Historical Advances in Structural and Molecular Biology and How They Impacted Vaccine Development.

Vaccines are among the greatest tools for prevention and control of disease. They have eliminated smallpox from the planet, decreased morbidity and mortality for major infectious diseases like polio, measles, mumps, and rubella, significantly blunted the impact of the COVID-19 pandemic, and prevented viral induced cancers such as cervical cancer caused by human papillomavirus. Recent technological advances, in genomics, structural biology, and human immunology have transformed vaccine development, enabling new technologies such as mRNA vaccines to greatly accelerate development of new and improved vaccines. In this review, we briefly highlight the history of vaccine development, and provide examples of where advances in genomics and structural biology, paved the way for development of vaccines for bacterial and viral diseases.

Design of a stabilized RBD enables potently neutralizing SARS-CoV-2 single-component nanoparticle vaccines.

Waning immunity and emerging variants necessitate continued vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Improvements in vaccine safety, tolerability, and ease of manufacturing would benefit these efforts. Here, we develop a potent and easily manufactured nanoparticle vaccine displaying the spike receptor-binding domain (RBD). Computational design to stabilize the RBD, eliminate glycosylation, and focus the immune response to neutralizing epitopes results in an RBD immunogen that resolves issues hindering the efficient nanoparticle display of the native RBD. This non-glycosylated RBD can be genetically fused to diverse single-component nanoparticle platforms, maximizing manufacturing ease and flexibility. All engineered RBD nanoparticles elicit potently neutralizing antibodies in mice that far exceed monomeric RBDs. A 60-copy particle (noNAG-RBD-E2p) also elicits potently neutralizing antibodies in non-human primates. The neutralizing antibody titers elicited by noNAG-RBD-E2p are comparable to a benchmark stabilized spike antigen and reach levels against Omicron BA.5 that suggest that it would provide protection against emerging variants.

Progress in vaccine development for infectious diseases-a Keystone Symposia report.

The COVID-19 pandemic has taught us many things, among the most important of which is that vaccines are one of the cornerstones of public health that help make modern longevity possible. While several different vaccines have been successful at stemming the morbidity and mortality associated with various infectious diseases, many pathogens/diseases remain recalcitrant to the development of effective vaccination. Recent advances in vaccine technology, immunology, structural biology, and other fields may yet yield insight that will address these diseases; they may also help improve societies' preparedness for future pandemics. On June 1-4, 2022, experts in vaccinology from academia, industry, and government convened for the Keystone symposium "Progress in Vaccine Development for Infectious Diseases" to discuss state-of-the-art technologies, recent advancements in understanding vaccine-mediated immunity, and new aspects of antigen design to aid vaccine effectiveness.

COVID-19 vaccine design using reverse and structural vaccinology, ontology-based literature mining and machine learning.

Rational vaccine design, especially vaccine antigen identification and optimization, is critical to successful and efficient vaccine development against various infectious diseases including coronavirus disease 2019 (COVID-19). In general, computational vaccine design includes three major stages: (i) identification and annotation of experimentally verified gold standard protective antigens through literature mining, (ii) rational vaccine design using reverse vaccinology (RV) and structural vaccinology (SV) and (iii) post-licensure vaccine success and adverse event surveillance and its usage for vaccine design. Protegen is a database of experimentally verified protective antigens, which can be used as gold standard data for rational vaccine design. RV predicts protective antigen targets primarily from genome sequence analysis. SV refines antigens through structural engineering. Recently, RV and SV approaches, with the support of various machine learning methods, have been applied to COVID-19 vaccine design. The analysis of post-licensure vaccine adverse event report data also provides valuable results in terms of vaccine safety and how vaccines should be used or paused. Ontology standardizes and incorporates heterogeneous data and knowledge in a human- and computer-interpretable manner, further supporting machine learning and vaccine design. Future directions on rational vaccine design are discussed.

SARS-CoV-2-Specific Vaccine Candidates; the Contribution of Structural Vaccinology.

SARS-CoV-2 vaccine production has taken us by storm. We aim to fill in the history of concepts and the work of pioneers and provide a framework of strategies employing structural vaccinology. Cryo-electron microscopy became crucial in providing three-dimensional (3D) structures and creating candidates eliciting T and B cell-mediated immunity. It also determined structural changes in the emerging mutants in order to design new constructs that can be easily, quickly and safely added to the vaccines. The full-length spike (S) protein, the S1 subunit and its receptor binding domain (RBD) of the virus are the best candidates. The vaccine development to cease this COVID-19 pandemic sets a milestone for the pan-coronavirus vaccine's designing and manufacturing. By employing structural vaccinology, we propose that the mRNA and the protein sequences of the currently approved vaccines should be modified rapidly to keep up with the more infectious new variants.

Structure-guided design of multi-epitopes vaccine against variants of concern (VOCs) of SARS-CoV-2 and validation through In silico cloning and immune simulations.

Severe Acute Respiratory Syndrome Corovirus2 (SARS-CoV-2) has been determined to be the cause of the current pandemic. Typical symptoms of patient having COVID-19 are fever, runny nose, cough (dry or not) and dyspnea. Several vaccines are available in markets that are tackling current pandemic. Many different strains of SAR-CoV-2 have been evolved with the passage of time. The emergence of VOCs particularly the B.1.351 ("South African") variant of SARS-CoV-2 has been reported to be more resistant than other SARS-CoV-2 strains to the current vaccines. Thus, the current research is focused to design multi-epitope subunit Vaccine (MEV) using structural vaccinology techniques. As a result, the designed MEV exhibit antigenic properties and possess therapeutic features that can trigger an immunological response against COVID-19. Furthermore, validation of the MEV using immune simulation and in silico cloning revealed that the proposed vaccine candidate effectively triggered the immune response. Conclusively, the developed MEV needs further wet lab exploration and could be a viable vaccine to manage and prevent COVID-19.

Targeting Viral Surface Proteins through Structure-Based Design.

The emergence of novel viral infections of zoonotic origin and mutations of existing human pathogenic viruses represent a serious concern for public health. It warrants the establishment of better interventions and protective therapies to combat the virus and prevent its spread. Surface glycoproteins catalyzing the fusion of viral particles and host cells have proven to be an excellent target for antivirals as well as vaccines. This review focuses on recent advances for computational structure-based design of antivirals and vaccines targeting viral fusion machinery to control seasonal and emerging respiratory viruses.

Bioinformatics and immunoinformatics to support COVID-19 vaccine development.

Severe acute respiratory syndrome coronavirus 2 has infected over 109 000 000 people with 2 423 443 deaths as of February 17, 2021. Currently, there are no approved or consistently effective treatments, and conventional vaccines may take several years for development and testing. In silico methods of bioinformatics, vaccinogenomics, immunoinformatics, structural biology, and molecular simulations can be used for more rapid and precise vaccine design. This paper highlights two major immunoinformatics strategies that are used in designing novel and effective vaccines and therapeutics: reverse vaccinology and structural vaccinology.

Computational design of SARS-CoV-2 spike glycoproteins to increase immunogenicity by T cell epitope engineering.

The development of effective and safe vaccines is the ultimate way to efficiently stop the ongoing COVID-19 pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Built on the fact that SARS-CoV-2 utilizes the association of its Spike (S) protein with the human angiotensin-converting enzyme 2 (ACE2) receptor to invade host cells, we computationally redesigned the S protein sequence to improve its immunogenicity and antigenicity. Toward this purpose, we extended an evolutionary protein design algorithm, EvoDesign, to create thousands of stable S protein variants that perturb the core protein sequence but keep the surface conformation and B cell epitopes. The T cell epitope content and similarity scores of the perturbed sequences were calculated and evaluated. Out of 22,914 designs with favorable stability energy, 301 candidates contained at least two pre-existing immunity-related epitopes and had promising immunogenic potential. The benchmark tests showed that, although the epitope restraints were not included in the scoring function of EvoDesign, the top S protein design successfully recovered 31 out of the 32 major histocompatibility complex (MHC)-II T cell promiscuous epitopes in the native S protein, where two epitopes were present in all seven human coronaviruses. Moreover, the newly designed S protein introduced nine new MHC-II T cell promiscuous epitopes that do not exist in the wildtype SARS-CoV-2. These results demonstrated a new and effective avenue to enhance a target protein's immunogenicity using rational protein design, which could be applied for new vaccine design against COVID-19 and other pathogens.