Title- Vaccine Informatics: Bioinformatics aided Vaccine design and

development and emerging technologies in vaccine development.

Abstract

Bioinformatics tools and strategies are used treating various diseases through vaccine design and
development furnishing a cutting edge in their development. Several approaches have been
applied to reduce the times and costs of vaccine development, mainly focusing on the selection
of appropriate antigens or antigenic structures, carriers, and adjuvants. This has been possible by
the fusion of computational technologies with the application of recombinant DNA technology,
the fast growth of biological and genomic information in database banks, and the possibility of
accelerated and massive sequencing of complete genomes

In addition to the invaluable role of traditional vaccines to prevent diseases, Reverse vaccinology
is an emerging vaccine development approach that starts with the prediction of vaccine targets by
bioinformatics analysis of microbial genome sequences. Predicted proteins are selected based on
desirable attributes. Normal wet laboratory experiments are conducted in a later stage to test all
or selected vaccine targets. The success of vaccination is reflected in its worldwide impact by
improving human and veterinary health and life expectancy. It has been asserted that
vaccination, as well as clean water, has had such a major effect on mortality reduction and
population growth.

In this publication we present the various advancements made in the field of vaccines and
preventive medicine aided by development latest Bioinformatics tools.

Introduction

Bioinformatics refers to the use of computer science, statistical modeling and algorithmic
processing to understand biological data. Bioinformatics is an example of how computer science
has revolutionized other fields. One such field is the preventive medicine which has observed
remarkable scientific and technological progress since the last century is the design and
development of vaccines aiding to prevent diseases.
Bioinformatics aim to solve biological problems using DNA and amino acid sequences and
related information by developing algorithms and biological software of computer to analyze and
record the data related to biology for example the data of genes, proteins, drug ingredients and
metabolic pathways. One goal of bioinformatics is to streamline and interpret, effectively and
timely, information from the genome, transcriptome, and/or proteome. This discipline aims to
promote health benefits including the area of vaccines.

While the history of vaccines is relatively short, vaccines have contributed to dramatic
improvements in public health worldwide. Jenner's description of smallpox prevention in 1796
is the most commonly recognized “start” of vaccine research in European historical documents,
although variolation had been practiced in Asia centuries earlier. Critical advances in vaccine
science took place in the late 19th and early 20th centuries, by scientists such as Pasteur, Koch,
von Behring, Calmette, Guérin, and Ehrlich. Discoveries by these early vaccine researchers
contributed to the development of antiserums, antitoxins, and live, attenuated bacterial vaccines.
The discovery of tissue culture methods for viral and bacterial propagation in vitro during the
period from 1930 to 1950 was a technical advance that enabled the development of vaccines
against many viruses including measles and polio. Further advances in cell culture techniques,
carbohydrate chemistry, molecular biology, and immunology have led to the modern era of
“subunit” vaccine development. The recombinant hepatitis B vaccine, one of the first subunit
vaccines, was licensed in 1986. This marked the beginning of the molecular biology phase of
vaccine development. At present, human vaccines are used in the prevention of more than thirty
infectious diseases. Due to the success of the smallpox eradication campaign in 1960s and 1970s,
the powerful impact of vaccines on human health is universally recognized. In addition, there
exist a large number of animal vaccines.

Exploitation of vaccination as a tool in fighting wide spread diseases has resulted in substantial
strides in the combat against many infectious diseases such as
influenza, smallpox, varicella, pertussis, diphtheria, tetanus, polio, hepatitis, and rotavirus. The
conventional vaccines, which include attenuated or killed agents, might take up to 15 years of
development; this includes cultivation of the desired microorganism at a larger scale and under
proper conditions as well as an effective inactivation with a subsequent evaluation of vaccine
immunogenicity. Although this kind of vaccines has saved countless lives, it can have
unfavorable consequences as adverse effects, induce the disease or, in some instances, even
death.

With the advent of computers and informatics, new approaches have been devised that facilitate
vaccine research and development. Immunoinformatics targets the use of mathematical and
computational approaches to address immunological questions. Since the 1980s, many
immunoinformatics methods have been developed and used to predict T-cell and B-cell immune
epitopes. Indeed, many predicted T- and B-cell immune epitopes are possible epitope vaccine
targets. Experimentally verified immune epitopes are now stored in web-based databases which
are freely available for further analysis. Immune epitope studies are crucial to uncover basic
protective immune mechanisms.

1. Vaccinomics and immunoinformatics

Both help in the characterization of host response to immunization, provides valuable

information on pathogen–host cell interaction to validate candidate antigens. The information
obtained from these disciplines also speeds the identification and characterization of new
antigens. Exploitation of recombinant DNA and sequencing technologies has led to a new
concept in vaccination in which isolated epitopes, capable of stimulating a specific immune
response, have been identified and used to achieve advanced vaccine formulations; replacing
those constituted by whole pathogen-formulations. In this context, bioinformatics approaches
play a critical role on analyzing multiple genomes to select the protective epitopes in silico. It is
conceived that cocktails of defined epitopes or chimeric protein arrangements, including the
target epitopes, may provide a rationale design capable to elicit convenient humoral or cellular
immune responses.

It is important to note that the standard bioinformatics web tools are not enough for detailed
analysis of whole genomes. The immunoinformatics is a discipline whose main objective is to
convert large-scale immunological data, using computational and mathematical approaches, to
understand and organize these large scale data to obtain immunologically meaningful
interpretations. The tools in this field are based on statistical and machine learning system and
are used for studies in modeling molecular interactions (such as antigen processing and
presentation) and also plays a role in defining new hypotheses related to understand the immune
system mechanisms

2. Single cell genomics

Single-cell genomics has helped unravel the population dynamics of unicellular organisms
(Blake et al. 2015; Gawad et al. 2016; Nair et al. 2014; Wang and Song 2017), cancer cells
(Navin et al. 2011), and developmental lineages (Lodato et al. 2015) in multicellular organisms.

Single-cell genomics is a powerful tool for determining the genetic architecture of complex
communities of unicellular organisms. In areas of high transmission, malaria patients are often
challenged by the activities of multiple Plasmodium falciparum lineages, which can potentiate
pathology, spread drug resistance loci, and also complicate most genetic analysis. Single-cell
sequencing of P. falciparum would be key to understanding infection complexity, though efforts
are hampered by the extreme nucleotide composition of its genome. Efforts to eradicate malaria,
of which nearly half of the human population is at risk, can greatly benefit from understanding
the genetic strategies that enable Plasmodium falciparum communities to persist. For instance,
genome sequencing has played a pivotal role in understanding the spread of drug-resistant
parasites (Miotto et al. 2015), global structuring of parasite populations (Manske et al. 2012), and
selection of vaccine candidate loci (Amambua-Ngwa et al. 2012). In locations where malaria is
endemic, patients are often infected with multiple parasite lineages (Conway et al. 1991; Conway
and McBride 1991; Nkhoma et al. 2012, 2013; Snounou et al. 1993). Fundamental details about
the individual malaria infections, such as the number of parasite lineages, their diversity and
relationship to one another, could be addressed by haplotype reconstruction from individual
cells.

3. Molecular Barcoding

This is used for Differentiating Parasite Populations and Their Use in Outbreak and Elimination
Programs. In outbreak investigations and during post-elimination monitoring of malaria, it will
be important to identify the geographic source of malaria parasites. Recently, a molecular
barcode study using 24 SNPs from the P. falciparum genome was developed and tested for its
utility in differentiating parasite populations. Further validation and improvement of such
molecular barcodes and curation of publicly shared databases housing these data will be
invaluable for public health investigations and tracking of drug-resistant parasite populations.
Using multi-locus genotyping of microsatellite markers, it has been shown that recent
Peruvian P. falciparum populations have evolved from five clonal lineages in the post-malaria
eradication era, demonstrating the utility of genomic data in facilitating the public health
response to control and eliminate malaria.

4. NGS – Next generation sequencing technology

Bioinformatics aided next generation sequencing (NGS) data analysis are promising to
identify clinically relevant viruses from a variety of specimen types. There is great interest in
the use of unbiased next-generation sequencing (NGS) technology for comprehensive
detection of pathogens from clinical samples (Dunne et al. 2012; Wylie et al. 2012; Chiu
2013; Firth and Lipkin 2013). Conventional diagnostic testing for pathogens is narrow in
scope and fails to detect the etiologic agent in a significant percentage of cases.

Unbiased NGS holds the promise of identifying all potential pathogens in a single assay
without a priori knowledge of the target. Given sufficiently long read lengths, multiple hits to
the microbial genome, and a well-annotated reference database, nearly all microorganisms
can be uniquely identified on the basis of their specific nucleic acid sequence. Thus, NGS has
widespread microbiological applications, including infectious disease diagnosis in clinical
laboratories (Dunne et al. 2012), pathogen discovery in acute and chronic illnesses of
unknown origin (Chiu 2013), and outbreak investigation on a global level (Firth and Lipkin
2013). Typically relevant pathogenic microorganisms. Computational analysis of
metagenomic NGS data for pathogen identification remains challenging for several reasons.
First, alignment/classification algorithms must contend with massive amounts of sequence
data.

To address these challenges, the most widely used approach is computational subtraction of
reads corresponding to the host (e.g., human), followed by alignment to reference databases
that contain sequences from candidate pathogens. Here we describe SURPI (‘‘sequence-
based ultra rapid pathogen identification’’), a cloud-compatible bioinformatics analysis
pipeline that provides extensive classification of reads against viral and bacterial databases in
 fast mode and against the entire NCBI and DB in comprehensive mode (Fig. 1A). Novel
pathogens are also identified in comprehensive mode by amino acid alignment to viral and/or
NCBI nr protein databases.

5. Development of therapeutic vaccines

Traditional vaccination is the prevention of a specific infectious disease by delivering an

immunogenic antigen derived from the surface of the infectious agent, resulting in immunity
against the foreign organism replicating and establishing an infection. A therapeutic vaccine,
however, can limit or eradicate an already present and established infectious agent or condition.
The development of therapeutic vaccines has depended in part on the ability of DNA vaccination
to induce both humoral and cell mediated immune responses by inoculation of plasmid DNA
containing sequences for transcription and translation, resulting in the in vivo synthesis of an
immunogenic peptide or protein.

Attempts are being made to develop a therapeutic vaccine against HIV that will induce virus-
specific cytotoxic T lymphocytes against HIV, with the goal of having activated T cells destroy
latently infected cells. Other efforts include developing therapeutic vaccines
against Helicobacter pylori, mucosal candidiasis, herpes viruses, and human papillomavirus.
DNA vaccination for hepatitis B virus has shown great promise. The delivery of viral DNA
sequences can induce long-lasting humoral and cell mediated immunity in mice infected with
hepatitis B virus.8,9 In transgenic mice, at least, there is a decrease in or clearance of the
hepatitis B surface antigen, with evidence of induction of antibodies and proliferation of CD4 T
cells.10 Clearly, the capabilities of the immune system to eliminate an infectious agent even after
an infection or disease is established could substantially improve human health. Other important
examples of therapeutic vaccine development include the development of vaccines against
certain cancers.

6. Machine Learning and Vaccine development

Within the last decade, biomedical tools such as genomics and systems biology have
dramatically converged with advances in bioinformatics and machine learning. These tools are
providing an unprecedented opportunity to understand the key components and rules of the
human immune system, transforming how we develop new vaccines and therapeutics.
Exploitation of recombinant DNA and sequencing technologies has led to a new concept in
vaccination in which isolated epitopes, capable of stimulating a specific immune response, have
been identified and used to achieve advanced vaccine formulations; replacing those constituted
by whole pathogen-formulations. In this context, bioinformatics approaches play a critical role
on analyzing multiple genomes to select the protective epitopes in silico. It is conceived that
cocktails of defined epitopes or chimeric protein arrangements, including the target epitopes,
may provide a rationale design capable to elicit convenient humoral or cellular immune
responses.

7. Molecular Docking
Molecular docking is another bioinformatics tool that can be utilized in the selection and
Design of target antigens. It consists of complexing two molecules (protein-protein or protein-
ligand) with best shape complementarity and minimal binding energy. In the field of
Structural vaccinology, molecular docking can be employed to predict the binding of epitopes
to antibodies or to MHC receptors. Candidate antigens can be evaluated through the binding
Energy of the complex, and even mutations can be introduced to improve binding, but
maintaining the specificity of the immune response

8. Vaccines against biological weapons of mass destruction

Interest has increased in biological weapons of mass destruction as terrorists look for methods
with which to inflict harm on the greatest number of people, with the lowest possible cost and
technology needs, while creating mass panic. While vaccines have been licensed against
smallpox, plague, anthrax, and others, only limited amounts of anthrax vaccine are being
produced in the United States for specific risk groups. Limited and ageing stockpiles of smallpox
and plague vaccine are available but are insufficient for large numbers of people.

Because of the ability of biological weapons to infect and kill large numbers of people, and the
risk of person-to-person transmission, vaccines are likely to be the only practical means of
protection.29,30 Second generation vaccines against anthrax, smallpox, and plague are being
developed, and vaccines against other agents of bioterrorism such as the haemorrhagic fever
viruses and others are also in development. However, major obstacles in producing such
vaccines for public use include the need for a financially viable market, the impossibility of
conducting human efficacy trials, the intangible risk: benefit ratio at the public health level, and
governments' reluctance to face the reality of bioterrorism.

Conclusion

Mathematical simulation methods have also been developed to model various vaccine-associated
areas, ranging from analysis of host-pathogen interactions and host-vaccine interactions to cost
cost-effectiveness analyses and simulation of vaccination protocols. The mathematical modeling
approaches have contributed dramatically to the understanding of fundamental protective
immunity and optimization of vaccination procedures and vaccine distribution. Computational
methods have also been applied to model the impact of alternative immunization strategies and
to detect outbreaks of vaccine preventable diseases and safety concerns related to vaccinations as
well. With the large amounts of vaccine literature and data becoming available, it is not only
challenging but crucial to perform vaccine literature mining, generate well-annotated and
comprehensive vaccine databases, and integrate various vaccine data to enhance vaccine
research. Computational vaccine literature mining will allow us to efficiently find vaccine
information. To effectively organize and analyze the huge amounts of vaccine data produced and
published in the post genomics and information era, many vaccine-related databases, such as the
VIOLIN vaccine database and analysis system (http://www.violinet.org/) [13] and AIDS vaccine
trials database (http://www.iavireport.org/trials-db/), have been developed and are available on
the web. However, relational databases are not ideal for data sharing since different databases
may use different schemas and formats. A biomedical ontology is a consensus-based controlled
vocabulary of terms and relations, with associated definitions that are logically formulated in
such a way as to promote automated reasoning.

In summary, vaccine informatics is an emerging field of research that focuses on the

development and applications of computational approaches to advance vaccine research and
development (R&D) and improve immunization programs. Vaccine informatics plays an
important role in every aspect of pre- and post licensure vaccine enterprises.
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