COMPUTER SIMULATION IN THE DEVELOPMENT OF VACCINES AGAINST COVID-19 BASED ON HLA-SYSTEM ANTIGENS

Genetic variability of population may explain different individual immune responses to the SARS-CoV-2 virus. The use of genome-based technologies makes it possible to develop vaccines by optimizing target antigens. The conventional approach to the development of attenuated or inactivated vaccines sometimes fail to provide potential immunity to the target antigen and has raised safety concerns in many preclinical and clinical trials. Subunit vaccines, such as those predicted by in silico research, can overcome these difficulties. The computer modeling methodology provides the scientific community with a more complete list of immunogenic peptides, including a number of new and cross-reactive candidates. Studies conducted independently of each other with different approaches provide a high degree of confidence in the reproducibility of results. Computer forecasting plays an important role in a quick and cost-effective solution to prevent further spread and ultimately eliminate the pandemic. Most of the effort to develop vaccines and drugs against SARS-CoV-2 is directed towards the thorn glycoprotein (protein S), a major inducer of neutralizing antibodies. Several vaccines have been shown to be effective in preclinical studies and have undergone clinical trials to combat COVID-19 infection. This review presents the profile of in silico predicted immunogenic peptides of the SARS-CoV-2 virus for subsequent functional validation and vaccine development, highlights current advances in the development of subunit vaccines to combat COVID-19, taking into account the experience that has been previously achieved with SARS-CoV and MERS-CoV. Immunoinformatics techniques reduce the time and cost of developing vaccines that together can stop this new viral infection.

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Platforms for Production of Protein-Based Vaccines: From Classical to Next-Generation Strategies

Biomolecules ◽

10.3390/biom11081072 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1072

Author(s):

Raquel Cid ◽

Jorge Bolívar

Keyword(s):

Infectious Diseases ◽

Mammalian Cells ◽

Vaccine Development ◽

Low Cost ◽

Cost Effective ◽

Insect Larvae ◽

Subunit Vaccines ◽

Effective Strategies ◽

Alternative Systems ◽

Inactivated Vaccines

To date, vaccination has become one of the most effective strategies to control and reduce infectious diseases, preventing millions of deaths worldwide. The earliest vaccines were developed as live-attenuated or inactivated pathogens, and, although they still represent the most extended human vaccine types, they also face some issues, such as the potential to revert to a pathogenic form of live-attenuated formulations or the weaker immune response associated with inactivated vaccines. Advances in genetic engineering have enabled improvements in vaccine design and strategies, such as recombinant subunit vaccines, have emerged, expanding the number of diseases that can be prevented. Moreover, antigen display systems such as VLPs or those designed by nanotechnology have improved the efficacy of subunit vaccines. Platforms for the production of recombinant vaccines have also evolved from the first hosts, Escherichia coli and Saccharomyces cerevisiae, to insect or mammalian cells. Traditional bacterial and yeast systems have been improved by engineering and new systems based on plants or insect larvae have emerged as alternative, low-cost platforms. Vaccine development is still time-consuming and costly, and alternative systems that can offer cost-effective and faster processes are demanding to address infectious diseases that still do not have a treatment and to face possible future pandemics.

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SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates

npj Vaccines ◽

10.1038/s41541-021-00292-w ◽

2021 ◽

Vol 6 (1) ◽

Cited By ~ 3

Author(s):

Nikolaos C. Kyriakidis ◽

Andrés López-Cortés ◽

Eduardo Vásconez González ◽

Alejandra Barreto Grimaldos ◽

Esteban Ortiz Prado

Keyword(s):

Neutralizing Antibodies ◽

Large Scale ◽

Vaccine Development ◽

Rna Virus ◽

Protein S ◽

Effective Vaccine ◽

Phase 3 ◽

Vaccine Candidates ◽

Advantages And Disadvantages ◽

The World

AbstractThe new SARS-CoV-2 virus is an RNA virus that belongs to the Coronaviridae family and causes COVID-19 disease. The newly sequenced virus appears to originate in China and rapidly spread throughout the world, becoming a pandemic that, until January 5th, 2021, has caused more than 1,866,000 deaths. Hence, laboratories worldwide are developing an effective vaccine against this disease, which will be essential to reduce morbidity and mortality. Currently, there more than 64 vaccine candidates, most of them aiming to induce neutralizing antibodies against the spike protein (S). These antibodies will prevent uptake through the human ACE-2 receptor, thereby limiting viral entrance. Different vaccine platforms are being used for vaccine development, each one presenting several advantages and disadvantages. Thus far, thirteen vaccine candidates are being tested in Phase 3 clinical trials; therefore, it is closer to receiving approval or authorization for large-scale immunizations.

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Self-Replicating RNA Viruses for RNA Therapeutics

Molecules ◽

10.3390/molecules23123310 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3310 ◽

Cited By ~ 13

Author(s):

Kenneth Lundstrom

Keyword(s):

Clinical Trials ◽

Phase I ◽

Tumor Cells ◽

Neutralizing Antibodies ◽

Ebola Virus ◽

Vaccine Development ◽

Rna Viruses ◽

Antibody Responses ◽

Phase Iii ◽

Phase I Clinical Trials

Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene therapy-based immunotherapy. Numerous studies in animal tumor models have demonstrated that self-replicating RNA viral vectors can generate antibody responses against infectious agents and tumor cells. Moreover, protection against challenges with pathogenic Ebola virus was obtained in primates immunized with alphaviruses and flaviviruses. Similarly, vaccinated animals have been demonstrated to withstand challenges with lethal doses of tumor cells. Furthermore, clinical trials have been conducted for several indications with self-amplifying RNA viruses. In this context, alphaviruses have been subjected to phase I clinical trials for a cytomegalovirus vaccine generating neutralizing antibodies in healthy volunteers, and for antigen delivery to dendritic cells providing clinically relevant antibody responses in cancer patients, respectively. Likewise, rhabdovirus particles have been subjected to phase I/II clinical trials showing good safety and immunogenicity against Ebola virus. Rhabdoviruses have generated promising results in phase III trials against Ebola virus. The purpose of this review is to summarize the achievements of using self-replicating RNA viruses for RNA therapy based on preclinical animal studies and clinical trials in humans.

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In silico identification of vaccine targets for 2019-nCoV

F1000Research ◽

10.12688/f1000research.22507.1 ◽

2020 ◽

Vol 9 ◽

pp. 145 ◽

Cited By ~ 7

Author(s):

Chloe Hyun-Jung Lee ◽

Hashem Koohy

Keyword(s):

T Cell ◽

In Silico ◽

Vaccine Development ◽

De Novo ◽

Cell Receptor ◽

Binding Potential ◽

Hla Alleles ◽

Immunogenic Peptides ◽

Novel Coronavirus ◽

Positional Weight

Background: The newly identified coronavirus known as 2019-nCoV has posed a serious global health threat. According to the latest report (18-February-2020), it has infected more than 72,000 people globally and led to deaths of more than 1,016 people in China. Methods: The 2019 novel coronavirus proteome was aligned to a curated database of viral immunogenic peptides. The immunogenicity of detected peptides and their binding potential to HLA alleles was predicted by immunogenicity predictive models and NetMHCpan 4.0. Results: We report in silico identification of a comprehensive list of immunogenic peptides that can be used as potential targets for 2019 novel coronavirus (2019-nCoV) vaccine development. First, we found 28 nCoV peptides identical to Severe acute respiratory syndrome-related coronavirus (SARS CoV) that have previously been characterized immunogenic by T cell assays. Second, we identified 48 nCoV peptides having a high degree of similarity with immunogenic peptides deposited in The Immune Epitope Database (IEDB). Lastly, we conducted a de novo search of 2019-nCoV 9-mer peptides that i) bind to common HLA alleles in Chinese and European population and ii) have T Cell Receptor (TCR) recognition potential by positional weight matrices and a recently developed immunogenicity algorithm, iPred, and identified in total 63 peptides with a high immunogenicity potential. Conclusions: Given the limited time and resources to develop vaccine and treatments for 2019-nCoV, our work provides a shortlist of candidates for experimental validation and thus can accelerate development pipeline.

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Twenty Years of Progress Toward West Nile Virus Vaccine Development

Viruses ◽

10.3390/v11090823 ◽

2019 ◽

Vol 11 (9) ◽

pp. 823 ◽

Cited By ~ 10

Author(s):

Jaclyn A. Kaiser ◽

Alan D.T. Barrett

Keyword(s):

Clinical Trials ◽

Single Dose ◽

West Nile Virus ◽

Vaccine Development ◽

Cost Effective ◽

Cumulative Number ◽

West Nile ◽

Transmitted Infection ◽

Large Outbreak ◽

Human Vaccine

Although West Nile virus (WNV) has been a prominent mosquito-transmitted infection in North America for twenty years, no human vaccine has been licensed. With a cumulative number of 24,714 neurological disease cases and 2314 deaths in the U.S. since 1999, plus a large outbreak in Europe in 2018 involving over 2000 human cases in 15 countries, a vaccine is essential to prevent continued morbidity, mortality, and economic burden. Currently, four veterinary vaccines are licensed, and six vaccines have progressed into clinical trials in humans. All four veterinary vaccines require multiple primary doses and annual boosters, but for a human vaccine to be protective and cost effective in the most vulnerable older age population, it is ideal that the vaccine be strongly immunogenic with only a single dose and without subsequent annual boosters. Of six human vaccine candidates, the two live, attenuated vaccines were the only ones that elicited strong immunity after a single dose. As none of these candidates have yet progressed beyond phase II clinical trials, development of new candidate vaccines and improvement of vaccination strategies remains an important area of research.

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A Rapid Bead-Based Assay For Screening Of SARS-CoV-2 Neutralising Antibodies

10.1101/2021.10.13.464050 ◽

2021 ◽

Author(s):

Santhik SL ◽

Pramod Darvin ◽

Aneesh Chandrasekharan ◽

Shanakara Narayanan Varadarajan ◽

Soumya Jaya Divakaran ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Fluorescent Protein ◽

Vaccine Development ◽

Neutralizing Antibody ◽

Life Time ◽

Cost Effective ◽

Fluorescent Imaging ◽

Antibody Detection ◽

Screening Assay ◽

Live Virus

Quantitative determination of neutralizing antibodies against SARS CoV2 is of paramount importance in immunodiagnostics, vaccine efficacy testing, and immune response profiling among the vaccinated population. Cost effective, rapid, easy-to-perform assays are essential to support the vaccine development process and immunosurveillance studies. Here, we describe a bead based screening assay for S1 neutralization using recombinant fluorescent proteins of hACE2 and SARS CoV2 S1, immobilized on solid beads employing nanobodies /metal-affinity tags. Nanobody-mediated capture of SARS CoV2 Spike (S1) on agarose beads served as the trap for soluble recombinant ACE2-GFPSpark, inhibited by neutralizing antibody. The first approach demonstrates single color fluorescent imaging of ACE2 GFPspark binding to His tagged S1 Receptor Binding Domain (RBD His) immobilized beads. The second approach is dual color imaging of soluble ACE2 GFPSpark to S1 Orange Fluorescent Protein (S1 OFPSpark) beads. Both methods showed a good correlation with the gold standard pseudovirion assay and can be adapted to any fluorescent platforms for screening. Life time imaging of the ACE2 GFPSpark confirmed the interaction of ACE2 and S1 OFPSpark on beads. The self-renewable source of secreted recombinant proteins from stable cells and its direct use without necessitating purification renders the platform a cost-effective and rapid one than the popular pseudovirion assay and live virus-based assays. Any laboratory with minimum expertise can rapidly perform this bead assay for neutralizing antibody detection using stable engineered cells.

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Mice immunized with the vaccine candidate HexaPro spike produce neutralizing antibodies against SARS-CoV-2

10.1101/2021.02.27.433054 ◽

2021 ◽

Author(s):

Chotiwat Seephetdee ◽

Nattawut Buasri ◽

Kanit Bhukhai ◽

Kitima Srisanga ◽

Suwimon Manopwisedjaroen ◽

...

Keyword(s):

Low Income ◽

Neutralizing Antibodies ◽

High Titer ◽

Physical Property ◽

Cost Effective ◽

Low Income Countries ◽

Subunit Vaccines ◽

Neutralization Activity ◽

Boost Regimen ◽

Global Logistics

Updated and revised versions of COVID-19 vaccines are vital due to genetic variations of the SARS-CoV-2 spike antigen. Furthermore, vaccines that are safe, cost-effective, and logistically friendly are critically needed for global equity, especially for middle to low income countries. Recombinant protein-based subunit vaccines against SARS-CoV-2 have been reported with the use of the receptor binding domain (RBD) and the prefusion spike trimers (S-2P). Recently, a new version of prefusion spike trimers, so called "HexaPro", has been shown for its physical property to possess two RBD in the "up" conformation, as opposed to just one exposed RBD found in S-2P. Importantly, this HexaPro spike antigen is more stable than S-2P, raising its feasibility for global logistics and supply chain. Here, we report that the spike protein HexaPro offers a promising candidate for SARS-CoV-2 vaccine. Mice immunized by the recombinant HexaPro adjuvanted with aluminium hydroxide using a prime-boost regimen produced high-titer neutralizing antibodies for up to 56 days after initial immunization against live SARS-CoV-2 infection. In addition, the level of neutralization activity is comparable to that of convalescence sera. Our results indicate that the HexaPro subunit vaccine confers neutralization activity in sera collected from mice receiving the prime-boost regimen.

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In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials

10.26434/chemrxiv.12123204.v3 ◽

2020 ◽

Author(s):

Seref Gul ◽

Onur Ozcan ◽

sinan asar ◽

Alper Okyar ◽

Ibrahim Barıs ◽

...

Keyword(s):

Clinical Trials ◽

Rna Polymerase ◽

Protein Interactions ◽

In Silico ◽

Cost Effective ◽

Md Simulations ◽

Viral Rna ◽

Free Energies ◽

Rna Dependent Rna Polymerase ◽

Approved Drugs

Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxyquinoline. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CLpro) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CLpro based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2-infected patients.

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Recombinant subunit vaccines for soil-transmitted helminths

Parasitology ◽

10.1017/s003118201700138x ◽

2017 ◽

Vol 144 (14) ◽

pp. 1845-1870 ◽

Cited By ~ 13

Author(s):

JASON B. NOON ◽

RAFFI V. AROIAN

Keyword(s):

Large Scale ◽

Vaccine Development ◽

Cost Effective ◽

Gastrointestinal Nematodes ◽

Human Beings ◽

Expression Systems ◽

Subunit Vaccines ◽

The Public ◽

Soil Transmitted Helminths ◽

Minimum Number

SUMMARYSoil-transmitted helminths (STHs) collectively infect one fourth of all human beings, and the majority of livestock in the developing world. These gastrointestinal nematodes are the most important parasites on earth with regard to their prevalence in humans and livestock. Current anthelmintic drugs are losing their efficacies due to increasing drug resistance, particularly in STHs of livestock and drug treatment is often followed by rapid reinfection due to failure of the immune system to develop a protective response. Vaccines against STHs offer what drugs cannot accomplish alone. Because such vaccines would have to be produced on such a large scale, and be cost effective, recombinant subunit vaccines that include a minimum number of proteins produced in relatively simple and inexpensive expression systems are required. Here, we summarize all of the previous studies pertaining to recombinant subunit vaccines for STHs of humans and livestock with the goal of both informing the public of just how critical these parasites are, and to help guide future developments. We also discuss several key areas of vaccine development, which we believe to be critical for developing more potent recombinant subunit vaccines with broad-spectrum protection.

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Vaccines against Coronavirus Disease: Target Proteins, Immune Responses, and Status of Ongoing Clinical Trials

Journal of Pure and Applied Microbiology ◽

10.22207/jpam.14.4.03 ◽

2020 ◽

Vol 14 (4) ◽

pp. 2253-2263

Author(s):

Rike Syahniar ◽

Maria Berlina Purba ◽

Heri Setiyo Bekti ◽

Mardhia Mardhia

Keyword(s):

Clinical Trials ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Host Cells ◽

Rapid Transmission ◽

Adequate Dosage ◽

Immunogenic Response ◽

Selection Of

The coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected more than 26 million individuals and caused 871,166 deaths globally. Various countries are racing against time to find a vaccine for controlling the rapid transmission of infection. The selection of antigen targets to trigger an immune response is crucial for vaccine development strategies. The receptor binding domain of the subunit of spike 1 protein is considered a promising vaccine candidate because of its ability to prevent attachment and infection of host cells by stimulating neutralizing antibodies. The vaccine is expected to mount a sufficient immunogenic response to eliminate the virus and store antigenic information in memory cells for long-term protection. Here, we review the ongoing clinical trials for COVID-19 vaccines and discuss the immune responses in patients administered an adequate dosage to prevent COVID-19.

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