Network-based algorithms have become increasingly essential in vaccine development. To predict possible epitopes, these algorithms employ methods like deep neural networks, gradient-boosting decision trees, and artificial neural networks [3]. MARIA and NetMHCPan4 are two examples of these vaccine development algorithms [3]. SARS-CoV-2 T-cell and B-cell epitopes have been identified using network-based algorithms [3]. Vaxign-ML is a machine-learning tool that uses network-based algorithms to rank non-structural proteins as potential SARS-CoV-2 vaccine candidates [3]. Machine learning models for the development of the COVID-19 vaccine have also used network-based algorithms [3]. These algorithms were used to identify stable binding SARS-CoV-2 epitopes with high prediction binding scores that can bind to HLA allotypes [3]. Using these techniques, researchers can gain a better understanding of the virus and create vaccines that are more effective at preventing its spread.

Network-based algorithms are a promising avenue for COVID-19 vaccine development. This is due to stochastic computational simulations demonstrating that network structure has a significant impact on disease spread [4]. As a result of using network-based algorithms, researchers can gain a better understanding of the COVID-19 spread process as well as prevention strategies. Simulations show that the “Ring of Vaccination” approach, for example, would vaccinate a large proportion of the population while preventing new COVID-19 waves [4]. Furthermore, the dynamics of the COVID-19 pandemic in various countries can be recapitulated using various network models [4]. Through the application of network-based algorithms in vaccine development, scientists can learn more about the transmission of COVID-19 and create vaccines that are more successful in halting the disease’s spread. Given the current pandemic, which has harmed millions of people globally and continues to pose a serious threat to public health, this is especially crucial.

One of the major challenges in developing a COVID-19 vaccine is the complex network structure of the virus and the human body. Several network-based algorithms have been proposed for drug and vaccine development [5], such as the novel network-based algorithm used in this study for drug discovery and development [6]. A multilayer network-based approach allows for simple, unambiguous modeling of complex systems, but it can be computationally intensive [7]. In addition, there is a global race to develop appropriate vaccines due to a dearth of potent medications and vaccines [4,5]. Traditional machine learning-based image classification algorithms can also be limited in their ability to aid in vaccine development [8]. Although several COVID-19 vaccines are now available, there is still a need for further research and clinical trials to develop a searchable drug repository and a better understanding of the disease. The development of new vaccines usually takes ten years; however, by enhancing our mechanistic and network-based understanding of disease, network-based algorithms may be able to shorten this time [9]. To investigate the efficacy of various vaccination approaches and stop fresh waves of COVID-19 infections, the epidemiological network model utilized in this research may prove to be a useful instrument [10]. However, there are still many issues that need to be resolved before network-based algorithms can significantly contribute to the creation of COVID-19 vaccines and treatments.

Expression-based algorithms are vital in vaccine development, as they optimize the immunogenicity and expression of the vaccine by enhancing the sequence to increase its efficacy and safety [11]. One expression-based technique that is frequently used in the development of mRNA vaccines to increase stability, safety, and efficacy is codon optimization [12]. The balance between host tRNA availability and codon usage frequency is adjusted to achieve this optimization, which improves translation efficiency and target antigen in vivo expression [12]. Additionally, if codon optimization is modified to account for the preference of skeletal muscle, intramuscular injections of mRNA vaccines can improve the immune response [12]. With just a few clicks, scientists can create a better sequence using a variety of online codon optimization tools and algorithms that are available for various research applications [12,13]. However, some of these optimization algorithms may have shortcomings, as seen with BioNTech and Moderna’s algorithms [12]. Expression-based algorithms can also be used to optimize mRNA sequences for production and expression in vaccine development [13]. For example, a baculovirus expression system and insect cells can be used to produce recombinant vaccines. Using the Sf9 insect cell expression system, this system was utilized to create the modified S protein found in the NVX-CoV2373 vaccine [11]. Recombinant S protein and RBD vaccines are made using expression-based algorithms, while protein subunit vaccines are likewise based on systemically expressed viral proteins or peptides using diverse cell-expressing systems [11]. Moreover, two residues (K986 and V987) can be changed to proline to stabilize the pre-fusion conformation of S protein [11]. Expression-based algorithms can also be used in quality control steps of vaccine development to ensure optimal expression and efficacy.

Developing a COVID-19 vaccine that is both safe and effective remains a major challenge. One vaccine based on the DNA platform and two vaccines based on the mRNA platform have currently been approved for widespread use [14]. Even though many DNA and mRNA vaccines against COVID-19 are in preclinical and clinical trials, the use of expression-based algorithms in vaccine development is still limited. Despite the use of machine learning, rational COVID-19 vaccine development is still dependent on understanding the fundamental host-coronavirus interactions and protective immune mechanisms. Vaccine development outcomes may differ depending on the experimental setting [15]. Through research, six proteins were discovered, including S protein and five non-structural proteins, which are adhesins and are crucial for host invasion and virus adhesion [15]. COVID-19 vaccine candidates were predicted using the reverse vaccinology tools Vaxign and Vaxign-ML [15]. The S, nsp3, and nsp8 proteins are expected to induce highly protective antigenicity; however, vaccine candidates developed using these proteins may suffer from safety issues and incomplete induction of protection [15]. The nsp3 protein was chosen for further study because it has not been examined in any coronavirus vaccine trials [15]. The MAC1 domain of the nsp3 protein has sequence homology with the human single ADP-ribosyltransferase PARP14, even though the entire virus as well as the S protein nucleocapsid are proteins and vaccine development against SARS and MERS tested membrane proteins [15]. Furthermore, viral adhesion proteins can activate T cells or cause autoreactions with self-antigens, reducing host reactivity to viruses [15]. Therefore, in addition to antigenicity, safety is also crucial for the development of COVID-19 vaccines [15]. Additionally, vaccination may pose safety risks that cannot be assessed by machine learning [15].

The development of COVID-19 vaccines, including those using expression-based algorithms, owes much to artificial intelligence and machine learning algorithms. Sharma noted that clinical trials developing COVID-19 vaccines and drugs benefit from the use of artificial intelligence-based models [16]. To rationally develop a COVID-19 vaccine, Ong explained how to apply reverse vaccinology and machine learning [15]. A vaccine created using an expression-based algorithm is Janssen’s COV-2-S vaccine, which uses a modified S protein of the Ad26 expression gene [11]. To develop a COVID-19 vaccine, Fang and colleagues developed a unique two-part vector system using taRNA containing a trans-replicon expression algorithm [12]. Furthermore, Magazino et al. studied the impact of vaccination on COVID-19 mortality using machine learning algorithms [17]. Amri et al. used an algorithm to compare the immunogenicity of full-length S-type and S1-type MERS-CoV vaccines to assess vaccine effectiveness [18]. Overall, these studies suggest that the development of COVID-19 vaccines, including those produced using expression-based algorithms, benefits from the application of artificial intelligence and machine learning algorithms.

An effective method for anticipating how ligands will interact with target proteins is to use integrated docking simulation algorithms. These algorithms obtain precise predictions of molecular interactions by utilizing virtual screening and multiple docking tools [19]. Integrated docking simulation algorithms such as PatchDock can provide the dynamic characteristics of the designed system and complexes and guess the interactions between molecules by simulating the real molecular docking environment [20]. An algorithm called PatchDock is used to undo docked molecules to form protein–protein complexes. It can accurately predict global properties such as the formation of hydrogen bonds and the conformation of molecules forming complexes [20]. Glide, AD Vina, and rDock are some other built-in docking simulation algorithms [19]. These tools were used to analyze potential ligand candidates that can inhibit SARS-CoV-2 Mpro [19]. Protein–ligand structures with low docking scores interact with amino acid residues in Mpro, and the docking score values derived from these algorithms indicate the effectiveness of the ligand [19]. Ultimately, integrated docking simulation algorithms provide a valuable means of predicting protein–ligand interactions, which can be used to design more effective drugs for a wide variety of diseases.

Integrated docking simulation algorithms are a useful tool for COVID-19 vaccine research and development. Potential vaccine targets like the spike S-protein are found using these algorithms [21]. Molecular docking and modeling are two important parts of in silico research that can help develop multi-epitope vaccines [21]. Linkers are crucial for maintaining the stability of protein structures by establishing flexible conformations, protein folding, and segregation of functional domains [21]. Epitopes removed in candidate vaccine constructs were calculated using SARS-CoV2 proteins using helper T lymphocytes, cytotoxic T lymphocytes, and B cells. Vaccine candidates are produced by fusing peptide epitopes with linkers to simplify vaccine design [21]. Molecular docking technology was used to study the immune receptor binding affinity of putative vaccine candidates [21]. Using scoring functions, molecular docking programs are crucial for early-stage drug discovery efforts as they can predict binding affinities between proteins and ligands [22,23]. Scientists around the world are using these integrated docking simulation algorithms for drug discovery in response to the COVID-19 pandemic [22]. One algorithm that can achieve this is the HADDOCK server, which can cluster different vaccines into different structures and clusters by docking them with the ACE-2 receptor. The top cluster score, Z-score, and water-refined models can be used to illustrate the docking interactions between the h-ACE-2 protein complex and suggested multi-epitopic vaccines. The static interaction parameters between the construct vaccines and ACE-2 are shown in a table. In the process of developing a COVID-19 vaccine, integrated docking simulation algorithms like the HADDOCK server can be used to find possible medications for the disease’s treatment [21]. To improve the immune response, construct vaccines with high antigenicity were mixed with multi-epitope vaccines [21]. The broad-spectrum peptide-binding repertoires of various HLA alleles were determined using docking simulation algorithms [21]. Various vaccine constructs were then employed, combining distinct epitopes from the S1 and S2 domains of the spike SARS-CoV-2 protein.

When developing COVID-19 vaccines, the use of integrated docking simulation algorithms can be very advantageous. To predict the antigenic epitopes against SARS-CoV-2 for the creation of the vaccine, these algorithms have been used in several studies [24]. The dynamics of biological macromolecules in response to different stimuli, such as interactions with other molecules, are studied through molecular dynamics simulations, which incorporate Newton’s laws of motion [23]. Molecular docking and dynamics simulations can be used not only to predict antigenic epitopes but also to investigate the binding interactions between ligand and protein molecules [25]. By sifting through a sizable compound library, this approach can find drug leads and make it easier to design novel drug candidates for COVID-19 therapies [22]. Additionally, FDA-approved medications can be virtually screened for the SARS-CoV-2 virus using computational ligand-receptor binding modeling techniques, which could lead to the discovery of possible repurposing medications [19]. Furthermore, an integrative docking and simulation-based approach can also be used to develop epitope-based COVID-19 vaccines. The application of these algorithms can expedite the development of drugs and vaccines by reducing the time and cost associated with experimental studies and providing insights into molecular interactions that may not be possible to observe experimentally.