Elsevier

Vaccine

Volume 27, Issues 25–26, 26 May 2009, Pages 3245-3250
Vaccine

Review
Genome-based approaches to develop vaccines against bacterial pathogens

https://doi.org/10.1016/j.vaccine.2009.01.072Get rights and content

Abstract

Bacterial infectious diseases remain the single most important threat to health worldwide. Although conventional vaccinology approaches were successful in conferring protection against several diseases, they failed to provide efficacious solutions against many others. The advent of whole-genome sequencing changed the way to think about vaccine development, enabling the targeting of possible vaccine candidates starting from the genomic information of a single bacterial isolate, with a process named reverse vaccinology. As the genomic era progressed, reverse vaccinology has evolved with a pan-genome approach and multi-strain genome analysis became fundamental for the design of universal vaccines. This review describes the applications of genome-based approaches in the development of new vaccines against bacterial pathogens.

Introduction

Despite advances in the treatment of infectious diseases, pathogenic microorganisms are still the most important threat to health worldwide. Remarkable progresses have been made in vaccine development in the last 200 years and vaccination has prevented illness and death for millions of individuals. However, efficacious treatments against many infectious disease agents or re-emerging infections still need to be discovered. For these reasons, novel vaccines together with new ways to discover and approach them are needed.

The oldest vaccines currently available are based on killed or live-attenuated microorganisms and on toxins detoxified by chemical treatment The knowledge of the pathogenesis of many microorganisms, the identification of the main virulence factors, and the characterization of the immune response after infection have been fundamental for the design of new vaccines based on highly purified antigenic components, on genetically detoxified toxins, and on polysaccharides or oligosaccharides conjugated to proteins [1].

The first important innovation in the vaccine field was the introduction of molecular biology and genetic techniques which allowed the development of two efficacious recombinant vaccines: the hepatitis B vaccine, which is based on a highly purified capsid protein [2], and the acellular vaccine against Bordetella pertussis, based on three highly purified proteins, including a genetically detoxified toxin [3], [4].

A second revolution in vaccine design started with the genomic era. The “shotgun sequencing” strategy was initially developed and applied to several genome projects allowing in 1995 the completion of the first sequence for a free-living organism (Haemophilus influenzae) by The Institute for Genomic Research (TIGR) [5]. Nowadays, new sequencing technologies are emerging [6]. A very promising and increasingly popular novel technology, commonly referred to as “454” technology, is now applied to the re-sequencing of a number of species and holds great promise for sequencing many additional genomes cheaply and rapidly when a complete reference genome is already available [7]. Thanks to these technical advances, in the last few years the number of available genomes has grown considerably with 725 bacterial sequences completed, and more than 2000 other microorganisms being sequenced in various laboratories around the world (GOLD Genomes OnLine database at http://www.genomesonline.org/). This panel of bacterial genomes already covers most of the pathogens impacting heavily on human health. By the vaccinology point of view, the complete genome of a bacterium represents a large reservoir of genes encoding for potential antigens that can be selected, screened and tested as vaccine candidates. Therefore, potentially surface-exposed proteins can be identified in a reverse manner, starting from the genome rather than from the microorganism. This novel approach has been termed “reverse vaccinology” [8] (Fig. 1).

In addition, the availability of complete annotated genome sequences, coupled with bioinformatics, has spawned the new scientific discipline of “comparative genomics” that can be applied to different strains, species and genera and represents a powerful approach for studying differences in phenotype, host range, and molecular evolution of virulence.

In this review we will describe how genomic information has been successful in the identification of novel potential vaccine candidates against various human pathogens, such as Neisseria meningitidis serogroup B, Streptococcus agalactiae, S. pneumoniae and its potential to be applied to all pathogens that are still waiting to be defeated.

Section snippets

The application of reverse vaccinology

The concept of reverse vaccinology was applied for the first time to serogroup B N. meningitidis (MenB).

N. meningitidis is the major cause of meningitis and sepsis, two devastating diseases that can kill children and young adults within hours, despite the availability of effective antibiotics. It is a Gram-negative bacterium that colonizes asymptomatically the upper nasopharinx tract of about 5–15% of human population. However, in a significant number of cases, the bacterium can traverse the

Pan-genome reverse vaccinology

While the genome sequence of a single strain reveals many aspects of the biology of a species, it fails to address how genetic variability drives pathogenesis within a bacterial species and also limits genome-wide screens for vaccine candidates or for antimicrobial targets to a single strain. The availability of genome sequences for different isolates of a single species enables quantitative analyses of their genomic diversity through comparative genomic analyses. The higher the number of

A pilus-based vaccine against S. pneumoniae

The value of a pan-genome approach is clearly exemplified by the multi-genome analysis that was applied to S. pneumoniae to identify pilus structures that can be used for the development of a multi-component pilus-based vaccine.

S. pneumoniae is one of the most important human pathogens, accounting for considerable morbidity and mortality rates worldwide. Pneumococci are the most common etiologic agent of community-acquired pneumonia, as well as bacterial meningitis, otitis media, and sepsis.

Comparative genome analysis: the third phase of reverse vaccinology

While in the case of GBS, comparative genome analysis has been applied to disease-causing isolates, an alternative approach is the comparison between pathogenic and non-pathogenic strains of the same species. This kind of analysis can provide the information necessary for the identification of antigens that really make the difference in pathogenesis. An elegant example of comparative genome analysis is that described for uropathogenic strains of E. coli, whereby a comparison of UPEC genomes

Conclusion

Classical reverse vaccinology approach made the first move in the new generation vaccine, being successful for the development of a vaccine against serogroup B N. meningitidis. In spite of that, it had to evolve in order to be successful against a more complex microorganism like S. agalactiae and opened the way to the new concept of pan-genome reverse vaccinology. Here all the efforts are concentrated in comparing many pathogenic strains of a species looking for the identification of antigens

Acknowledgements

We thank Giorgio Corsi for artwork and Ilaria Ferlenghi and Fabiola Giusti for providing us with the picture showing double immunogold labeling of a pneumococcal strain expressing PI-1 and PI-2 types of pili.

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