In-Silico Approach in the Development of *Salmonella* Epitope Vaccine

*Hidajah Rachmawati, Raditya Weka Nugraheni and Firasti A.N. Sumadi*

## **Abstract**

In the case of infection control, one of our primary concerns is typhoid fever. According to WHO, typhoid prevalence in Indonesia is highly endemic. There is also the problem with the low efficacy of the available vaccine to prevent the disease. Therefore, there is an urgent need to develop a highly effective typhoid vaccine. One of the phases in vaccine development is an exploratory phase, a research-intensive phase of the vaccine development process designed to identify natural or synthetic antigens that might help prevent or treat a disease through computer in silico prediction targets. The vaccines developed through epitope peptide are designed to be safer, more efficacious, and less expensive than traditional vaccines. A thorough understanding of the disease agent, particularly critical epitopes to induce the appropriate immunological reaction, is required to achieve these aims. Mapping epitope sequences or antigenic peptides from pathogenic proteins recognized by B cells and T cells is crucial for vaccine development. Once the epitopes were identified, the polypeptide production could be produced through protein recombinant technology. The polypeptide vaccine, in the end, could be delivered using a liposomal delivery system.

**Keywords:** epitope, vaccine, typhoid, infection, control

## **1. Introduction**

#### **1.1 The urgency of infection control**

Research about vaccines is urgently required because vaccinations are still the most effective way to prevent illness, disability, and death from vaccine-preventable diseases, such as Diphtheria, Pertussis, and Tetanus. WHO reported that global immunization successfully averts 2–3 million deaths of children every year. However, this achievement can still be improved, which means an additional 1,5 million deaths can be prevented. 19,4 million children worldwide are still missing out on essential vaccines. One of the critical strategies to improve global vaccine coverage is to provide the vaccine at all times and all places, in the best quality.

In the case of infection control, one of the major concerns is typhoid fever. According to WHO, typhoid prevalence in Indonesia is highly endemic. Typhoid disease still has to get serious attention because of its increasingly complex problems, making it difficult to manage, treat, and prevent [1]. This problem becomes even more difficult with the increasing resistance to commonly used antibiotic drugs. At present, there have even been reported cases of resistance to many drugs (multidrug resistance) spread throughout the world [2]. There is also a problem with the low efficacy of the available vaccine to prevent the disease. Therefore, there is an urgent need to develop a highly effective typhoid vaccine.

#### **2. Six stage vaccine development**

According to the CDC [3], there are six vaccine development stages: exploratory, preclinical, clinical development, regulatory review, approval, manufacturing, and quality control.

**Exploratory:** This research-intensive phase of the vaccine development process is designed to identify "natural or synthetic antigens that might help prevent or treat a disease." Antigens might include weakened strains of a particular virus/bacteria.

**Preclinical:** During this phase, researchers use tissue-culture or cell-culture systems and animal testing to determine whether the candidate vaccine will produce immunity. Many candidate vaccines do not move on to the next stage of development because they fail to produce that immunity or prove harmful to test subjects.

**Clinical development:** At this point, a sponsor, usually a private company, submits an application for an Investigational New Drug (IND) to the U.S. Food and Drug Administration (FDA) or BPOM (*Badan Pengawas Obat dan Makanan,* National Food, and Drug Agency) in Indonesia. This step summarizes findings to date and describes how the drug will be tested and created. An institution that will host the clinical trial holds a review board for approval of the application. The FDA has 30 days to approve the application. Once the proposal has been approved, the vaccine must pass three trial stages of human testing.

**Regulatory review and approval**: If a vaccine passes through all three clinical development phases, the vaccine developer submits the registration documents to the regulatory board.

**Manufacturing:** Major drug manufacturers provide the infrastructure, personnel, and equipment necessary to create mass quantities of vaccines. They also reap the profits of successful or widely distributed drugs.

**Quality control:** The approval and distribution are far from the end of the line. Stakeholders must adhere to procedures that allow them to track whether a vaccine is performing as anticipated.

### **3. Improving safety and efficacy of typhoid vaccine using epitope vaccine**

On the other hand, there are vaccine safety and efficacy issues that cannot be ignored. There are three different types of vaccination developed for *S. typhi*: live-attenuated pathogens, inactivated pathogens, and sub-unit vaccines. From the safety point of view, sub-unit vaccines provide better safety profiles because they only use specific proteins and could not be reverted into a virulent form. However, conventional protein isolation usually results in a minimal yield; thus, we need to develop an epitope vaccine. Epitope vaccine is a part of the subunit vaccine, which only uses the antigen's epitope area. The interaction of epitopes and antibodies are particular, and the peptides are well characterized. Therefore, we can produce the peptides for the epitope vaccine using the recombinant technique.

Until now, vaccines for typhoid fever that have been available and show the safety and effectiveness of several clinical trials and are recommended by the CDC

#### *In-Silico Approach in the Development of* Salmonella *Epitope Vaccine DOI: http://dx.doi.org/10.5772/intechopen.96313*

(Center for Disease Control and Prevention, USA) are oral Ty21a vaccine and ViCPS vaccine (Vi capsular polysaccharide) given parenterally [4]. Ty21a is a vaccine that uses a weakened organism (oral attenuated vaccine). This orally administered vaccine is technically more comfortable to use because it does not cause pain but can be virulent if given to an immunocompromised individual. ViCPS vaccine is a parenterally administered independent T-cell antigen that gives uncomfortable pain to the patients [5].

The development of bioinformatics tools and advances in recombinant DNA technology (rDNA) and the knowledge on the host immune response and the genetic background of the pathogen will lead to new vaccines against diseases that currently have few or no control measures in just 1 or 2 years. Through computer in silico predictions to define targets. The vaccines developed through rDNA technologies are safer, more efficacious, and less expensive than traditional vaccines. A thorough understanding of the disease agent, particularly critical epitopes to induce the appropriate immunological reaction, is required to achieve these aims [6].

The epitope is part of the antigen that would be recognized by the antibody [7]. Different epitopes of protein antigens can be identified based on sequences from amino acids or different conformational forms. Some epitopes are hidden in antigen molecules and exposed as a result of physicochemical changes. Epitope vaccine is part of the subunit/peptide vaccine. Peptide vaccines can be used to induce broadspectrum immunity against some serological variants (serovar) or certain pathogenic strains by formulating several non-contiguous immunodominant epitopes and conserved epitopes between different serovars/pathogenic strains.

On the other hand, due to the relatively small peptides, they are often immunogenic weak on their own and therefore require carrier molecules to add chemical stability and adjuvants to induce a robust immune response. Allergenicity and molecular reactogenicity of the carrier itself increases the complexity of the peptide vaccine design. Making peptide vaccines are generally considered safe and costeffective when compared to conventional vaccines [8].
