Oral and nasal vaccination: current prospects, challenges, and impact of nanotechnology-based delivery systems

Abstract Currently, mucosal vaccine administration has stood out as an easier and non-invasive application method. It can also be used to induce local and systemic immune responses. In the COVID-19 pandemic context, nasal and oral vaccines have been developed based on different technological platforms. This review addressed relevant aspects of mucosal vaccine administration, with emphasis on oral and nasal vaccinations, in addition to the importance of using nanotechnology-based delivery systems to enable these strategies.

Strategic construction of mRNA vaccine derived from conserved and experimentally validated epitopes of avian influenza type A virus: a reverse vaccinology approach.

Purpose: The development of vaccines that confer protection against multiple avian influenza A (AIA) virus strains is necessary to prevent the emergence of highly infectious strains that may result in more severe outbreaks. Thus, this study applied reverse vaccinology approach in strategically constructing messenger RNA (mRNA) vaccine construct against avian influenza A (mVAIA) to induce cross-protection while targeting diverse AIA virulence factors. Materials and Methods: Immunoinformatics tools and databases were utilized to identify conserved experimentally validated AIA epitopes. CD8+ epitopes were docked with dominant chicken major histocompatibility complexes (MHCs) to evaluate complex formation. Conserved epitopes were adjoined in the optimized mVAIA sequence for efficient expression in Gallus gallus. Signal sequence for targeted secretory expression was included. Physicochemical properties, antigenicity, toxicity, and potential cross-reactivity were assessed. The tertiary structure of its protein sequence was modeled and validated in silico to investigate the accessibility of adjoined B-cell epitope. Potential immune responses were also simulated in C-ImmSim. Results: Eighteen experimentally validated epitopes were found conserved (Shannon index <2.0) in the study. These include one B-cell (SLLTEVETPIRNEWGCR) and 17 CD8+ epitopes, adjoined in a single mRNA construct. The CD8+ epitopes docked favorably with MHC peptide-binding groove, which were further supported by the acceptable ΔGbind (-28.45 to -40.59 kJ/mol) and Kd (<1.00) values. The incorporated Sec/SPI (secretory/signal peptidase I) cleavage site was also recognized with a high probability (0.964814). Adjoined B-cell epitope was found within the disordered and accessible regions of the vaccine. Immune simulation results projected cytokine production, lymphocyte activation, and memory cell generation after the 1st dose of mVAIA. Conclusion: Results suggest that mVAIA possesses stability, safety, and immunogenicity. In vitro and in vivo confirmation in subsequent studies are anticipated.

Immunoinformatics Approaches in Designing Vaccines Against COVID-19.

Since the onset of the COVID-19 pandemic, a number of approaches have been adopted by the scientific communities for developing efficient vaccine candidate against SARS-CoV-2. Conventional approaches of developing a vaccine require a long time and a series of trials and errors which indeed limit the feasibility of such approaches for developing a dependable vaccine in an emergency situation like the COVID-19 pandemic. Hitherto, most of the available vaccines have been developed against a particular antigen of SARS-CoV, spike protein in most of the cases, and intriguingly, these vaccines are not effective against all the pathogenic coronaviruses. In this context, immunoinformatics-based reverse vaccinology approaches enable a robust design of efficacious peptide-based vaccines against all the infectious strains of coronaviruses within a short frame of time. In this chapter, we enumerate the methodological trajectory of developing a universal anti-SARS-CoV-2 vaccine, namely, "AbhiSCoVac," through advanced computational biology-based immunoinformatics approach and its in-silico validation using molecular dynamics simulations.

Relapsing myocarditis following initial recovery of post COVID-19 vaccination in two adolescent males - Case reports.

Whilst there has been significant public health benefits associated with global use of COVID-19 spike protein vaccines, potential serious adverse events following immunization have been reported. Acute myocarditis is a rare complication of COVID19 vaccines and often it is self-limiting. We describe two cases experiencing recurrent myocarditis following mRNA COVID-19 vaccine despite a prior episode with full clinical recovery. Between September 2021-September 2022 we observed two male adolescents with recurrent myocarditis related to mRNA-based-COVID19 vaccine. During the first episode both patients presented with fever and chest pain few days after their second dose of BNT162b2 mRNA Covid-19 Vaccine (Comirnaty®). The blood exams showed increased cardiac enzymes. In addition, complete viral panel was run, showing HHV7 positivity in a single case. The left ventricular ejection fraction (LVEF) was normal at echocardiogram but cardiac magnetic resonance scanning (CMR) was consistent with myocarditis. They were treated with supportive treatment with full recovery. The 6 months follow-up demonstrated good clinical conditions with normal cardiological findings. The CMR showed persistent lesions in left ventricle 's wall with LGE. After some months the patients presented at emergency department with fever and chest pain and increased cardiac enzymes. No decreased LVEF was observed. The CMR showed new focal areas of edema in the first case report and stable lesions in the second one. They reached full recovery with normalization of cardiac enzymes after few days. These case reports outline the need of strict follow-up in patients with CMR consistent with myocarditis after mRNA-based-COVID19 vaccine. More efforts are necessary to depict the underlying mechanisms of myocarditis after SARS-CoV2 vaccination to understand the risk of relapsing and the long-term sequelae.

A Novel Design of COVID-19 Vaccine with High Effectiveness and Popularization

In December 2019, a virus named SARS-CoV-2 broke out in Wuhan in China. The spread of the virus has brought great challenges to the global medical system. At present, over 6 million people died of the diseases caused by the virus. Under these situations, various corresponding vaccines such as Oxford, Pfizer, and Moderna vaccines have been developed and applied to the population. Nevertheless, due to the development of variants of the virus such as Delta and Omicron, there has been a decline in the effectiveness of current vaccines to some extent. Moreover, the proportion of people who have been inoculated with the COVID-19 vaccine in low-income countries is less than 20%. In this case, we designed a new vaccine to deal with these problems. Specifically, we utilized the antigens (RBD, HR1, and HR2) of the virus to cope with its potential variants of it, increasing the effectiveness of the vaccine. Moreover, we designed a new cell expression system to increase the efficiency of vaccine production by using CHO cells as host cells, Neo gene as a selective marker, CMV as a promoter, MBP as affinity tag, and β-globin as a terminator. Eventually, it was worth stating that our designed vaccine was hypothesized to be practicable and functional, it just started one step on the way to tackling the variants of this virus and increasing the productivity of the vaccine. The detailed experiments still needed to be implemented to verify the feasibility of our design. © 2023 SPIE.

Epitope Masking during a Recall Response: Implications for Covid and Hiv Vaccines

Some of the first immunological experiments of the 20th century-on antibody feedback inhibition-demonstrated that past exposure does not merely expedite the humoral response to secondary challenges but, rather, alters the nature of that response. Despite this history, the mechanisms underpinning these classic observations and their relationship to modern vaccine design remain obscure. Circulating antibodies produced during a primary challenge can have enhancing or, conversely, inhibitory effects on later humoral responses. Using preclinical vaccine models, we dissected this apparent contradiction to find that the interaction between serum antibodies and the entry of cognate naive B cell lineages to germinal centers was determined by the interplay of breadth, affinity, and titer. Epitope-focused vaccine designs for HIV-1 elicit circulating antibodies capable of entirely obstructing their cognate naive B cells, with important implications for the ongoing design of boostphase immunogens. Conversely, SARS-CoV receptor binding domain (RBD) immunization elicits a polyclonal serum response that enhances the proportion of high-affinity cognate B cells in germinal centers, providing a partial explanation for the effectiveness of current boost protocols but also presaging diminishing returns unless new epitopes are introduced. The resolution of these surface-level contradictions points toward a unified interactive model and emphasizes that, to move vaccinology forward, the basic biology of the humoral immune system cannot remain a black box.

Computational approaches in COVID-19 vaccine development

The deadly outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that began in Wuhan city of China, late in 2019, has caused thousands of causalities globally, where the infected subjects show severe respiratory illness, fever, and pneumonia-like symptoms. The efforts to design a safe, cost-effective, and most importantly efficient coronavirus disease 2019 (COVID-19) vaccine have been fruitful so far, and approximately 10 vaccines have been approved by the World Health Organization and many more in trials. However, this virus possesses the exceptional ability to rapidly mutate and spread at an exponential level. Research and development activities around the world, directed at vaccine development, were accelerated after the SARS-CoV-2 gene sequence was made publicly available. The economic and humanitarian pressure of the ongoing COVID-19 pandemic is necessitating evaluation of alternative vaccine production platforms and the use of innovative paradigms to speed up the development. Hence, more determination is required to develop vaccines that have higher efficacy and specificity. Some of the regimes being followed are discussed in this chapter along with the current developments. © 2023 Elsevier Inc. All rights reserved.

The story of a pandemic foretold: Focus on the covid-19 vaccine

In November 2002, cases of Severe Acute Respiratory Syndrome (SARS) appeared in Canton and later in Guangzhou, Beijing, Hanoi, Vietnam, Hong Kong and other cities in Southeast Asia. In 2012, 10 years after the SARS episode, another coronavirus respiratory syndrome developed in the Middle East and South Korea from Saudi Arabia. At the end of 2019, it was again "far from home" that a new episode in the evolution of coronaviruses took place. The ability of SARS coronaviruses to cross the species barrier is a major factor in the amplification of viral pathogens from host species to intermediate species and then to humans. Despite the 2002-2003 SARS episode, there is still no vaccine against SARS-CoV-1. Collectively, national and international health policy and research bodies ignored previous warnings. Covid-19 is still rampant in many countries as we enter the year 2021. © ISTE Ltd 2022.

Glycan masking in vaccine design: Targets, immunogens and applications.

Glycan masking is a novel technique in reverse vaccinology in which sugar chains (glycans) are added on the surface of immunogen candidates to hide regions of low interest and thus focus the immune system on highly therapeutic epitopes. This shielding strategy is inspired by viruses such as influenza and HIV, which are able to escape the immune system by incorporating additional glycosylation and preventing the binding of therapeutic antibodies. Interestingly, the glycan masking technique is mainly used in vaccine design to fight the same viruses that naturally use glycans to evade the immune system. In this review we report the major successes obtained with the glycan masking technique in epitope-focused vaccine design. We focus on the choice of the target antigen, the strategy for immunogen design and the relevance of the carrier vector to induce a strong immune response. Moreover, we will elucidate the different applications that can be accomplished with glycan masking, such as shifting the immune response from hyper-variable epitopes to more conserved ones, focusing the response on known therapeutic epitopes, broadening the response to different viral strains/sub-types and altering the antigen immunogenicity to elicit higher or lower immune response, as desired.

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.

Deciphering the immunogenic T-cell epitopes from spike protein of SARS-CoV-2 concerning the diverse population of India.

Scientists are rigorously looking for an efficient vaccine against the current pandemic due to the SARS-CoV-2 virus. The reverse vaccinology approach may provide us with significant therapeutic leads in this direction and further determination of T-cell/B-cell response to antigen. In the present study, we conducted a population coverage analysis referring to the diverse Indian population. From the Immune epitope database (IEDB), HLA- distribution analysis was performed to find the most promiscuous T-cell epitope out of In silico determined epitope of Spike protein from SARS-CoV-2. Epitopes were selected based on their binding affinity with the maximum number of HLA alleles belonging to the highest population coverage rate values for the chosen geographical area in India. 404 cleavage sites within the 1288 amino acids sequence of spike glycoprotein were determined by NetChop proteasomal cleavage prediction suggesting the presence of adequate sites in the protein sequence for cleaving into appropriate epitopes. For population coverage analysis, 179 selected epitopes present the projected population coverage up to 97.45% with 56.16 average hit and 15.07 pc90. 54 epitopes are found with the highest coverage among the Indian population and highly conserved within the given spike RBD domain sequence. Among all the predicted epitopes, 9-mer TRFASVYAW and RFDNPVLPF along with 12-mer LLAGTITSGWTF and VSQPFLMDLEGK epitopes are observed as the best due to their decent docking score and best binding affinity to corresponding HLA alleles during MD simulations. Outcomes from this study could be critical to design a vaccine against SARS-CoV-2 for a different set of populations within the country.Communicated by Ramaswamy H. Sarma.

Designing of cytotoxic T lymphocyte-based multi-epitope vaccine against SARS-CoV2: a reverse vaccinology approach.

SARS-CoV2 is a single-stranded RNA virus, gaining much attention after it out broke in China in December 2019. The virus rapidly spread to several countries around the world and caused severe respiratory illness to humans. Since the outbreak, researchers around the world have devoted maximum resources and effort to develop a potent vaccine that would offer protection to uninfected individuals against SARS-CoV2. Reverse vaccinology is a relatively new approach that thrives faster in vaccine research. In this study, we constructed Cytotoxic T Lymphocytes (CTL)-based multi-epitope vaccine using hybrid epitope prediction methods. A total of 121 immunogenic CTL epitopes were screened by various sequence-based prediction methods and docked with their respective HLA alleles using the AutoDock Vina v1.1.2. In all, 17 epitopes were selected based on their binding affinity, followed by the construction of multi-epitope vaccine by placing the appropriate linkers between the epitopes and tuberculosis heparin-binding hemagglutinin (HBHA) adjuvant. The final vaccine construct was modeled by the I-TASSER server and the best model was further validated by ERRAT, ProSA, and PROCHECK servers. Furthermore, the molecular interaction of the constructed vaccine with TLR4 was assessed by ClusPro 2.0 and PROtein binDIng enerGY prediction (PRODIGY) server. The immune simulation analysis confirms that the constructed vaccine was capable of inducing long-lasting memory T helper (Th) and CTL responses. Finally, the nucleotide sequence was codon-optimized by the JCAT tool and cloned into the pET21a (+) vector. The current results reveal that the candidate vaccine is capable of provoking robust CTL response against the SARS-CoV2.Communicated by Ramaswamy H. Sarma.

VPAgs-Dataset4ML: A Dataset to Predict Viral Protective Antigens for Machine Learning-Based Reverse Vaccinology

Reverse vaccinology (RV) is a computer-aided approach for vaccine development that identifies a subset of pathogen proteins as protective antigens (PAgs) or potential vaccine candidates. Machine learning (ML)-based RV is promising, but requires a dataset of PAgs (positives) and non-protective protein sequences (negatives). This study aimed to create an ML dataset, VPAgs-Dataset4ML, to predict viral PAgs based on PAgs obtained from Protegen. We performed seven steps to identify PAgs from the Protegen website and non-protective protein sequences from Universal Protein Resource (UniProt). The seven steps included downloading viral PAgs from Protegen, performing quality checks on PAgs using the standard BLASTp identity check ≤30% via MMseqs2, and computational steps running on Google Colaboratory and the Ubuntu terminal to retrieve and perform quality checks (similar to the PAgs) on non-protective protein sequences as negatives from UniProt. VPAgs-Dataset4ML contains 2145 viral protein sequences, with 210 PAgs in positive.fasta and 1935 non-protective protein sequences in negative.fasta. This dataset can be used to train ML models to predict antigens for various viral pathogens with the aim of developing effective vaccines.Dataset: https://doi.org/10.17632/w78tyrjz4z.1Dataset License: CC BY 4.0

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.

Koronavírus-világjárvány - a COVID-19-kaleidoszkóp ma (2022. május).

The article attempts to review the principal epidemiological data of the coronavirus pandemic (COVID-19) based on the rapidly changing and expanding international and domestic literature. The review covers the so-called "long COVID-19" as well as the latest pharmacological and immunotherapeutic developments. The manuscript deals with the future of innovative vaccinology, the so-called 'pan-vaccines' developed through artificial intelligences and nanotechnology. Orv Hetil. 2022; 163(24): 935-942.

mRNA vaccines: The future of prevention of viral infections?

Messenger RNA (mRNA) vaccines against COVID-19 are the first authorized biological preparations developed using this platform. During the pandemic, their administration has been proven to be a life-saving intervention. Here, we review the main advantages of using mRNA vaccines, identify further technological challenges to be met during the development of the mRNA platform, and provide an update on the clinical progress on leading mRNA vaccine candidates against different viruses that include influenza viruses, human immunodeficiency virus 1, respiratory syncytial virus, Nipah virus, Zika virus, human cytomegalovirus, and Epstein-Barr virus. The prospects and challenges of manufacturing mRNA vaccines in low-income countries are also discussed. The ongoing interest and research in mRNA technology are likely to overcome some existing challenges for this technology (e.g., related to storage conditions and immunogenicity of some components of lipid nanoparticles) and enhance the portfolio of vaccines against diseases for which classical formulations are already authorized. It may also open novel pathways of protection against infections and their consequences for which no safe and efficient immunization methods are currently available.

Towards a Future of Personalized Vaccinology: Study on Individual Variables Influencing the Antibody Response to the COVID-19 Vaccine.

The COVID-19 pandemic has hugely impacted many different aspects of human health, and vaccination is one of the most effective weapons to manage it. However, many different factors, such as age, gender, comorbidities and lifestyles, play a role in the response to infections and vaccines. We carried out this study to evaluate the potential role played by some individual factors in the production of anti-COVID-19 antibodies in the light of personalized and future vaccinology. We conducted an observational study consisting of a retrospective phase, exploiting previous data about anti-COVID-19 antibody responses, with a prospective phase to investigate individual variables through the use of a questionnaire. The antibody response after the COVID-19 vaccination was inversely related to old age, increased BMI and the number of smoking years, while a positive correlation was found with moderate alcohol consumption and especially with circulating levels of vitamin D, as clearly shown by the multivariate regression analysis. Our study showed that a number of variables are involved in the COVID-19 vaccine antibody response. These findings are very important and can be considered in the light of a future and personalized vaccinology.

COVID-19 vaccinology landscape in Africa.

More than two years after the start of COVID-19 pandemic, Africa still lags behind in terms vaccine distribution. This highlights the predicament of Africa in terms of vaccine development, deployment, and sustainability, not only for COVID-19, but for other major infectious diseases that plague the continent. This opinion discusses the challenges Africa faces in its race to vaccinate its people, and offers recommendations on the way forward. Specifically, to get out of the ongoing vaccine shortage trap, Africa needs to diversify investment not only to COVID-19 but also other diseases that burden the population. The continent needs to increase its capacity to acquire vaccines more equitably, improve access to technologies to enable local manufacture of vaccines, increase awareness on vaccines both in rural and urban areas to significantly reduce disease incidence of COVID-19 and as well as other prevalent diseases on the African continent such as HIV and TB. Such efforts will go a long way to reduce the disease burden in Africa.