Since the British physician Edward Jenner introduced his smallpox vaccine to the Western world in the late eighteenth century, classical vaccinology has become one of the most successful countermeasures in the constant battle against infectious diseases. In many cases, governmental programs for exhaustive vaccination were able to push the number of new infections per year to almost zero [ 1 ]. Prominent examples include the vaccination against smallpox that effectively eradicated the disease, and against polio, where incidence rates have dropped by more than 99 % since the late 1980s. Despite the ongoing success of classical vaccination strategies, a number of infectious diseases have remained recalcitrant to vaccine development, largely due to the inherent constraints of classical vaccine technology.

Usually the vaccine administered is a biological suspension of either inactivated or killed cells, polysaccharide capsules, or toxoids [ 2 ]. However, in many cases it is challenging to prepare a potent vac cine against a specific pathogen. Non-culturable microorganisms, antigens which are not expressed in vitro, pathogens with antigenic determinants that can trigger detrimental autoimmune reactions, as well as extremely heterogeneous strains are only a few of the severe difficulties classical vaccinologists are confronted with today.

Recently, a new impetus was given to current vaccine research thanks to the growing number of available complete microbial genomes. Based on the assumption that all (protein) antigens a pathogen can express at any time are encoded in its genome (and therefore available to the scientist without cultivation), the idea is to combine bioinformatics and biotechnology to identify protein candidates for vaccine development. As this approach begins with the genome sequence, in contrast to starting from an entire living microorganism, it is called “ reverse vaccinology ” [ 3 , 4 ]. The first projects based on this approach used genome information only to naïvely select surface-localized proteins as a pool of possible candidates for subsequent classical animal experiments. In their pioneering work for the development of a vaccine against Neisseria meningitidis B (MenB), R. Rappouli and colleagues collected 570 surface-localized proteins, of which about 350 could successfully be cloned and expressed in Escherichia coli . The purified proteins were then used to immunize mice, and the resulting sera were subjected to various immunoassays to test for the candidate protein’s efficacy as a vaccine. The researchers found 28 proteins which showed consistently positive results in all immunoassays and were able to induce antibodies with bactericidal activity [ 5 ]. Furthermore, five of these candidates were also highly conserved in the genome of distantly related strains. A subset of these candidates became the basis for the development of a vaccine called “4CMenB,” which contains three recombinant protein antigens combined with outer membrane vesicles derived from the meningococcal strain NZ98/254 and has obtained market authorization for the European Union in January 2013 (Bexsero, Novartis International AG [ 6 ]). Reverse vaccinology has since developed enormously, in particular by using increasingly sophisticated bioinformatic methods to mine the information provided by complete genomes.

 References

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[1] WHO UNICEF World Bank (2009) State of the world’s vaccines and immunization. World Health Organization, Geneva

 [2] Flower DR (2009) Bioinformatics for vaccinology. Wiley, Chichester, UK

[3] Rinaudo CD, Telford JL, Rappuoli R et al (2009) Vaccinology in the genome era. J Clin Invest 119:2515–2525

 [4] Seib KL, Zhao X, Rappuoli R (2012) Developing vaccines in the era of genomics: a decade of reverse vaccinology. Clin Microbiol Infect 18:109–116

[5] Pizza M, Scarlato V, Masignani V et al (2000) Identification of vaccine candidates against serogroup B meningococcus by whole- genome sequencing. Science 287:1816–1820

[6] Medicinal products and human use. Bexsero. Technical report, European Medicines Agency. http://www.ema.europa.eu/docs/ en_GB/document_library/EPAR_

مواضيع ذات صلة

Pan-Genomic Analysis

Improving Vaccines over Natural Immune Responses

Selecting Vaccine Antigens

Principles of Vaccine Development

A Brief History of Vaccination

Development of Vaccines for Tuberculosis and Meningitis

Development of Vaccines for Viral Hepatitis, Coronavirus, and Norovirus

Development of Powerful Influenza Vaccines

Vaccines for HIV and Ebola Virus

Vaccines for Diseases Associated with Urban Areas in the Developing Countries

HIV Vaccine

Yellow Fever Vaccine