**1. Introduction**

Parasitic helminths that cause human and veterinary diseases can be found in two phyla: *Nematoda* and *Platyhelminthes*. Helminth diseases carry a significant global burden and collectively infect over 1 billion people [1], and cause a disproportionate number of neglected tropical diseases (NTDs). They are a significant cause of morbidity, and often result in permanent disabilities, impaired responses to other infections leading to worse outcomes, and significant social and economical burden upon patients [2–5]. Helminth diseases of livestock further threaten human health and economic development by adversely affecting food security. Antimicrobial treatments are available for helminth infections; however, they come with significant challenges. The number of available drug classes is small, and the ones that are available cause significant side effects and do not protect against reinfection [6]. As drug resistance has been observed in animal nematode models, the catastrophic potential for treatmentrefractory infections exists [7, 8]. These challenges indicate that the ideal strategy for

helminth disease control is prevention rather than treatment. Despite this, there are no known effective vaccines to protect humans against diseases, such as filariasis which carry a high morbidity rate [9, 10]. While practical measures, such as skin coverings (*i.e.*, shoes, waders) and vector control, aid in prevention; these strategies would optimally be coupled with vaccination to ultimately meet the goals of reducing or eliminating disease burden. Continuity of care, treatment side effects, and the potential for drug resistance underscore the urgent need for anti-helminth vaccine development.

Vaccine development against helminth diseases has historically been challenging for a variety of reasons. Helminths are diploid organisms with multiple life stages that are notoriously immunomodulatory. They are able to migrate to multiple tissues and possess numerous immune evasion strategies. The combination of the transient antigen profiles and complex Type 2 immune responses have rendered efforts to immunize patients with killed organisms, attenuated organisms, or single immunogens unsuccessful [11–13]. Many experimental vaccines for ruminant helminth diseases, such as echinococcosis and fascioliasis, have been described, and a vaccine that protects sheep and goats from Barber's pole worm (Barbervax®, developed by the Moredun Foundation) has been licensed in the United Kingdom, Australia, and South Africa. The development of Barbervax® was a lengthy process because of the technology available at the time. Additionally, Barbervax® and other experimental vaccines suffer from modest efficacy and at times complicated dosing regimens. Vaccines for human helminth diseases have yet to be licensed due to failures of traditional vaccine design approaches.

The advent of the "-omics" era has led to renewed enthusiasm for vaccine development against helminth diseases and other NTDs. Vaccines similar to Barbervax® can now be designed and modified in a fraction of the time required. Research efforts utilizing genomics, transcriptomics, and proteomics have been undertaken to identify potential antigens and evaluate their expression kinetics during infection and chronic disease as well as their potential to evolve in response to vaccinated populations. Ultimately, multiomics approaches to vaccine design for helminth infections have the potential to address a multitude of complex factors that are involved in the host–parasite interaction, the intricacies of vaccine design, and the evolutionary implications that follow the introduction of any and all selective pressures. In this chapter, we explore genomic, transcriptomic, and proteomic approaches to the design of vaccines against helminth diseases.

### **2. "Omic" technologies and reverse vaccinology**

Vaccine design was historically approached by manipulating whole infectious agents or their toxins, either by inactivating them or attenuating them. Nextgeneration vaccines (*i.e.*, those deriving from molecular and synthetic biology) are rooted in reverse vaccinology, wherein design begins by examining the complete genomes, transcriptomes, or proteomes of pathogens. Advances made toward anti-helminth vaccines will undoubtedly rely on reverse vaccinology via multi-omic analysis.

The field of genetic and genomic studies has significantly progressed in the last few decades. Scientists have progressed from analyzing single genes and their functions to studying the entire genetic complements—genomes—of organisms. The field of pathogen genomics has facilitated the development of numerous precise diagnostics and vaccines. These vaccines almost exclusively target viral or bacterial pathogens, however [14]. While it is possible to identify potential antigens based on gene sequences, actual transcribed and translated epitopes may look vastly different, and

#### *Perspective Chapter: Multi-Omic Approaches to Vaccine Development against Helminth Diseases DOI: http://dx.doi.org/10.5772/intechopen.102621*

may not elicit the expected immune response. As such, genomics alone may not be the most reliable informant of a potential vaccine target, due to variations in transcription and protein processing that take place. Section 3 of this chapter aims to review genomic approaches to vaccine development against helminth diseases and elucidate critical concepts and issues related to this approach.

As opposed to a genome, a transcriptome is a collection of all non-ribosomal RNA within a cell type, tissue, or organism under a specific set of circumstances or at a specific stage of the life cycle. The study of transcriptomics allows for the focus to be placed on gene expression throughout various steps of the life cycle and under different conditions [15]. Recently, the availability of sequencing technologies has made both genomics and transcriptomics relatively low-cost analyses that can be routinely performed in many laboratories. Transcriptomic analysis of helminths suffered from a bottleneck due to a lack of publicly available genomic databases for parasitic helminths until recently. Some of these challenges still persist, however, because helminths contain many unique sequences that have not previously been annotated with correlation to an associated protein in other organisms [16]. Additionally, transcriptomics can be used to provide insight into immunomodulation and thus vaccine interference mechanisms by being used as profiling tools to screen infected hosts. While transcriptomic analysis provides greater sensitivity in predicting potential antigens that will be expressed during infection, it cannot account for post-transcriptional regulation of protein expression or any non-canonical post-translational modifications. Section 4 of this chapter aims to review transcriptomic approaches to vaccine development against helminth diseases and elucidate critical concepts and issues related to this approach.

Thematically similar to a transcriptome, a proteome is the full complement of mature, modified proteins present under specific conditions within specific cells or tissues [17]. The proteomic analysis allows target-based approaches to parasite interventions, including the development of anti-helminth vaccines. Previously, transcriptomes of pathogens have been used to identify vaccine targets; however, proteomics allows for a greater likelihood of true representation of potential antigens present during infection. This is especially important for helminths and other parasites because protein expression varies greatly based on the life-cycle stage [18, 19]. By describing a parasitic helminth's proteome, we can gain a better insight into antigenic targets that are present at each life stage of the parasite. Similar to transcriptomic analysis, proteomic studies of infected hosts can also aid in understanding and circumventing helminth immunomodulatory mechanisms that could adversely affect vaccine efficacy. These studies can be critical in aiding complex vaccine designs such that poor or adverse responses can be avoided. Section 5 of this chapter aims to review proteomic approaches to vaccine development against helminth diseases and elucidate critical concepts and issues related to this approach.

### **3. Genomic approaches to vaccine development for helminth diseases**

The advent of high-throughput genome sequencing has fundamentally changed the approach to vaccine design, enabling the evaluation and fine-scale targeting of potential vaccine antigens throughout the parasite life cycle. Structural genomic, functional genomic, and epigenomic approaches allow for the identification of an estimated 10- to 100-fold more new antigens for vaccine design and drug target candidates as compared to conventional methods in the same time frame [20].

Furthermore, the completion of the Human Genome Project allows for the evaluation of potential antigens for molecular mimicry by parasites that could cause pathological responses to vaccines, and for a thorough understanding of host-pathogen interactions during active infection that could impact vaccine-derived protection [21].

The use of genome-wide applications for human vaccine development has already been observed for bacterial and viral pathogens. The complete genome sequence of *Neisseria meningitidis* Group B, the agent of meningococcal meningitis, was used to identify several candidate vaccine antigens [22]. Potential antigens were later successfully narrowed down using reverse vaccinology approaches [23]. More recently, the development of both mRNA and Adenovirus-vectored vaccines for the viral pathogen SARS-CoV-2 relied exclusively on viral genomics [24].

The first parasitic nematode, whose genome was sequenced, was *Brugia malayi* [25], and technological advances have allowed for the sequencing of several more human and animal parasites over the past two decades [26–31]. The continually expanding amount of genomic data is available in numerous public databases, including generalized repositories, such as GenBank and EBI, and specialized resources, such as WormBase and HelmDB [16, 32–34]. Additionally, veterinary parasites, such as *Haemonchus contortus*, serve as a model for genomically-based vaccine development due to its status as the only helminth with a commercially available vaccine and its phylogenetic position that makes it an excellent candidate to be compared to *Caenorhabditis elegans*, a model organism closely related to numerous human parasites [35, 36].

Despite their numerous advantages, genomic analyses have several drawbacks. Genomic analyses allow for the identification of numerous potential vaccine antigens; however, antigen target selection for vaccine development can be clouded by the immense number of options, many of which may be nonfunctional or promote regulatory responses in helminths and should be eliminated from vaccine formulations [37]. This was previously observed in the development of candidate vaccines against *Schistosoma mansoni*, where genomic analyses and reverse vaccinology yielded multiple antigen sites and peptides for vaccine development, none of which were protective [38, 39]. Genome sequences also include noncoding intron sections that have to be eliminated during the development process leading to more time-consuming than necessary. Similarly, genomic technology may recommend the creation of monovalent vaccines for helminths that may prove ineffective, as the vaccines may only confer partial immunity [12], or may prove ineffective in human candidates [40].
