Computer-Aided Vaccine Design

Abstract

Vaccines, and their discovery, are topics of singular importance in present-day biomedical science. The discovery of vaccines has hitherto been primarily empirical in nature, and it is only now that this is giving way, albeit very slowly, to a more rational approach, supported and enhanced by computer-based methods. In this context, the book Computer-Aided Vaccine Design by Tong and Ranganathan is a welcome new addition to the growing list of biomedical texts that address the computational discovery of vaccines and their components.

For infectious disease, sanitation and vaccination provide by far-and-away the most efficient and efficacious, as well the most cost-effective, prophylactic treatments available. Moreover, for a wide range of communicable and non-communicable diseases, including certain autoimmune diseases, vaccination as a strategy offers great potential for future therapy. The discovery of vaccination is generally credited to Edward Jenner, although Jesty and others definitely preceded him; he was the first properly to publish on vaccination with cowpox, and, through his contacts, to lay the concept before the scientific establishment and the public. Vaccination as a science took another 80 years, and the polymathic scientific genius of Louis Pasteur, to blossom: Pasteur and his successors developed empirical methods that ushered in a great boom era in vaccine discovery, lasting into the mid-twentieth century. As the list of vaccine-targetable diseases waned, interest in vaccine discovery and development also waned, only to revive at the turn of the millennium, prompted by new and resurgent diseases, and the threat from bio-terrorism.

Vaccination is principally concerned with providing protective immunity by stimulating the humoral and cell mediated adaptive immune systems, generating effective and appropriate adaptive immune responses, to be subsequently activated by infection. The prime goal is the generation of long lasting immunity against microbial pathogens via the production of diverse immune memory cells. As a consequence of their long and fascinating history, many types of vaccine are available, as are many methods of vaccine discovery. Thus whole pathogen, subunit, and carbohydrate epitope vaccines can be discovered using attenuation, chemical or heat treatment, or by culturing pathogens, and by laboriously extracting proteins or carbohydrates that evoke an immune response. Recently, genomic techniques—so-called reverse vaccinology—have begun to deliver on their potential, as the discovery of Bexsero has ably demonstrated. Bexsero is a recombinant sub-unit vaccine targeting meningococcal serogroup B, the primary cause of life-threatening bacterial meningitis in Europe.

Last, but not least, we should add the computational or computer-aided discovery of immunogenic proteins and epitopes to the mix of vaccine discovery techniques, not so much for its success as for its potential. Since immunogenic proteins identified as antigens from pathogen genomes are potential subunit vaccines and immunogenic epitopes are the vital components of epitope ensemble vaccines, the potential of predictive computational vaccine identification is clear, if woefully underexploited. Moreover, the realization of epitope ensemble vaccines moves vaccinology into the same arena of design as pharmaceutical drug discovery. Computer-based discovery promises to be highly efficient, potentially saving considerable time, effort, and resource in the discovery of epitopes and other immunogenic molecules. It is this area that Computer-Aided Vaccine Design by Joo Chuan Tong and Shoba Ranganathan seeks to address.

The book has a fairly linear structure, outlining, in a most logical and straightforward fashion, the core ideas necessary to implement computer-supported epitope discovery in a biomedical context. It begins with an outline of contents, and all the usual paraphernalia one finds in books, such as lists of abbreviations and author profiles. A very brief preface acts as an introduction. This is followed by a pair of background chapters on the cellular and humoral adaptive immune response respectively; the book then moves forward into an exploration of bioinformatics as opposed to biology, beginning with underpinning technology. This takes the form of a couple of chapters on available databases and database structures and construction. Next are two very succinct chapters dealing with available prediction methods targeting cellular and humoral epitopes; that is, epitopes bound by MHCs and epitopes bound by antibodies. The chapter on antibody-mediated prediction didn’t, for me at least, strike cautious enough a tone; the accuracy of B-cell epitope prediction is so low, and so questionable the data upon which they are based, that rather more caveats need to be stressed when discussing them. What is needed are specially devised and conducted experiments to underpin the development of robust and reliable in silico methods, particularly in the area of B-cell epitope; yet all equivalent areas of immunoinformatics, even the most accurate and well understood, would likewise benefit from bespoke experiments directed at developing powerful and robust algorithms.

Tong and Ranganathan’s book is focused, in the main, on epitope discovery as the prelude to the design of vaccines based around ensembles of immunogenic epitopes. This much is clear from a brief perusal of the contents of the book. The ability to induce neutralizing antibodies of peptides corresponding to B cell epitopes was documented in the early 1980s. Vaccines based upon peptides would represent the distillation of those parts of a pathogen that can induce host protection. Bittle was the first to demonstrate the feasibility of peptides in vaccine design by using a linear B cell epitope identified from the Foot and Mouth Virus (FMV) viral capsid protein that offered protection to viral challenge. The first viable epitope vaccine was reported in 1994, and gave protection to dogs from canine parvovirus. A number of epitope ensemble vaccines containing T cell epitopes have entered clinical trials. These include vaccines for Alzheimer disease, and for the malaria parasite, as well as a poly-epitope vaccine for the measles virus.

Multi epitope ensemble vaccines can be designed, much as other pharmaceutical products—drugs and such like—are; generally epitopes are specifically identified on a case-by-case experimental basis or, increasingly, are predicted using sophisticated bioinformatics techniques. Experimental determination of epitopes is notoriously redundant, painfully slow, and laboriously inefficient. The types of approach discussed in Computer-Aided Vaccine Design offer an alternative approach, one based on using computational methods to short-cut the process, much as computer-aided design is used successful in all kinds of industries. But more than this pragmatic benefit, there are many pathogens for which attenuated, heat, or chemically treated whole pathogen vaccines and even subunit vaccines are ineffective in engendering potent immune responses. Perhaps, the best example is Hepatitis C virus, where attempts to create an effective recombinant HCV subunit vaccine have yet to prove successful, unlike vaccines for HAV and HBV. Recombinant whole protein vaccines have been explored with some thoroughness: the E1 and E2 proteins have been a particular focus, as have non-structural proteins NS1 and NS2. While others, including Novartis, have pursued HCV core protein as a putative recombinant vaccine. Immunological memory is not as effective as in Hepatitis A, B, or E vaccines, as it is rarely sterilizing. Indeed, development of a HCV vaccine has proved problematic since HCV is highly variable and an antibody response to the virus, which proved effective against HBV and HAV, is thus unlikely to work. Targeting the cellular arm of the adaptive immune system and simultaneously, using conserved epitopes is thus a far more likely route to a successful HCV vaccine.

So the utilitarian benefit of this book is well founded, but what of the Book itself? First let us ask: is it any good? Computer-Aided Vaccine Designby Tong and Ranganathan is certainly short and concise; indeed, to a harsh and uncharitable mind, it might seem to border on the exiguous. Such brevity may thus seem a disadvantage to many, even an overwhelming one. Yet others may see this as a keen advantage, with the core ideas and techniques stripped clean of distractions and digressions. The flipside of this, of course, is that the book might be criticized for lacking context—background or examples of use and application—and thus may prove unsatisfying for those who crave a deeper, fully fleshed-out exposition; but then there are plenty of books already offering such fare.

The book is fairly technical without being burdened by overwhelming detail. It tries to deliver digestible bite-sized information quickly without confusing readers with overly deep discussions of the relative strengths and weaknesses of different approaches and ideas; thus this book would seem appropriate material for undergraduate or masters students who typically want just the bare bones of a subject laid before them without the confusing inconvenience of context, detail, and caveats. So, this book is designed more, it seems, for the novice than the expert, though a not inconsiderable technical understanding is required to make full use of this text. The book is light on detail and lacks worked examples of how the various algorithms, strategies, and ideas laid out in the book could be best put to use in a practice context.

Epitope-based vaccines have thus been in development for the last three decades, but tend to reach phase III trials and progress no further. Much of this is due to their low intrinsic immunogenicity: compared with whole pathogen vaccines, individual epitopes provide too few—and too homogeneous—a challenge to the immune system to be fully effective as vaccines. Thus, it is interesting that the book also contains chapters focusing on disease informatics, safety evaluation from an in silico perspectives, and the computational discovery of adjuvants. There is thus a tacit recognition that we need to do more than find a handful of immunogenic peptides to make a good epitope ensemble vaccine. Having said that, compared with the excellent earlier chapters, alluded to above, these are the weakest of the chapters offered by Tong and Ranganathan.

The chapter on disease informatics—which, like several other chapters here, is very brief—deals with modeling disease at the genome level. It is not, in itself, anything more than a very truncated taster for a deeper study of this important discipline. Likewise, the chapter on safety runs to only a few pages, and spends much of its time on a discussion of the computational evaluation of AMDE/tox for small molecule drugs, before a brief discussion of predicting allergenicity.

The final chapter deals with adjuvants. Adjuvants are molecular entities that increase the immune response to poorly immunogenic vaccines. They come in various flavors. Alum and Fruend’s adjuvant are widely used and have been for most of the last century, but more recently adjuvants of other kinds have emerged: protein-based adjuvants, liposomal adjuvants, and small molecule adjuvants, which are either based on oligonucleotides, synthetically-complex natural products, or drug-like small molecules. And it is this class of small molecule adjuvants that the book targets, discussing the storage and design of virtual chemical libraries. Again, the opportunity has been lost to do more than just touch this as an area; we can only hope that the authors do better justice to this fascinating topic in future editions of Computer-Aided Vaccine Design.

So, in sum, this is a pithy and concise exposition of an under-appreciated area of one of the most vital and important areas of modern bioscience. The book is not without flaws but many of these are subjective, in that some would see its flaws as virtues and vice versa. I would cite its lack of context; but to many, context is little more than unneeded distraction. Just as there is no single method, no single tool that can unerringly identify new vaccines, there is no single book that can effectively distil all the complexity of this fascinating subject. Computational epitope discovery offers extra value to the practicing vaccinologist, and Computer-Aided Vaccine Designby Tong and Ranganathan offers much of value to the developing field of computational vaccinology as both a teaching resource and a no-nonsense introduction to the discipline.

Tong JC, Ranganathan S, editors. 1. Woodhead Publishing; 2013. Computer-aided vaccine design.

10.4161/hv.26687