Computer aided selection of candidate vaccine antigens

Flower et al. Immunome Research 2010, 6(Suppl 2):S1 http://www.immunome-research.com/content/6/S2/S1 IMMUNOME RESEARCH REVIEW Open Access Computer aided selection of candidate vaccine antigens Darren R Flower1,2*, Isabel K Macdonald2,3, Kamna Ramakrishnan2,4, Matthew N Davies5, Irini A Doytchinova6 Abstract Immunoinformatics is an emergent branch of informatics science that long ago pullulated from the tree of knowledge that is bioinformatics. It is a discipline which applies informatic techniques to problems of the immune system. To a great extent, immunoinformatics is typified by epitope prediction methods. It has found disappointingly limited use in the design and discovery of new vaccines, which is an area where proper computational support is generally lacking. Most extant vaccines are not based around isolated epitopes but rather correspond to chemically-treated or attenuated whole pathogens or correspond to individual proteins extract from whole pathogens or correspond to complex carbohydrate. In this chapter we attempt to review what progress there has been in an asyet-underexplored area of immunoinformatics: the computational discovery of whole protein antigens. The effective development of antigen prediction methods would significantly reduce the laboratory resource required to identify pathogenic proteins as candidate subunit vaccines. We begin our review by placing antigen prediction firmly into context, exploring the role of reverse vaccinology in the design and discovery of vaccines. We also highlight several competing yet ultimately complementary methodological approaches: sub-cellular location prediction, identifying antigens using sequence similarity, and the use of sophisticated statistical approaches for predicting the probability of antigen characteristics. We end by exploring how a systems immunomics approach to the prediction of immunogenicity would prove helpful in the prediction of antigens. Vaccines, vaccination, and vaccinology: a brief introductory orientation Vaccines are agents – either molecular or supramolecular - which can stimulate protective immunity against microbial pathogens and the diseases they cause. Protective immunity is a specific and enhanced adaptive immune response to subsequent re-infection or, when luck holds, infection by related organisms. Such augmented immunity is mediated by the exacerbation of immune memory, which militates against the effects of infectious organisms. The word vaccine itself is derived from vacca (Latin for cow). [1][2][3]. It is a thing of near universal agreement that mass vaccination - synergising as it does with the herd immunity it helps engender - is the most effective and efficacious prophylactic treatment currently available for contagious disease. Humankind is commonly affected by over seventy infectious diseases, many of which are or * Correspondence: 1 School of Life and Health Sciences, University of Aston, Aston Triangle, Birmingham, B4 7ET, UK Full list of author information is available at the end of the article will be targets for vaccines. There are in excess of fifty licensed vaccines, half of which are deemed to be in common use. Most vaccines prevent childhood infections or are used by travellers to tropical or subtropical regions; only a minority combat disease in third-world countries. As recently as the late 1960s, there were over 10 million cases of smallpox spread through 31 countries, with about two million deaths a year, yet now smallpox is wholly and totally eradicated. Poliomyelitis or Polio is the other key global disease close to eradication. In 1991, the Pan American Health Organization eliminated polio from the Western Hemisphere. In the First World, the annual death rate arising for contagious diseases such as polio, diphtheria, or measles is less than one in a thousand. The Global Polio Eradication Program has now greatly reduced the prevalence of Polio in the rest of the world. Only 784 cases of polio were reported in 2003. Nevertheless, Polio remains endemic in Nigeria, Afghanistan, Pakistan, and India. Despite such outrageous and egregious success, many major issues persist. No licensed vaccines exist for HIV and malaria, two of the World Health Organization © 2010 Flower et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Flower et al. Immunome Research 2010, 6(Suppl 2):S1 http://www.immunome-research.com/content/6/S2/S1 (WHO)’s three big global killers, and there are no realistic hopes for such vaccines appearing in the short to medium term. Bacille Calmette Guérin (BCG), the only vaccine licensed currently for the third major world disease, tuberculosis, has only limited efficacy [4]. Add to this the 35 new, previously unknown infectious diseases identified in the past 25 years: HIV, Marburg’s disease, SARS, dengue, West Nile, and over 190 human infections with the potentially pandemic H5N1 influenza. It is commonly believed that new contagious diseases will continue to emerge in the 21st century. The world of the 21st century is threatened by parasitic diseases and emerging zoonotic infections; antibiotic-resistant bacteria; and bioterrorism [2] The vaccine arena has long been neglected, partly as a consequence of the extraordinary success just adumbrated, but activity within it is now feverish and febrile [5,6]. Dozens of vaccine candidates have passed through phase II clinical trials, and during the past decade, vaccines in late development have numbered over 150. Unlike antibiotics, resistance to vaccines is negligible. In the same way that vaccines target many kinds of disease, themselves caused by microbial pathogens of all types, so there are many types of fundamentally distinct vaccine. See Figure 1. These include attenuated or inactivated whole pathogens, subunit vaccines, peptide vaccines, and vaccines based on carbohydrates, amongst others. Historically, the Page 2 of 16 most successful and prevalent types vaccines have been those based on attenuated – that is “weaken” or noninfective - whole pathogen vaccines, for example BCG for TB or Sabin’s Polio vaccine. Safety concerns have fomented other vaccine strategies to develop, which focus on antigens and latterly epitopes as the intrinsic component of single or composite vaccines. Hepatitis B vaccine is an antigen - or subunit – based vaccine. While many epitope-based vaccines have now entered clinical trials, they are yet to fulfil their potential, medically or commercially. Antigens, immunogenicity, and subunit vaccines Subunit vaccines are typically but not exclusively protein molecules and their discovery is often based around a somewhat haphazard, essentially empirical search for antigenic or immunogenic protein antigens. The wo (...truncated)