A Strategic Guide to Improve and De-risk Vaccine Development: CEPI's CMC Framework.

The Coalition for Epidemic Preparedness Innovations (CEPI) has developed a robust CMC (Chemistry, Manufacturing, and Controls) Framework to enhance the likelihood of successful vaccine development. This Framework serves as a comprehensive guide, aiding developers in building effective strategies to overcome the challenges posed by the different phases of vaccine development, including the ones often referred to as the "valleys of death". The Framework lists stage-appropriate deliverables, categorized and refined, spanning five key areas: manufacturing process, formulation and stability, analytics, supply chain, and compliance. By emphasizing the critical aspects of CMC development, CEPI's objective is to expedite the progression of vaccine candidates from research to deployment, reducing delays, mitigating risks, and optimizing the overall development process, all while upholding uncompromising quality standards, ultimately increasing the probability of success.

Evaluation of Reproductive Histology Response of Adult Fasciola hepatica in Goats Vaccinated with Cathepsin L Phage-Exposed Mimotopes.

Fasciolosis, a globally re-emerging zoonotic disease, is mostly caused by the parasitic infection with Fasciola hepatica, often known as the liver fluke. This disease has a considerable impact on livestock productivity. This study aimed to evaluate the fluke burdens and faecal egg counts in goats that were administered phage clones of cathepsin L mimotopes and then infected with F. hepatica metacercariae. Additionally, the impact of vaccination on the histology of the reproductive system, specifically related to egg generation in adult parasites, was examined. A total of twenty-four goats, which were raised in sheds, were divided into four groups consisting of six animals each. These groups were randomly assigned. The goats were then subjected to two rounds of vaccination. Each vaccination involved the administration of 1 × 1013 phage particles containing specific mimotopes for cathepsin L2 (group 1: PPIRNGK), cathepsin L1 (group 2: DPWWLKQ), and cathepsin L1 (group 3: SGTFLFS). The immunisations were carried out on weeks 0 and 4, and the Quil A adjuvant was used in combination with the mimotopes. The control group was administered phosphate-buffered saline (PBS) (group 4). At week 6, all groups were orally infected with 200 metacercariae of F. hepatica. At week 22 following the initial immunisation, the subjects were euthanised, and adult F. hepatica specimens were retrieved from the bile ducts and liver tissue, and subsequently quantified. The specimens underwent whole-mount histology for the examination of the reproductive system, including the testis, ovary, vitellaria, Mehlis' gland, and uterus. The mean fluke burdens following the challenge were seen to decrease by 50.4%, 62.2%, and 75.3% (p < 0.05) in goats that received vaccinations containing cathepsin L2 PPIRNGK, cathepsin L1 DPWWLKQ, and cathepsin L1 SGTFLFS, respectively. Animals that received vaccination exhibited a significant reduction in the production of parasite eggs. The levels of IgG1 and IgG2 isotypes in vaccinated goats were significantly higher than in the control group, indicating that protection is associated with the induction of a mixed Th1/Th2 immune response. The administration of cathepsin L to goats exhibits a modest level of efficacy in inducing histological impairment in the reproductive organs of liver flukes, resulting in a reduction in egg output.

Enteroviruses: epidemic potential, challenges and opportunities with vaccines.

Enteroviruses (EVs) are the most prevalent viruses in humans. EVs can cause a range of acute symptoms, from mild common colds to severe systemic infections such as meningitis, myocarditis, and flaccid paralysis. They can also lead to chronic diseases such as cardiomyopathy. Although more than 280 human EV serotypes exist, only four serotypes have licenced vaccines. No antiviral drugs are available to treat EV infections, and global surveillance of EVs has not been effectively coordinated. Therefore, poliovirus still circulates, and there have been alarming epidemics of non-polio enteroviruses. Thus, there is a pressing need for coordinated preparedness efforts against EVs.This review provides a perspective on recent enterovirus outbreaks and global poliovirus eradication efforts with continuous vaccine development initiatives. It also provides insights into the challenges and opportunities in EV vaccine development. Given that traditional whole-virus vaccine technologies are not suitable for many clinically relevant EVs and considering the ongoing risk of enterovirus outbreaks and the potential for new emerging pathogenic strains, the need for new effective and adaptable enterovirus vaccines is emphasized.This review also explores the difficulties in translating promising vaccine candidates for clinical use and summarizes information from published literature and clinical trial databases focusing on existing enterovirus vaccines, ongoing clinical trials, the obstacles faced in vaccine development as well as the emergence of new vaccine technologies. Overall, this review contributes to the understanding of enterovirus vaccines, their role in public health, and their significance as a tool for future preparedness.

Leveraging artificial intelligence in vaccine development: A narrative review.

Vaccine development stands as a cornerstone of public health efforts, pivotal in curbing infectious diseases and reducing global morbidity and mortality. However, traditional vaccine development methods are often time-consuming, costly, and inefficient. The advent of artificial intelligence (AI) has ushered in a new era in vaccine design, offering unprecedented opportunities to expedite the process. This narrative review explores the role of AI in vaccine development, focusing on antigen selection, epitope prediction, adjuvant identification, and optimization strategies. AI algorithms, including machine learning and deep learning, leverage genomic data, protein structures, and immune system interactions to predict antigenic epitopes, assess immunogenicity, and prioritize antigens for experimentation. Furthermore, AI-driven approaches facilitate the rational design of immunogens and the identification of novel adjuvant candidates with optimal safety and efficacy profiles. Challenges such as data heterogeneity, model interpretability, and regulatory considerations must be addressed to realize the full potential of AI in vaccine development. Integrating emerging technologies, such as single-cell omics and synthetic biology, promises to enhance vaccine design precision and scalability. This review underscores the transformative impact of AI on vaccine development and highlights the need for interdisciplinary collaborations and regulatory harmonization to accelerate the delivery of safe and effective vaccines against infectious diseases.

Understanding the Regulatory Pathways Used to Develop, Evaluate, Authorize, and Approve New Drugs and Vaccines in the United States.

The United States (U.S.) Food and Drug Administration (FDA) oversees the safety and quality of drugs and vaccines that are used in the U.S. Administration of the FDA falls under the jurisdiction of the U.S. Department of Health and Human Services (HHS). The regulatory oversight of the FDA is complex and comprehensive, requiring the various roles and responsibilities to be divided across six main centers. The activities of two of these centers, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are the primary focus of this review.

Factors associated with acceleration of clinical development for infectious diseases: a cross-sectional analysis of 10-year EMA registration data.

Background: Clinical trials feature centrally in the development of drugs and vaccines to determine safety and efficacy. Clinical development can be slow and may have a duration of more than ten years. Global public health threats such as Ebola virus disease (EVD) and COVID-19 have demonstrated that it is possible to accelerate clinical trials while maintaining safety and efficacy. We investigated acceleration in clinical trials over the past decade and identified factors associated with acceleration for drugs targeting infectious diseases. Methods: A cross-sectional study was performed of all medicinal compounds targeting infectious diseases that received marketing authorisation by the European Medicines Agency (EMA) between 2012 and 2022. We calculated median clinical development time in years between the first phase 1 trial enrolment date and the authorisation date. Multivariable linear regression analysis was performed to identify factors associated with shorter development times. Findings: Eighty-one trajectories were included. The median clinical development time was 7.3 years (IQR 4.4-12.3). The fastest times belonged to drugs and vaccines targeting COVID-19 (1.3 years, IQR 0.8-1.6), EVD (5.5 years, IQR 5.1-5.8), and Hepatitis A-E (5.5 years, IQR 3.9-8.2). Factors associated with shorter development times were outbreak setting (-5.4 years [95% CI, -8.2 to -2.6]), accelerated assessment status (-4.0 years [95% CI, -7.6 to -0.5]), and drugs with combined compounds (-2.7 years [95% CI, -4.9 to -0.4]). Interpretation: Clinical development time for infectious disease-related drugs and vaccines was relatively short, and outbreak setting and accelerated EMA assessment were associated with shorter development times. Funding: Amsterdam Public Health research institute.

Clinical Application of Adenovirus (AdV): A Comprehensive Review.

Adenoviruses are non-enveloped DNA viruses that cause a wide range of symptoms, from mild infections to life-threatening diseases in a broad range of hosts. Due to the unique characteristics of these viruses, they have also become a vehicle for gene-transfer and cancer therapeutic instruments. Adenovirus vectors can be used in gene therapy by modifying wild-type viruses to render them replication-defective. This makes it possible to swap out particular viral genes for segments that carry therapeutic genes and to employ the resultant vector as a means of delivering genes to specified tissues. In this review, we outline the progressive development of adenovirus vectors, exploring their characteristics, genetic modifications, and range of uses in clinical and preclinical settings. A significant emphasis is placed on their crucial role in advancing gene therapy, cancer therapy, immunotherapy, and the latest breakthroughs in vaccine development for various diseases.

Potential of mRNA-based vaccines for the control of tick-borne pathogens in one health perspective.

The One Health approach, which integrates the health of humans, animals, plants, and ecosystems at various levels, is crucial for addressing interconnected health threats. This is complemented by the advent of mRNA vaccines, which have revolutionized disease prevention. They offer broad-spectrum effectiveness and can be rapidly customized to target specific pathogens. Their utility extends beyond human medicine, showing potential in veterinary practices to control diseases and reduce the risk of zoonotic transmissions. This review place mRNA vaccines and One Health in the context of tick-borne diseases. The potential of these vaccines to confer cross-species immunity is significant, potentially disrupting zoonotic disease transmission cycles and protecting the health of both humans and animals, while reducing tick populations, infestations and circulation of pathogens. The development and application of mRNA vaccines for tick and tick-borne pathogens represent a comprehensive strategy in global health, fostering a healthier ecosystem for all species in our interconnected world.

Deciphering the Potential of Probiotics in Vaccines.

The demand for vaccines, particularly those prepared from non-conventional sources, is rising due to the emergence of drug resistance around the globe. Probiotic-based vaccines are a wise example of such vaccines which represent new horizons in the field of vaccinology in providing an enhanced and diversified immune response. The justification for incorporating probiotics into vaccines lies in the fact that that they hold the capacity to regulate immune function directly or indirectly by influencing the gastrointestinal microbiota and related pathways. Several animal-model-based studies have also highlighted the efficacy of these vaccines. The aim of this review is to collect and summarize the trends in the recent scientific literature regarding the role of probiotics in vaccines and vaccinology, along with their impact on target populations.

Mycobacterium tuberculosis-Human Immunodeficiency Virus Infection and the Role of T Cells in Protection.

Tuberculosis (TB), primarily caused by Mycobacterium tuberculosis (M. tb), remains a widespread fatal health issue that becomes significantly detrimental when coupled with HIV. This study explores the host's innate and adaptive immune system response to TB in HIV immunocompromised patients, highlighting the significant role of CD8+ T cells. While the crucial role of macrophages and cytokines, like TNF-α and IFN-γ, in managing the host's immune response to M. tb is examined, the emphasis is on the changes that occur as a result of HIV coinfection. With the progression of HIV infection, the primary source of IFN-γ changes from CD4+ to CD8+ T cells, especially when latent TB advances to an active state. This study sheds light on the necessity of developing new preventative measures such as vaccines and new treatment approaches to TB, especially for immunocompromised patients, who are at a higher risk of life-threatening complications due to TB-HIV coinfection.

Immunoinformatic prediction to identify Staphylococcus aureus peptides that bind to CD8+ T-cells as potential vaccine candidates.

Background and Aim: Staphylococcus aureus, with its diverse virulence factors and immune response evasion mechanisms, presents a formidable challenge as an opportunistic pathogen. Developing an effective vaccine against S. aureus has proven elusive despite extensive efforts. Autologous Staphylococcus lysate (ASL) treatment has proven effective in triggering an immune response against bovine mastitis. Peptides that stimulate the immune response can be the subject of further research. The study aimed to use immunoinformatics tools to identify epitopes on S. aureus surface and secretory proteins that can bind to major histocompatibility complex class I (MHC I) and CD8+ T-cells. This method aids in discovering prospective vaccine candidates and elucidating the rationale behind ASL therapy's efficacy. Materials and Methods: Proteins were identified using both literature search and the National Center for Biotechnology Information search engine Entrez. Self and non-self peptides, allergenicity predictions, epitope locations, and physicochemical characteristics were determined using sequence alignment, AllerTOP, SVMTriP, and Protein-Sol tools. Hex was employed for simulating the docking interactions between S. aureus proteins and the MHC I + CD8+ T-cells complex. The binding sites of S. aureus proteins were assessed using Computer Atlas of Surface Topography of Proteins (CASTp) while docked with MHC I and CD8+ T-cells. Results: Nine potential S. aureus peptides and their corresponding epitopes were identified in this study, stimulating cytotoxic T-cell mediated immunity. The peptides were analyzed for similarity with self-antigens and allergenicity. 1d20, 2noj, 1n67, 1nu7, 1amx, and 2b71, non-self and stable, are potential elicitors of the cytotoxic T-cell response. The energy values from docking simulations of peptide-MHC I complexes with the CD8+ and T-cell receptor (TCR) indicate the stability and strength of the formed complexes. These peptides - 2noj, 1d20, 1n67, 2b71, 1nu7, 1yn3, 1amx, 2gi9, and 1edk - demonstrated robust MHC I binding, as evidenced by their low binding energies. Peptide 2gi9 exhibited the lowest energy value, followed by 2noj, 1nu7, 1n67, and 1d20, when docked with MHC I and CD8 + TCR, suggesting a highly stable complex. CASTp analysis indicated substantial binding pockets in the docked complexes, with peptide 1d20 showing the highest values for area and volume, suggesting its potential as an effective elicitor of immunological responses. These peptides - 2noj, 2gi9, 1d20, and 1n67 - stand out for vaccine development and T-cell activation against S. aureus. Conclusion: This study sheds light on the design and development of S. aureus vaccines, highlighting the significance of employing computational methods in conjunction with experimental verification. The significance of T-cell responses in combating S. aureus infections is emphasized by this study. More experiments are needed to confirm the effectiveness of these vaccine candidates and discover their possible medical uses.

Inactivation of an Indonesian isolate of foot-and-mouth disease virus using formaldehyde.

Background and Aim: Foot-and-mouth disease (FMD) is a highly contagious viral disease that endangers livestock and the environment with significant economic consequences. This study aimed to validate the inactivation of the Indonesian isolate of foot-and-mouth disease virus (FMDV) with various formaldehyde concentration. Materials and Methods: The experiment started with FMDV being adapted on BHK-21 cells until cytopathic effects (CPE) appeared. The biological titer of the virus was determined using the 50% tissue culture infectious dose (TCID50) assay. The virus was inactivated by exposing the isolate to different formaldehyde (FA) concentrations (0.025%, 0.05%, 0.1%, and 0.2%) at 37°C for 24 h, and residual infectivity was assessed using CPE scoring of reinoculated BHK-21 cells. Results: 72 h post-inoculation, the virulence of the FMDV isolate was indicated by complete CPE on BHK-21 monolayer cells, with a TCID50 value of 109/mL; CPE scoring did not signify significant differences (p < 0.05) among 0.025%, 0.05%, 0.1%, 0.2% FA, and the negative control. All treatment groups showed significant differences (p < 0.05) from the positive control (C+). FA concentrations inactivated the FMDV isolate under the given conditions. 0.025% and 0.05% FA continued to display CPE through the third passage, while 0.2% FA did not significantly differ from 0.1% FA (p > 0.05). 0.1% FA is the optimal concentration for safely and effectively inactivating FMDV. Conclusion: All of the formaldehyde concentrations can completely inactivate the FMDV isolate, with the most optimal and safe concentration being 0.1%.

From Protection to Prevention: Redefining Vaccines in the Context of Antimicrobial Resistance.

Antimicrobial resistance (AMR) poses a significant threat to global health, compromising the effectiveness of treatments and increasing medical risks. In this crisis, the importance of vaccines in reducing AMR is being increasingly acknowledged, although not thoroughly explored. This literature review asserts that vaccines can significantly lessen the occurrence of infections, thereby reducing the need for antibiotics and limiting the emergence of resistance. Vaccines play a crucial role in antimicrobial stewardship programs by preventing diseases that would otherwise necessitate the use of antibiotics. Expanding vaccine coverage supports responsible usage of antimicrobials and aligns with global health priorities to maintain effective medical interventions. This review emphasizes the need for equitable funding and policy support for vaccine initiatives comparable to new antibiotics and diagnostic techniques. Moreover, it calls for more detailed investigations into vaccines' economic and health benefits in managing AMR, highlighting their potential as cost-effective solutions to this urgent health challenge. Through a careful analysis of existing literature, this review highlights the fundamental role of vaccines in transforming the landscape of AMR, shifting the focus from a protective approach to a preventive health strategy.

Rapid production of COVID-19 subunit vaccine candidates and their immunogenicity evaluation in pigs.

The emergence of various variants of concern (VOCs) necessitates the development of more efficient vaccines for COVID-19. In this study, we established a rapid and robust production platform for a novel subunit vaccine candidate based on eukaryotic HEK-293 T cells. The immunogenicity of the vaccine candidate was evaluated in pigs. The results demonstrated that the pseudovirus neutralizing antibody (pNAb) titers reached 7751 and 306 for the SARS-CoV-2 Delta and Omicron variants, respectively, after the first boost. Subsequently, pNAb titers further increased to 10,201 and 1350, respectively, after the second boost. Additionally, ELISPOT analysis revealed a robust T-cell response characterized by IFN-γ (171 SFCs/106 cells) and IL-2 (101 SFCs/106 cells) production. Our study demonstrates that a vaccine candidate based on the Delta variant spike protein may provide strong and broad protection against the prototype SARS-CoV-2 and VOCs. Moreover, the strategy for the efficient and stable expression of recombinant proteins utilizing HEK-293 T cells can be employed as a universal platform for future vaccine development.

Designing High Binding Affinity Peptides for MHC Class I Using MAM: An In Silico Approach.

The availability of extensive MHC-peptide binding data has boosted machine learning-based approaches for predicting binding affinity and identifying binding motifs. These computational tools leverage the wealth of binding data to extract essential features and generate a multitude of potential peptides, thereby significantly reducing the cost and time required for experimental procedures. MAM is one such tool for predicting the MHC-I-peptide binding affinity, extracting binding motifs, and generating new peptides with high affinity. This manuscript provides step-by-step guidance on installing, configuring, and executing MAM while also discussing the best practices when using this tool.

The JMU-SalVac-System: A Novel, Versatile Approach to Oral Live Vaccine Development.

Salmonella enterica Serovar Typhi Ty21a (Ty21a) is the only licensed oral vaccine against typhoid fever. Due to its excellent safety profile, it has been used as a promising vector strain for the expression of heterologous antigens for mucosal immunization. As the efficacy of any bacterial live vector vaccine correlates with its ability to express and present sufficient antigen, the genes for antigen expression are traditionally located on plasmids with antibiotic resistance genes for stabilization. However, for use in humans, antibiotic selection of plasmids is not applicable, leading to segregational loss of the antigen-producing plasmid. Therefore, we developed an oral Ty21a-based vaccine platform technology, the JMU-SalVac-system (Julius-Maximilians-Universität Würzburg) in which the antigen delivery plasmids (pSalVac-plasmid-series) are stabilized by a ΔtyrS/tyrS+-based balanced-lethal system (BLS). The system is made up of the chromosomal knockout of the essential tyrosyl-tRNA-synthetase gene (tyrS) and the in trans complementation of tyrS on the pSalVac-plasmid. Further novel functional features of the pSalVac-plasmids are the presence of two different expression cassettes for the expression of protein antigens. In this study, we present the construction of vaccine strains with BLS plasmids for antigen expression. The expression of cytosolic and secreted mRFP and cholera toxin subunit B (CTB) proteins as model antigens is used to demonstrate the versatility of the approach. As proof of concept, we show the induction of previously described in vivo inducible promoters cloned into pSalVac-plasmids during infection of primary macrophages and demonstrate the expression of model vaccine antigens in these relevant human target cells. Therefore, antigen delivery strains developed with the JMU-SalVac technology are promising, safe and stable vaccine strains to be used against mucosal infections in humans.

African swine fever virus proteins against host antiviral innate immunity and their implications for vaccine development.

African swine fever virus (ASFV) poses a significant threat to global swine populations, necessitating a profound understanding of viral strategies against host antiviral innate immunity. This review synthesizes current knowledge regarding ASFV proteins and their intricate interactions with host defenses. Noteworthy findings encompass the modulation of interferon signaling, manipulation of inflammatory pathways, and the impact on cellular apoptosis. The implications of these findings provide a foundation for advancing vaccine strategies against ASFV. In conclusion, this review consolidates current knowledge, emphasizing the adaptability of ASFV in subverting host immunity. Identified research gaps underscore the need for continued exploration, presenting opportunities for developing targeted vaccines. This synthesis provides a roadmap for future investigations, aiming to enhance our preparedness against the devastating impact of ASFV on global swine populations.

Pandemic preparedness through vaccine development for avian influenza viruses.

Influenza A viruses pose a significant threat to global health, impacting both humans and animals. Zoonotic transmission, particularly from swine and avian species, is the primary source of human influenza outbreaks. Notably, avian influenza viruses of the H5N1, H7N9, and H9N2 subtypes are of pandemic concern through their global spread and sporadic human infections. Preventing and controlling these viruses is critical due to their high threat level. Vaccination remains the most effective strategy for influenza prevention and control in humans, despite varying vaccine efficacy across strains. This review focuses specifically on pandemic preparedness for avian influenza viruses. We delve into vaccines tested in animal models and summarize clinical trials conducted on H5N1, H7N9, and H9N2 vaccines in humans.

The Platform Technology Approach to mRNA Product Development and Regulation.

mRNA-lipid nanoparticle (LNP) medicinal products can be considered a platform technology because the development process is similar for different diseases and conditions, with similar noncoding mRNA sequences and lipid nanoparticles and essentially unchanged manufacturing and analytical methods often utilised for different products. It is critical not to lose the momentum built using the platform approach during the development, regulatory approval and rollout of vaccines for SARS-CoV-2 and its variants. This review proposes a set of modifications to existing regulatory requirements for mRNA products, based on a platform perspective for quality, manufacturing, preclinical, and clinical data. For the first time, we address development and potential regulatory requirements when the mRNA sequences and LNP composition vary in different products as well. In addition, we propose considerations for self-amplifying mRNA, individualised oncology mRNA products, and mRNA therapeutics. Providing a predictable development pathway for academic and commercial groups so that they can know in detail what product characterisation and data are required to develop a dossier for regulatory submission has many potential benefits. These include: reduced development and regulatory costs; faster consumer/patient access and more agile development of products in the face of pandemics; and for rare diseases where alternatives may not exist or to increase survival and the quality of life in cancer patients. Therefore, achieving consensus around platform approaches is both urgent and important. This approach with mRNA can be a template for similar platform frameworks for other therapeutics and vaccines to enable more efficient development and regulatory review.