation (FISH) has become one of the major techniques in environmental microbiology. The original version of this technique often suffered from limited sensitivity due to low target copy number or target inaccessibility. In recent years there have been several developments to amend this problem by increasing signal intensity. This review summarises various approaches for signal amplification, focussing especially on two widely recognised varieties, tyramide signal amplification and multiply labelled polynucleotide probes. Furthermore, new applications for FISH are discussed, which arise from the increased sensitivity of the method.     

A new generation of HIV vaccines

WHO estimates that currently there are 40 million individuals living with HIV and there are 16000 new infections daily, worldwide. The best strategy to control the AIDS epidemic would be the development of an effective vaccine. New strategies for vaccine development have gained momentum over the past decade, some of which show greater promise in macaque models than did earlier protein-subunit or recombinant-canarypox strategies. These new vaccines include DNA vaccines and live viral vectors, and have been based on the generation of high levels of antiviral T cells. These vaccines do not prevent infection, but rather control virus replication with a rapid expansion and then contraction of antiviral T cells in response to the challenge infection. These recent vaccine successes in macaques raise hope that a vaccine can be developed that will successfully limit both the development of AIDS and viral transmission.     

Directed next generation sequencing for phylogenetics: An example using Decapoda (Crustacea)

We propose a method using next generation sequencing technology for phylogenetics. The method is PCR based, requires little training beyond basic lab skills and is both cost and time effective. With this method we generated data for and produced a phylogeny of Decapoda that demonstrates this method's potential, the quality of the data, and the ability for the method to fit or even replace current Sanger based methods of generating DNA data for phylogenetic reconstruction. Finally, we discuss advantages and current challenges of the directed next generation sequencing approach.     

Poly(2-oxazoline) hydrogels as next generation three-dimensional cell supports

Synthetic hydrogels selectively decorated with cell adhesion motifs are rapidly emerging as promising substrates for 3D cell culture. When cells are grown in 3D they experience potentially more physiologically relevant cell–cell interactions and physical cues compared with traditional 2D cell culture on stiff surfaces. A newly developed polymer based on poly(2-oxazoline)s has been used for the first time to control attachment of fibroblast cells and is discussed here for its potential use in 3D cell culture with particular focus on cancer cells toward the ultimate aim of high-throughput screening of anticancer therapies. Advantages and limitations of using poly(2-oxazoline) hydrogels are discussed and compared with more established polymers, especially polyethylene glycol (PEG).     

Poly(2-oxazoline) hydrogels as next generation three-dimensional cell supports

Synthetic hydrogels selectively decorated with cell adhesion motifs are rapidly emerging as promising substrates for 3D cell culture. When cells are grown in 3D they experience potentially more physiologically relevant cell–cell interactions and physical cues compared with traditional 2D cell culture on stiff surfaces. A newly developed polymer based on poly(2-oxazoline)s has been used for the first time to control attachment of fibroblast cells and is discussed here for its potential use in 3D cell culture with particular focus on cancer cells toward the ultimate aim of high-throughput screening of anticancer therapies. Advantages and limitations of using poly(2-oxazoline) hydrogels are discussed and compared with more established polymers, especially polyethylene glycol (PEG).     

"Antibodies--Europe. Engineering the next generation of antibodies"

Meeting report: “Antibodies-Europe. Engineering the Next Generation of Antibodies” News from academia: FEBS/EMBO Women in Science Award 2008 Teaching biotech: The stem cell game