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Bioinformatics: A new approach to vaccine development

Daniel Misael Garza García

BS, Genome Biotechnology

Universidad Autónoma de Nuevo León

Special thanks to Juan Manuel Martínez Villalobos

The battle against microorganisms capable of causing diseases such as some viruses and bacteria, have represented one of the longest battles for humanity and as advances in biology and medicine increase, better alternatives are increasingly being used to counteract these diseases and in turn, to protect ourselves in case we face them again. Vaccines fulfil this function; they can prepare the immune system by providing it with the necessary elements that help it learn and understand about the infectious agent in order to generate immunity against it.

The first reports of the vaccination date back to the 7th century, when Indian Buddhists ingested snake venom to become immune to its effects. In the 10th century China, “variolization” was carried out, a practice that sought to obtain protection against smallpox by introducing the virus into a susceptible person, in order to reduce its virulence. Centuries later, the names of various scientists would be marked in history, due to their contributions in the development of vaccines. Such is the case with Francis Home and Edward Jenner, for their contributions to the development of a vaccine against measles and smallpox, respectively.

The chemist and biologist Louis Pasteur, who discovered the human rabies vaccine, testing it on the child Joseph Meister, who would become the first human protected against this infection.

And so on, Jaime Ferrán and Beumer-Peiper, who would develop vaccines against typhoid fever and cholera, respectively; each one of these researchers made a difference in their contribution to vaccine development by promoting immunity in individuals who used their vaccines to protect themselves.

Characteristics of an ideal epitope for use as a vaccine
Immunogenicity is the ability to induce a humoral or cell-mediated immune response. A substance that induces a specific immune reaction is called an immunogen. Antigenicity is the ability to specifically bind to end-response products such as secreted antibodies and T-cell surface receptors.

Molecules that have immunogenicity possess antigenicity, but not the reverse. Some small molecules, called haptens, are antigenic but incapable of inducing a specific immune reaction by themselves, that is, they lack immunogenicity. In attempts to develop a vaccine, as well as a synthetic peptide, it is necessary to analyze the amino acid sequence of a protein antigen in order to determine hydrophobic peptides.
T cell epitopes are almost always composed of internal peptides that are mostly hydrophilic residues. Consequently, synthetic hydrophobic peptides are more likely to represent T cell epitopes, while synthetic hydrophilic peptides represent accessible B cell epitopes and give rise to an antibody-based response.

Bioinformatics is the result of the fusion between information technology and computer science. The use of technology in biological research has led to current information management strategies that allow better data storage, as well as better analysis models.
Bioinformatics played a major role in the 90´s, emerging as a research area due to the development of sequencing projects such as the human genome. The development of bioinformatics has led to the discovery of relationships between mutations, alterations in biological functions, evolution of different organisms, as well as the enormous contribution to disciplines such as genomics, proteomics and phylogenetics. Furthermore, bioinformatics enables the comparison and analysis of different kinds of biological data in a fast and reliable way.

Currently, there are secondary bases, also called knowledge bases because they contain the accumulated biological knowledge necessary to understand the functioning and levels of biological organization. These bases include all protein families with their functional domains and their three-dimensional structures, as well as the different signalling pathways.

The fold recognition method (threading) assumes that the three-dimensional structures of the proteins are more conserved than the sequences. There are various techniques to carry out such recognition, such as the prediction of secondary structures and advanced sequence comparisons or tests of sequence compatibility with a known three-dimensional folding.

AB initio prediction
Ab initio prediction consists of finding the most stable three-dimensional protein structure with a computer program from the linear amino acid sequence, which corresponds to the conformation with the lowest energy. Ab initio modeling is of great importance in disciplines such as proteomics since it allows predicting the structure of a protein, and in physicochemical principles it allows to mimic the folding of proteins. At present, ab initio precision is low, and success is limited to small proteins (<100 residues).

Reverse vaccinology
The availability of the genomes of many microorganisms of medical importance has allowed the discovery of new antigens that had not been found by conventional techniques, emerging a new approach in the development of vaccines. This approach has been called reverse vaccinology. It is based on the analysis of genome sequences, with the use of bioinformatics tools that make it possible to identify the most probable antigens to be candidates to induce an immune response.

Candidate proteins are selected based on the prediction of their function, such as accessibility and secretion, to later be cloned, expressed and analyzed to confirm their cellular localization in vitro and using animal models, evaluate their immunogenicity and protective capacity.

The application of bioinformatics using the reverse vaccinology approach allowed for the first time the development of a vaccine against the serogroup B Neisseria meningitis (MenB) from the identification of epitopes by analyzing the genome sequence. Furthermore, the development of vaccines using reverse vaccinology has been successfully applied against other pathogenic microorganisms, such as Bacillus anthracis, Porphyromonas gingivalis, Chlamydia pneumoniae, Streptococcus pneumoniae, Helicobacter pylori and Mycobacterium tuberculosis.

Currently, the accumulated knowledge in disciplines such as virology, molecular biology, immunology, and bioinformatics have allowed the development of new strategies for the design of vaccines. It is possible to classify this advance in different generations according to their development characteristics; the first generation is based on live, weakened or inactivated microorganisms, the second on proteins that can stimulate the immune system through recombinant antigens (proteins that are produced in bacteria, yeasts, plants) and finally, the third generation, vaccines of DNA, which contain the genetic information of the pathogen allowing our cells to synthesize the elements necessary to generate immunity.

This is how bioinformatics represents the fusion of biological and computational sciences that in general seeks to increase the understanding of complex biological processes. The human genome project set the tone for new discoveries, showing a clear example of the potential of bioinformatics in human health, thus revolutionizing the methods established by Pasteur.

Reference (Jan-21-A3)

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