“Only clean water has contributed to improving global health more than vaccines.” Such a simple and enticing sentence by Bagnoli and Grandi is the opening statement that sets the trend for a book well-written and presented such that the richness of its contents can be easily devoured by an interested reader. But make no mistake, it is by no means a book to eat in one seating. Some proper studying compared to mere reading may be necessary to integrate its knowledge.
The seemingly conventional title Advances in Vaccine Research hides a gem of brave writing, with a hybrid character between a textbook, a handbook and a compilation of scientific summary reports. It provides historic, actual and future views on the various key issues within the field of vaccinology. It is not just a collection of articles for the proficient up to date vaccinologist but a piece useful to students, teachers, vaccine professionals and the ‘vaccine aficionado.’
Although dense it does not feel heavy on the eyes because all authors spike their chapters with snippet-like trivia observations that enhance the dynamic interaction with the pages (e.g., during last century vaccination has led to a 30 years increase in average life-span), appealing section titles that inform while subliminally conveying innovation (e.g., Reversing Pasteur's Paradigm), and factual hallmark achievements spicing up the subtleties (e.g., the anti-Neisseria meningitidis vaccine Bexsero, that validates reverse vaccinology approaches).
A skillfully written preface sets the stage, provides a guidance to tackle the book and offers fundamental take home messages. Any panel of experts would agree on the key issues on the basic science, novel tools and technologies toward rational vaccine design: antigen discovery, interactions with the host, immune correlates of protection, adjuvants, reverse and structural vaccinology, synthetic biology, conjugate and mucosal vaccines, delivery systems, and in vitro/in vivo animal models, …. All of them and more are explored in the book. Other fundamental concepts are also presented, like the brave new world of ‘personalized/individualized/stratified vaccinology'or the incipient opportunity of analyzing repertoires (TCRs, BCRs, Ig receptors, epigenomic changes, or viral/bacterial quasispecies) indicated in various chapters (e.g., Censini et al., Rho, and Britten and Tureci).
Framed against the backdrop of issues like the antibiotic resistance threat or the failures to combat several microorganisms, an overarching theme across the whole book is the essential need of basic research for vaccine development.
The final paragraph of the preface clearly states the intended roles of this piece “to illustrate the impressive technological advances that is increasing the quality standards of vaccines and is paving the way to develop vaccines against diseases for which efficacious medical treatments are still lacking -not only infectious diseases but also cancer- the ‘vaccines for the 2020’.”
Book structure
The book is structured in 2 sections. A larger first section is a laudable up-to-date textbook-like piece highlighting where we have been, where we are, and where we aim to be in the field of vaccinology. Illustrated with the targets of those vaccine efforts it seats on a core of technological advances enabling progress. The key narrative drivers are the challenges to attain protection through immune-prophylaxis or –therapy.
Following a similar writing style, Part II contains a series of monographic chapters around a set of targets selected because of their health-care impact as well as their reticence to becoming vaccine development successes; namely, malaria, tuberculosis, Salmonella, Staphylococcus aureus, HIV, RSV and cancer.
As stated on its preface, the cost-effective public health measures that vaccines are demand a noteworthy sustained investment to market for a so far moderate success rate (ca. 6%). One can discern an arduous path ahead to come up with the vaccines that remain. Such risky business benefits from rational design to enable the process.
The first 4 chapters rejoice in the art -science I must say- of bioinformatics mining of the most intimate details of biological information (DNA and proteins) in the context of its significance in vaccinology – the ‘omics’. It seems a suitable opener to the book, given the paramount contribution of the ‘omics’ in vaccine research advancement. Nonetheless, the preface already provides the healthy view that the –omics are not a solution but a contribution to the basic science that will enable further success of this translational discipline.
From there the book continues with structural vaccinology, host receptors and mediators (cellular and humoral), T- and B-cell inducing vaccines, delivery and cancer immunotherapy.
A review per chapter of Part I
Whether purposely or not, the various authors have written their articles in an academically meaningful succession, thus it seems reasonable to continue following a ‘per chapter’ review.
Censini and co-authors follow the preface with an exquisite first chapter which is the epitome of the quality of the chapters to follow. The composition is a bit ‘heavy’ but the contents are impactful, innovative, and visionary. It includes topics like epi-drugs, statements like “we are in the era of teleporting life” or section titles like ‘next generation sequencing and biological holism in vaccine research and development’. Similarly, they manage to embed key subjects like synthetic biology and reverse vaccinology, within a technical chapter on sequencing. Building on the chronological history of vaccine development, they go then into pedagogically explaining the technical advances of the present, near future plans and distant future perspectives.
Besides a vast range of genomic and computing technologies, from pioneering DNA sequencing to third generation systems, they also display the advances, flaws and new technologies in the path toward improving sensitivity, accuracy and resolution helping to circumvent the sequencing errors that greatly affected downstream processing of sequencing projects.
The ground they cover is broad, e.g., the evolution toward ‘faster and cheaper’ tools that has paved the path of synthetic biology, social issues of vaccinology like the universal availability of vaccines, or crucial complications in the crossroads between vaccinology and the microbiology of infectious diseases of the next decade (e.g., superinfections, reemerging pathogens and the microbiome). They stress the significance of ascertaining the mechanisms of microbial pathogenesis understanding transcriptional/proteomic changes in host and pathogen, to culminate in the ‘omics’, data mining and reverse vaccinology. Effectively they recognize the need to study the system as a system, from single genomes to multiple genomes and from multiple cells to single cells.
The authors recognize great predictive difficulty in vaccine design introduced by population immune response diversity and pathogen variability. Systems vaccinology and its core search on molecular signatures comes to the rescue. And so concepts like immunome, antigenome, comparative (vaccinated vs. control) bar-coding/multiplexing or stable antigenic profiles by means of antibody-mediated immunity are embedded here. They highlight the power of ‘pan-genomic’ knowledge to recognizing genomic heterogeneity (e.g., commensals vs. pathogens) and of genome-wide epigenetic profiling to characterize the T-cell differentiation to acute and chronic infections during the preclinical evaluation of vaccines.
This chapter in fact describes the process of vaccine development in itself, although focused on earliest stage target selection, it also presents steps of preclinical development/clinical evaluation. Beyond vaccine formulations the process involves delivery systems, immunization schemes, vaccine evaluations with biological correlates of protection (and suitable reliable animal models). The ultimate aim: speed; a faster transition between phases, development times, production and higher safety/efficacy.
The chapter by Mina Rho in computational approaches is pertinently placed after sequencing technologies. The generation of large data sets on the pathogen, the host and their interaction entails demanding analysis, particularly in the advent of single cell sequencing at nucleotide resolution. Rho covers from the essential bioinformatic identification of the genomic norm/variation to infection and vaccination to the understanding of communities. The advantages and disadvantages of various algorithms are discussed, and so are alignments, the unveiling of insertion/deletion variants, sequence assembly, gene and epitope prediction, the bioinformatics of transcriptomics and phylogenetics, the analysis of differential expression, and the discovery of new infectious agents (metagenomics). It is an informative chapter with introductory fragments and interesting snippets of biological information. Albeit arduous for the untrained eye it places the reader before a contextual list of everything there is to know on the bioinformatics of sequencing projects.
In a smaller-size piece Hazen and Rasko follow suit addressing the questions ‘we can find detailed information from genomes and ‘epigenomes’, so what?’. ‘Which differences between organisms play a significant role in pathogenesis/virulence?’ Besides various other aspects of comparative genomics, these authors clearly delineate a crucial distinction between the good ol’ term of ‘virulence factors’ and that of ‘biomarkers’, some unveiled through comparative genomics.
Proteomics, applied to vaccine research, is addressed by Biagini and Norais in a well-structured chapter where they highlight the importance of the combination of proteomics with functional genomics and in vivo confirmation. Rooted in history they walk us from the original Edman degradation for peptide sequencing to label-free technologies. They relate “the evolution of proteomics from a descriptive to a quantitative science and report its application in the vaccinology field,” from the early phase of target discovery into downstream phases. As examples, on the identification of new virulence/oncogenic factors, the discrimination of expression profiles during the stages of infection/carriage, or commensal to pathological “switches.”
Donnarumma and co-authors take us to the level of vaccinology beyond primary sequences and linear epitopes into the 3-D molecular features recognized by the immune system toward rational vaccine design, diagnostics and immunotherapy. We are only at the beginning of a tale of the search for immunologically meaningful molecular signatures of the pathogen. Consequently, the authors develop the narrative from where we are to what technological tools may take us where we need to go, their power and limitations. Their focus resides on B-cell epitopes and prokaryotic efforts. Although a technique-orientated chapter, it is not arid, the authors manage to generate several layers of cumulative appeal: the technology description, illustrations of existing/ potential applications, and attention grabbing notions.
Wrammer and Murali-Krishna have generated a chapter appealing to all audiences, including students. One can benefit from descriptions on the development and works of immune system, the link between receptor variety and systemic/mucosal function, and the corresponding investigation-enabling technologies. It is through T-cell and B-cell receptors where they navigate. A collection of well-dissected examples in vaccine and immunotherapeutics adds to its richness. Once of the themes within the book is also present here, the discrimination between receptor screenings from cell populations and single cells.
The next chapter is on the skin vaccination route is centered on the mechanisms of the immune response on the skin, its players and mediators. Combadière and Perrin introduce a detailed anatomical/histological view of the skin, followed by the skin immunological processes for pathogen detection, [antigen] presentation, uptake and processing. The subtle but crucial differences on the immune output to a pathogenic input by different skin layers is clearly outlined, and the role of adjuvants and nanotechnology are center pieces.
Sefik Sanal Alkan continues with the theme of immune system receptors but with a view on the use of agonists of pattern recognition receptors (PRRs; TLR receptors in particular) as the newest line of vaccine adjuvants – an area deemed to intensify in the near future. In fact, the chapter by Alkan is a little trip into the very early stage of innate immunity. A few useful diagrams/cartoons help to understand the diversity in pathogen recognition. A brief synopsis of the adjuvant landscape sets the scene for a detailed yet entertaining contextual explanation on the advances on TLR receptor agonists. The significance of antigen/agonist cellular compartmentalization, TLRs cross-talk, and the interplay between them and other elements of the innate immune system are addressed.
The functional and convenient but somewhat “artificial” distinctions between innate, adaptive, humoral and cellular responses introduced by Alkan are further underlined by Murphy and McLoughlin. In their chapter, they describe the multiple roles of the T cell-mediated immune defense as well as the potential of “managing” them) toward enhanced vaccine efficacy. The significance of such approach is framed on the face of the rather ineffective antibody responses to certain pathogens, like commensal or environmental organisms susceptible to become opportunistic pathogens (e.g., S. aureus) or non-culturable or antigenically hypervariable pathogens. This is the natural follow-up to a chapter on PRRs: what happens after the PRRs and their cognate PAMPs (pathogen-associated molecular patterns) ligate? Which are the steps of downstream, the signal transduction cascades. Another textbook fashion chapter, comprehensive, didactic and worth reading. Essentials on T-cell types (features, differentiation, effectors and functions) are covered including the less characterized Th22 or γδT-cells and hybrid (innate/adaptive) cell types (i.e., NKT or γδT-cells). A clear rationale as to why the stimulation of specific T-cell types (and cellular memory) would facilitate clearance of selected pathogens is also provided. Aware of the immune correlates confines they devote distinct attention to species-specific findings in T-cell immunology. The chapter is sealed off by a welcomed diagram on what an ideal vaccine would need to do.
The more technologically orientated chapter by Sarah Gilbert is a perfect follow up to what Murphy and McLoughlin had to say. She dives into technologies that may enable effective T-cell responses and their characterization. Peptide and DNA vaccines, VLPs, virus-vectored vaccines, are some of the sections of this well-organized chapter. Adding to one of the book common themes Gilbert emphasizes the need for suitable biomarkers that enable to infer efficacy in humans from successful animal protection (e.g., malaria). She also introduces novel concepts, like heterologous prime-boost immunization or the need/proposal to transfer information between the fields of infectious disease and cancer therapy to progress beyond the current limitations of vaccinology. Such concluding notion opens the door to the chapter by Britten and Tureci on cancer immunotherapy. They introduce the integration of NGS, immunoinformatic prioritization of highly immunogenic mutant epitopes, and RNA-vaccines, to target widely diverse problem of cancer. A significant contribution by this chapter are the advances on tools for the accurate prediction of the mutanome with an impact on T-cell response induction. The newness of the topic translates into a chapter that deposits the strength not in comprehensive detail but on cutting edge innovation.
Part II: Review
The large and in depth overview of the world of vaccine development encompassing the first section of the book leads to a second section of monographic chapters on some of the usual suspects refractory to vaccine success. Malaria among the protozoa (Bejon et al.), tuberculosis (Agger) and S. aureus among the prokaryotes, and RSV and HIV, which also appeared as illustrations in preceding chapters.
One again, the reliance on animal models that are not ideal surrogates of human infection is put forward as a key cause of such lack of fortune, for instance in RSV (Shaw and co-authors) or S. aureus (Wang and Lee). Importantly, issues of interest brought up for specific pathogens/diseases like RSV are possibly generic across the board. For instance, passive prophylaxis being prohibitive because of cost and impracticality, the promising avenue of maternal immunization, biochemically fastidious antigens, formulations that exaggerate immunological responses resulting on secondary effects, or the use of nucleic acid-based antigen vaccines to circumvent the risks of live attenuated or vectored vaccines. MacLennan illustrates the lack of cross-protection across strains using Salmonella serovars. Last but not least within this section there is an essential chapter by Fecci and co-authors on immunotherapy, reviewing “the current state, applications, adjuncts, and challenges to the successful immune-based treatment of cancer, emphasizing clinical trials.” A number of immunotherapeutic modalities are covered from early-generation inactivated tumor cell immunizations to the less explored anti-idiotype antibody vaccines. The various mechanisms of tumor immune-escape or the limit of the patient pool of peptide vaccines because of HLA-constraints on epitope binding ability, are 2 of the many challenges presented in another chapter not-to-be-missed.
In the spirit of being critical one could always argue that although the book has several drawings, diagrams and tables, it feels a bit dry; it could have benefitted from more illustrations, color, and other publishing tools for emphasis. But being reflective, the book hits its mark and I would recommend it as a must have. In fact, the book leaves the reader looking forward to a sequel in a few years and to an ‘as-soon-as-possible’ complementary counterpart covering issues of ‘infrastructure’, aspects of translation and industry, like GMP and biomanufacturing. Capitalizing on the statement by Censini and co-authors at the end of their chapter, the best is yet to come.