Adjuvants are essential for effective vaccine formulation, but currently only a few adjuvants with limited efficacies and application scopes are available. To address this issue, we explored covalent conjugates of monophosphoryl lipid A (MPLA) and 2,4-dinitrophenylamine (DNPA) as a new type of adjuvant. Immunological studies in mice prove that MPLA-DNPA conjugates can help a model vaccine induce robust IgG antibody and adaptive immune responses against carbohydrate and protein antigens and are much more potent adjuvants than alumthe positive controland the MPLA + DNPA mixture. Detailed profiling and comparison of the cytokines/chemokines elicited by various adjuvants suggest that the MPLA-DNPA conjugates can activate macrophages, monocytes, dendritic, T, T helper, and other immune cells to promote cellular immunity against vaccines. The results suggest a synergistic effect of covalently linked MPLA and DNPA, which act via interacting with the Toll-like receptor and recruiting endogenous anti-DNPA antibodies, respectively. Moreover, the linker between MPLA and DNPA shows a major impact on this synergistic effect, especially for the carbohydrate antigen. Eventually, the MPLA-DNPA conjugate with a longer linker containing a triazole moiety is identified as a promising adjuvant for both carbohydrate and protein vaccines worthy of further research and development.

Rickettsia is a genus of bacteria that are obligate intracellular parasites and are responsible for the febrile diseases known collectively as Rickettsioses. The emergence of antibiotic resistance is an escalating concern and thus developing a vaccine against Rickettsia is of paramount importance due to the significant public health threat posed by these bacteria. Thus, we employed structural vaccinology guided by machine learning algorithms to explore the virulence landscape of Rickettsia prowazekii to design a multi-epitopes-based vaccine (MEVC) that is immunogenic and safe. From a pool of virulence factors, we shortlisted five targets including sca0, sca1, sca4, sca5 and tlyA that were classified as non-allergenic as well as antigenic. The immune epitopes mapping results shortlisted five CTL epitopes, five HTL (IFN+) epitopes and five B cell epitopes as the best choice to design a vaccine construct of 475 amino acids. Various parameters were used to validate the designed MEVC which involved prediction of physiochemical properties, modeling and validation of the 3D structure, interaction with the immune receptors such as TLR2 (Toll-like receptor) and TLR4. Moreover, all-atoms simulation and binding free energy (BFE) results revealed a stable and favorable dynamic properties determined by these complexes. Jcat revealed that the improved sequence exhibits a GC content of 48.14% and a CAI (Codon Adaptation Index) value of 1.0. We used a multi-dose criterion at different time intervals i.e., 1st, 84th and 170th day to understand the immune potential of our constructed vaccine. The results provide a comprehensive overview of immune factors that ensure effective antigen memory cells generation after each injection, as predicted by the in silico pipeline. However, limitations in current algorithms particularly their inability to fully account for HLA polymorphism and the lack of experimental and clinical validation remain major shortcomings of the study. These issues should be addressed in future research to support the development of a robust immune response against Rickettsia infections.

Effective subunit vaccine development requires selecting appropriate adjuvant formulations to trigger desired adaptive immune responses. This study explores the immunogenicity and tuberculosis (TB) vaccine potential of antigens (Ags) combined with Toll-like receptor 4 (TLR4) adjuvants and a stimulator of interferon genes (STING) agonist.

In this work, we investigated the combination of Ags with TLR4 adjuvants (monophosphoryl lipid A / dimethyldioctadecylammonium bromide; MPL/DDA or glucopyranosyl lipid adjuvant-stable emulsion; GLA-SE) and a STING agonist, c-di-GMP (CDG). Mice were immunized three times by intramuscular injections at 3-week intervals. The effects of integrating Ags in these adjuvant formulations on the immune response were evaluated, focusing on the generation of Th1-biased, polyfunctional Ag-specific CD4+ T cells and their localization in the lung and spleen. To assess protection, immunized mice were aerogenically challenged with either conventional or ultra-low doses of Mycobacterium tuberculosis (Mtb) 4 weeks after the last immunization. Subsequently, bacterial load and pulmonary inflammation were assessed.

Integrating ESAT6 Ag in TLR4 and CDG adjuvant formulations remarkably boosted Th1-biased, polyfunctional ESAT6-specific CD4+ T cells in the lungs and spleen, providing durable protection against Mtb infection. The inclusion of CDG promoted mucosal localization of ESAT6-specific CD4+ T cells resembling resident memory phenotypes in the lung parenchyma and increased Ag-specific CD4+ T cells in lung vasculature. Immunization with another vaccine Ag candidate, Ag85B, in GLA-SE plus CDG similarly increased Ag85B-specific CD4+ T cells in the spleen and both lung compartments. Following ultra-low dose Mtb challenge, ESAT6 or Ag85B/GLA-SE/CDG immunizations significantly reduced bacterial loads compared to non-, Bacillus Calmette-Guérin (BCG)-, and ESAT6 or Ag85B/GLA-SE-immunized groups. Importantly, the inclusion of CDG decreased killer cell lectin-like receptor subfamily G member 1 (KLRG1) expression among Ag-specific CD4+ T cells in the lung, correlating with enhanced lung-homing evidenced by expanded lung parenchyma Ag-specific CD4+ T cells, including less-differentiated Th1 cells.

This study highlights that CDG, when used in combination with TLR4 adjuvants, enhances long-term protective immunity, offering a promising strategy for subunit TB vaccine development.

Goatpox is a highly contagious disease caused by the Capripoxvirus, primarily affecting sheep and goats. Breeds like the Saanen are particularly vulnerable, especially in enzootic areas, and face risks not only from the disease itself but also from adverse reactions to live attenuated vaccines. This study compares inactivated and attenuated vaccines to find the safest and most effective vaccination strategy for Saanen goats against the Goatpox Virus (GTPV). In this study, 375 pure-breed Saanen goats were strategically divided into four groups to explore the most effective vaccination protocols for combating combinations of vaccines. In contrast, one group remained unvaccinated as a control. After vaccination, the goats were challenged by exposure to naturally infected animals to assess the vaccines' protective efficacy. PCR assays and the Virus Neutralization method were also conducted.

Group G1 exhibited no adverse reactions following two inactivated vaccines, with only mild and brief signs observed in a small number of goats (2%) after the live attenuated vaccine. Group G2, which received an inactivated vaccine followed by a live attenuated vaccine, had mild lesions in 18.66% of the goats after vaccination. In contrast, Group G3, which only received the live attenuated vaccine, showed a high morbidity rate of 82% and a mortality rate of 22%, with severe clinical signs and Pox lesions. Following the challenge, no signs of GTPV infection were observed in Groups G1, G2, and G3, whereas the control group exhibited 100% morbidity and 72% mortality, confirming the vaccine's protective efficacy.

This study found that a protocol using two inactivated vaccine doses at one-month intervals, followed by a live attenuated vaccine and annual boosters, effectively immunizes vulnerable breeds against GTPV without causing adverse reactions. This approach prevents complications and supports breeding in GTPV-enzootic regions.

Thousands of articles were published about the COVID-19 disease and hundreds about the immune response. But still little is known about the features of SARS-CoV-2-specific immunity in elderly. The aim of current research was to evaluate the age-related peculiarities of antibody mediated humoral immune response following SARS-CoV-2 infection. Our study presents an intriguing divergence from the classical concept of immunosenescence, where aging has been assumed to cause poor antibody responses, reduced or inefficient vaccination, and overall blunted immune responses in elderly people. Our findings were opposite to some of these expectations; participants aged over 60 expressed elevated titers of anti-SARS-CoV-2 antibodies in comparison to younger adults. Analyzing the data of relative neutralization and avidity of anti-SARS-Cov-2 (S) antibodies we propose that although older adults produce a higher quantity of antibodies, their functional efficiency appears relatively reduced exhibiting lower neutralizing capacity and binding strength per antibody compared to younger adults. We can assume that the immune system of the elderly may require a higher level of antibody production to obtain a comparable level of protection. Our findings highlight the intricate nature of immune responses in convalescent older adults. This has particular relevance to understanding immunity and vaccine responses in different age groups.

Bacterial flagellins are recognized for their potent immunomodulatory properties and potential as vaccine adjuvants. They activate innate and adaptive immune responses by interacting with Toll-like receptor 5 (TLR5) and the cytosolic NOD-like receptor protein 4 (NLRC4) inflammasome, thereby enhancing immune responses. This study investigates the impact of various truncated flagellin derivatives, derived from Escherichia coli (EHEC EDL933) and lacking specific domains, on TLR5 activation and their adjuvant properties. We generated several truncated flagellin mutants and assessed their ability to activate TLR5 in vitro and their immunoadjuvant effects in vivo. Our data show that only the FliCH7, FliCNC, FliCH7-FaeG, and FliCNC-FaeG proteins, which lack the hypervariable region (HVP) but retain both the amino- and carboxy-terminal regions, significantly enhanced TNF-α and IL-8 production compared to other flagellin derivatives. These findings underscore the essential roles of both conserved terminal regions in TLR5 activation. Notably, the FliCNC truncated mutant exhibited TLR5 activation comparable to that of native flagellin and induced higher antibody titers when co-administered with a model antigen or used as a fusion protein. Our results suggest that the HVR is not essential for flagellin's immunoadjuvant activity and that its removal enhances flagellin's ability to activate the innate immune system. This study provides valuable insights into optimizing flagellin derivatives for vaccine development, offering a more potent platform for enhancing immune responses against a range of pathogens.

Nanotechnology has revolutionized cancer treatment by providing innovative solutions through nanocancer therapies, nanovaccines, and nanoparticles. This review focuses on the application of these technologies in colorectal cancer (CRC), highlighting their progression from preclinical studies to clinical trials. Nanoparticles, including liposomes, silica, gold, and lipid nanoparticles, possess unique properties that enhance drug delivery, improve therapeutic efficacy, and minimize systemic toxicity. Additionally, nanovaccines are being developed to elicit robust immune responses against CRC cells. This paper offers a comprehensive overview of the current state of nanotechnology-based treatments for CRC, emphasizing key preclinical studies and clinical trials that demonstrate their potential. Furthermore, the review discusses the challenges faced in this field. It outlines future directions for research, underscoring the need for ongoing efforts to translate these promising technologies into practical clinical applications.

Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, has been robustly linked to the pathogenesis of nasopharyngeal carcinoma (NPC). The mechanism of EBV-induced NPC involves complex interactions between viral proteins and host cell pathways. This review aims to comprehensively outline the mechanism of EBV-induced NPC and the latest advances in targeted EBV vaccines for prophylaxis and treatment. This review explores the intricate molecular mechanisms by which EBV contributes to NPC pathogenesis, highlighting viral latency, genetic and epigenetic alterations, and immune evasion strategies. It emphasizes the pivotal role of key viral proteins, including EBNA1, LMP1, and LMP2A, in carcinogenesis. Subsequently, the discussion shifts towards the development of targeted EBV vaccines, including preventive vaccines aimed at preventing primary EBV infection and therapeutic vaccines aimed at treating diagnosed EBV-related NPC. The review underscores the challenges and future directions in the field, stressing the importance of developing innovative vaccine strategies and combination therapies to improve efficacy. This review synthesizes current insights into the molecular mechanisms of EBV-induced NPC and the development of EBV-targeted vaccines, highlighting the potential use of mRNA vaccines for NPC treatment.

Bacterial lysate proteins (BLPs) serve as potential immunostimulants, recognized by pattern recognition receptors (PRRs) on immune cells, eliciting a robust immune response. In this study, THP-1 macrophages were treated with varying doses of BLPs derived from Streptococcus pyogenes (SP), Streptococcus agalactiae (SA), and Serratia marcescens (SM). The results showed significant increases (p  < 0.05) in pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-12, granulocyte macrophage-colony stimulating factor (GM-CSF), eotaxin, and macrophage inflammatory protein (MIP)-1α, except for 5 µg of all BLPs for TNF-α and eotaxin, and 5 µg of SP for IL-12 production. No significant differences were found between the corresponding doses of SP and SA or SP and SM, except for GM-CSF in all doses, while SA and SM only showed a difference at the 5 µg dose for GM-CSF. Furthermore, there were no significant differences between the 10 and 20 µg doses of all BLPs, indicating that doses higher than 10 µg do not significantly enhance the pro-inflammatory response. Combination doses of SP + SM and SA + SM did not show significant differences, except for IL-1β, suggesting no synergistic effect. Cytotoxicity was observed to increase with higher BLP concentrations in a dose-dependent manner, with combinations of SP + SM and SA + SM exhibiting greater cytotoxicity than the individual BLPs. Proteomic analysis of BLPs identified immunostimulatory proteins, including heat shock proteins (HSPs; ClpB, DnaK, and GroEL), metabolic enzymes (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), enolase, and arginine deiminase (ADI)), and surface and secreted proteins (ESAT-6-like protein, CRISPR-associated endonuclease Cas9, OmpA, porin OmpC, and serralysin), which are involved in immune modulation, bacterial clearance, and immune evasion. This study underscores the potential of bacterial proteins as vaccine adjuvants or supplementary therapies; however, further research is essential to find a balance between immune activation and inflammation reduction to develop safer and more effective immunostimulants.

BACKGROUNDThe high-dose quadrivalent influenza vaccine (QIV-HD) showed superior efficacy against laboratory-confirmed illness compared with the standard-dose quadrivalent influenza vaccine (QIV-SD) in randomized controlled trials with the elderly. However, specific underlying mechanism remains unclear.METHODSThis phase IV randomized controlled trial compared early innate responses induced by QIV-HD and QIV-SD in 59 individuals aged > 65 years. Systemic innate cells and gene signatures at day 0 (D0) and D1 as well as hemagglutinin inhibition antibody (HIA) titers at D0 and D21 after vaccination were assessed.RESULTSQIV-HD elicited robust humoral response with significantly higher antibody titers and seroconversion rates than QIV-SD. At D1 after vaccination, QIV-HD recipients showed significant reduction in innate cells, including conventional DCs and NK cells, compared with QIV-SD, correlating with significantly increased HIA titers at D21. Blood transcriptomic analysis revealed greater amplitude of gene expression in the QIV-HD arm, encompassing genes related to innate immune response, IFNs, and antigen processing and presentation, and correlated with humoral responses. Interestingly, comparative analysis with a literature dataset from young adults vaccinated with influenza standard-dose vaccine highlighted strong similarities in gene expression patterns and biological pathways with the elderly vaccinated with QIV-HD.CONCLUSIONQIV-HD induces higher HIA titers than QIV-SD, a youthful boost of the innate gene expression significantly associated with high HIA titers.TRIAL REGISTRATIONEudraCT no. 2021-004573-32.

Vaccination has been instrumental in curbing the transmission of SARS-CoV-2 and mitigating the severity of clinical manifestations associated with COVID-19. Numerous COVID-19 vaccines have been developed to this effect, including BioNTech-Pfizer and Moderna's mRNA vaccines, as well as adenovirus vector-based vaccines such as Oxford-AstraZeneca. However, the emergence of new variants and subvariants of SARS-CoV-2, characterized by enhanced transmissibility and immune evasion, poses significant challenges to the efficacy of current vaccination strategies. In this review, we aim to comprehensively outline the landscape of emerging SARS-CoV-2 variants of concern (VOCs) and sub-lineages that have recently surfaced in the post-pandemic years. We assess the effectiveness of existing vaccines, including their booster doses, against these emerging variants and subvariants, such as BA.2-derived sub-lineages, XBB sub-lineages, and BA.2.86 (Pirola). Furthermore, we discuss the latest advancements in vaccine technology, including multivalent and pan-coronavirus approaches, along with the development of several next-generation coronavirus vaccines, such as exosome-based, virus-like particle (VLP), mucosal, and nanomaterial-based vaccines. Finally, we highlight the key challenges and critical areas for future research to address the evolving threat of SARS-CoV-2 subvariants and to develop strategies for combating the emergence of new viral threats, thereby improving preparedness for future pandemics.

Vaccine formulations are a successful strategy against pathogen transmission because vaccine candidates induce effective and long-lasting memory immune responses (B and CD4+ T cells) at systemic and mucosal sites. Extracellular vesicles of lipoproteins, bioactive compounds from plants and invertebrates (sponges) encapsulated in liposomes, and glycoproteins can target these sites. The vaccine candidates developed can mimic microbial pathogens in a way that successfully links the innate and adaptive immune responses. In addition, vaccines plus adjuvants promote and maintain an inflammatory response. In this review, we aimed to identify the host-pathogen interface as a rich source of candidate targets for vaccine-induced protective and long-lasting memory immune responses.

Monitoring the immune response to vaccination encompasses both significant challenges and promising opportunities for scientific advancement. The primary challenge lies in the inherent complexity and interindividual variability of immune responses, influenced by factors including age, genetic background, and prior immunological history. This variability necessitates the development of sophisticated, highly sensitive assays capable of accurately quantifying immune parameters such as antibody titers, T-cell responses, and cytokine profiles. Furthermore, the temporal dynamics of the immune response require comprehensive longitudinal studies to elucidate the durability and quality of vaccine-induced immunity. Challenges of this magnitude pave the way for immunological research advancements and diagnostic methodologies. Cutting-edge monitoring techniques, such as high-throughput sequencing and advanced flow cytometry, enable deeper insights into the mechanistic underpinnings of vaccine efficacy and contribute to the iterative design of more effective vaccines. Additionally, the integration of analytical tools holds the potential to predict immune responses and tailor personalized vaccination strategies. This will be addressed in this review to provide insight for enhancing public health outcomes and fortifying preparedness against future infectious disease threats.

Parainfluenza viruses are a common cause of respiratory illness in many species. In this study, experimental, alphavirus-derived RNA particle vaccines either with or without adjuvant were evaluated against porcine parainfluenza virus 1 (PPIV1) challenge and compared to live virus exposure. Groups of ten, three-week-old pigs were vaccinated intramuscularly with an adjuvanted RNA particle (RPAdj/C) or non-adjuvanted RP (RP/C) or administered an intranasal live exposure (LE/C) dose of PPIV1 at 0- and 21-days post vaccination (DPV) followed by challenge with PPIV1 at 40 DPV. In addition, two groups were included as non-vaccinated, non-challenged (NV/NC) and non-vaccinated, challenged (NV/C) controls. Intranasal virus exposure and RP vaccination, regardless of adjuvant, reduced PPIV1 shedding in nasal swabs by 5 days post inoculation (DPI). All vaccinated or exposed pigs seroconverted as shown by enzyme-linked immunosorbent assay and serum virus neutralization. The antibody isotype detected in bronchoalveolar lavage fluid (BALF) LE/C was predominantly IgA while RP vaccination induced an IgG response. Reduced PPIV1 antigen was observed in the LE/C, RP/C and RPAdj/C groups in lung, trachea, or nasal turbinate epithelium. Additionally, the RPAdj vaccine significantly reduced nasal shedding compared to NV/C pigs although not as much as LE/C pigs. These results suggest vaccination could mitigate PPIV1 infection in commercial systems.

Despite progress in developing antiviral drugs and vaccines, infections continue to be a significant challenge. Interleukin-4 (IL-4) is crucial for regulating immune responses and mediating allergic reactions. This research aims to improve the predictive accuracy of IL-4-inducing peptides by tackling data imbalance and enhancing feature extraction. Specifically, we introduce a new approach that utilizes SMOTE and ENN for balancing the dataset and applies a 30-layer ESM-2 model for extracting deep features. The extracted features are subsequently processed through a Gated Recurrent Unit (GRU) model, which is optimized through hyperparameter tuning. Our method achieves notable improvements, with an AUC of 0.98 and an accuracy of 93.1 %, highlighting its potential to support future immunotherapy and vaccine development efforts. The PLM-IL4 web server is freely accessible at http://www.bioai-lab.com/PLM-IL4, and the datasets used in this research are also available for download from the website.

Vaccines are an essential tool to significantly reduce pathogen-related morbidity and mortality. However, our ability to rationally design vaccines and identify correlates of protection remains limited. Here, we employed an immune organoid approach to capture human adaptive immune response diversity to influenza vaccines and systematically identify host and antigen features linked to vaccine response variability. Our investigation identified established and unique immune signatures correlated with neutralizing antibody responses across seven different influenza vaccines and antigens. Unexpectedly, heightened ex vivo tissue frequencies of T helper (Th)1 cells emerged as both a predictor and a correlate of neutralizing antibody responses to inactivated influenza vaccines (IIVs). Secondary analysis of human public data confirmed that elevated Th1 signatures are associated with antibody responses following in vivo vaccination. These findings demonstrate the utility of human in vitro models for identifying in vivo correlates of protection and establish a role for Th1 functions in influenza vaccination.

DNA vaccines are a novel form of vaccination that aims to harness genetic material to produce targeted immune responses. Nevertheless, their therapeutic application is hampered by low transfection efficacy, immunogenicity, and instability. Nanoparticle (NP) - based delivery systems are beneficial in enhancing DNA stability, increasing DNA uptake by antigen-presenting cells (APCs), and controlling antigen release. Some key progress includes the polymeric, lipid-based, and hybrid NPs and biocompatible carriers with inherent adjuvant effects. These systems have helped to enhance the antigen cross-presentation and T-cell activation significantly. In addition, biocompatible hybrid nanocarriers, antigen cross-presentation strategies, and next-generation sequencing (NGS) technologies are speeding up the identification of new antigens, while AI and machine learning are facilitating the development of efficient delivery systems. This review aims to assess how NPs have contributed to improving the effectiveness of DNA vaccines for treating diseases, cancer, and emerging diseases, as well as advancing the next generation of DNA vaccines.

The development of 3D-printed microneedle (MN) technology is a significant step in vaccine delivery, providing a painless, effective, and adaptable substitute for conventional injection-based techniques. Direct transdermal vaccination distribution without the need for needles is made possible by microneedle patches, which employ a variety of tiny needles that dissolve when they penetrate the skin. By using 3D printing to precisely customise microneedles' size, shape, and density to meet particular vaccine requirements, administration control can be improved and vaccine efficiency may even be increased. Furthermore, rapid prototyping made possible by 3D printing speeds up the development process, enabling quicker testing and improvement of vaccines. Additionally, this scalable technology can greatly increase vaccine accessibility, particularly in environments with limited resources. Research indicates that by directly interacting with the skin's immune-rich layers, microneedle patches enhance antigen delivery and elicit a strong immune response. Because MN technology offers a useful, self-administrable vaccination approach with little waste, it has significant potential for use in public health applications, notably during pandemics. This study emphasises how 3D-printed microneedle patches have the potential to revolutionise vaccination procedures and increase vaccine accessibility globally.

Measles is a highly contagious viral disease, particularly severe in infants. Protection in early life is provided by maternally transferred antibodies, but this period is shorter in infants of previously vaccinated mothers (PVMs) compared to infants of previously measles-infected mothers (PIMs). Earlier measles-mumps-rubella (MMR) vaccination may compensate for this. To evaluate immune responses, 6-month-old infants were randomized to receive early MMR or placebo. This study reports the cellular immune outcomes and summarizes serological and T-cell responses.

A double-blind, randomized trial involved 6540 Danish infants aged 5-7 months, eligible if birth weight exceeded 1000 grams and gestational age was ≥32 weeks. Participants were randomized 1:1 to receive M-M-RVaxPro or placebo. Blood samples were collected before intervention, four weeks after intervention, and four weeks after routine MMR at 15 months. Peripheral blood mononuclear cells (PBMCs) were prepared, and an IFN-γ specific ELISpot assay measured measles-specific T cells.

Among 750 infants (341 MMR, 409 placebo) in the cellular immunogenicity trial, a significant cellular immune response was observed one-month post-intervention in the MMR group compared to placebo (geometric mean ratio [GMR]: 12.3; 95% CI: 6.9-21.9). The cellular conversion rate (CCR) in the MMR group was 45%, comparable to the previously reported seroconversion rate. However, following routine MMR at 15 months, a reduced cellular response was observed in the early MMR group (GMR: 0.6; 95% CI: 0.3-0.9). Post-routine MMR, CCRs were 66% (MMR) and 74% (placebo). The immune conversion rate (ICR, defined as seroconversion and/or T-cell response) reached 99% in both groups post-routine MMR.

Early MMR at 6 months elicited significant measles-specific cellular responses, though the CCR was lower than after routine MMR at 15 months. However, when combining serological and cellular responses, 99% of infants achieved immune conversion by 15 months. Early MMR could help reduce measles burden in infants in endemic settings without compromising subsequent immunizations.

ClinicalTrials.gov, identifier NCT03780179, EudraCT 2016-001901-18.

Globally, periodontal diseases, mainly driven by polymicrobial biofilms, are a widespread concern of social medicine due to their considerable incidence and tie-up to systemic disorders like diabetes, cardiovascular diseases, and complications during pregnancy. Traditional treatments focus on mechanical debridement and antimicrobial therapies, but these approaches have limitations, including recurrence and antibiotic resistance. Periodontal vaccines offer a promising alternative by targeting the immunological mechanisms underlying periodontal disease. This review explores the current state of periodontal vaccine development, highlighting key antigens, vaccine delivery systems, and preclinical and clinical advancements. Special emphasis is placed on antigen selection, host variability, immune tolerance, and future directions to overcome these barriers. This article highlights the advancements and challenges in periodontal vaccine research, offering insights into the capability of immunoprophylaxis as a groundbreaking way to manage periodontal diseases.

Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis booster responses and generate experimental data for the explicit purpose of model evaluation. We here describe our second computational prediction challenge using this resource, where we benchmarked 49 algorithms from 53 scientists. We found that the most successful models stood out in their handling of nonlinearities, reducing large feature sets to representative subsets, and advanced data preprocessing. In contrast, we found that models adopted from literature that were developed to predict vaccine antibody responses in other settings performed poorly, reinforcing the need for purpose-built models. Overall, this demonstrates the value of purpose-generated datasets for rigorous and open model evaluations to identify features that improve the reliability and applicability of computational models in vaccine response prediction.

Traditional vaccinology has primarily focused on neutralizing antibody titers as the main correlate of vaccine efficacy, often overlooking the multifaceted roles of antibody Fc effector functions in orchestrating protective immune responses. Fc-mediated immune responses play a pivotal role in immune modulation and pathogen clearance. Emerging evidence from natural infections and vaccine studies highlights the critical contribution of Fc effector functions in determining the quality and durability of immunity. This work explores the limitations of current vaccine evaluation paradigms that prioritize neutralization over Fc effector mechanisms. It also describes findings from a study showing an unexpected role for SARS-CoV-2 anti-spike antibodies: both convalescent plasma and patient-derived monoclonal antibodies (mAbs) lead to maximum phagocytic capacity by monocytes at low concentrations, whereas at higher concentrations the phagocytic capacity was reduced. Given that the severity of COVID-19 disease and antibody titers are strongly positively correlated, this work challenges the paradigm that high antibodies offer better protection against severe disease. It is proposed that humoral and cellular responses elicited by vaccination should never be higher than those produced by natural infection. By integrating antibody Fc effector functions into vaccine development, a paradigm shift is proposed that emphasizes synergic antibody responses. Such an approach could transform vaccine efficacy assessment, enhance protection against dangerous pathogens, and drive innovation in vaccine design.

Viruses pose a significant threat to humans by causing numerous infectious and potentially fatal diseases. Understanding how the host's innate immune system recognizes viruses is essential to understanding pathogenesis and ways to control viral infection. Innate immunity also plays a critical role in shaping adaptive immune responses induced by vaccines. Recently developed adjuvants often include nucleic acids that stimulate pattern recognition receptors which are essential components of innate immunity necessary for activating antigen-presentation cells and thereby bridging innate and adaptive immunity. Therefore, understanding viral nucleic acid sensing by cytosolic sensors is essential, as it provides the potential means for developing new vaccine strategies, including effective adjuvants.

The clinical use of cancer vaccines is hampered by the low magnitude of induced T-cell responses and the need for repetitive antigen stimulation. Here, we demonstrate that liposomal formulations with incorporated STING agonists are optimally suited to deliver peptide antigens to dendritic cells in vivo and to activate dendritic cells in secondary lymphoid organs. One week after liposomal priming, systemic administration of peptides and a costimulatory agonistic CD40 antibody enables ultrarapid expansion of T cells, resulting in massive expansion of tumor-specific T cells in the peripheral blood two weeks after priming. In the MC-38 colon cancer model, this synthetic prime-boost regimen induces rapid regression and cure of large established subcutaneous cancers via the use of a single tumor-specific neoantigen. These experiments demonstrate the feasibility of liposome-based heterologous vaccination regimens to increase the therapeutic efficacy of peptide vaccines in the context of immunogenic adjuvants and costimulatory booster immunizations. Our results provide a rationale for the further development of modern liposomal peptide vaccines for cancer therapy.

Targeting the delivery of vaccines to dendritic cells (DCs) is challenging. Here we show that, by mimicking the fast and strong antigen processing and presentation that occurs during the rejection of xenotransplanted tissue, xenogeneic cell membrane-derived vesicles exposing tissue-specific antibodies can be leveraged to deliver peptide antigens and mRNA-encoded antigens to DCs. In mice with murine melanoma and murine thymoma, xenogeneic vesicles encapsulating a tumour-derived antigenic peptide or coated on lipid nanoparticles encapsulating an mRNA coding for a tumour antigen elicited potent tumour-specific T-cell responses that inhibited tumour growth. Mice immunized with xenogeneic vesicle-coated lipid nanoparticles encapsulating an mRNA encoding for the spike protein of severe acute respiratory syndrome coronavirus 2 elicited titres of anti-spike receptor-binding domain immunoglobulin G and of neutralizing antibodies that were approximately 32-fold and 6-fold, respectively, those elicited by a commercialized mRNA-lipid nanoparticle vaccine. The advantages of mimicking the biological recognition between immunoglobulin G on xenogeneic vesicles and fragment crystallizable receptors on DCs may justify the assessment of the safety risks of using animal-derived biological products in humans.

Vaccination is the primary method of preventing influenza infection and complications in young children. We evaluated the efficacy and safety of a single dose of MEDI3250 (intranasal, quadrivalent, live attenuated influenza vaccine) in healthy Japanese children during the 2016/17 influenza season.

In this multicenter, randomized, double-blind, phase 3 study (jRCT2080223345), participants aged 2-18 years received MEDI3250 or placebo (2:1), stratified by age (2-6 years, 7-18 years). The primary and secondary endpoints were the incidence of confirmed symptomatic onset of influenza caused by a circulating wild-type strain or by a vaccine-matched strain, respectively. Safety outcomes included the incidence of adverse events (AEs) and vaccine-related AEs.

Overall, 910 participants received MEDI3250 (n = 608) or placebo (n = 302). For the primary endpoint (regardless of the influenza subtype), the incidence of influenza onset was 25.5 % (MEDI3250) and 35.9 % (placebo); relative risk reduction, 28.8 % (95 % confidence interval, 12.5 %, 42.0 %). For the secondary endpoint (vaccine-matched strain), the incidence was 10.9 % (MEDI3250) and 17.2 % (placebo); relative risk reduction, 36.6 % (95 % confidence interval, 6.5 %, 56.8 %). Solicited AEs occurred in 67.6 % (MEDI3250) and 63.6 % (placebo). Most events were mild; nasal discharge was most common (59.2 % [MEDI3250] and 52.6 % [placebo]). Unsolicited AEs occurred in 36.0 % (MEDI3250) and 33.1 % (placebo). The most common unsolicited vaccine-related AE was diarrhea (2.3 %, both groups).

MEDI3250 had a greater preventive effect against influenza onset in Japanese children than placebo; no new safety signals were observed relative to previous clinical and post-marketing studies of MEDI3250.

The lymphatic system plays an important role in health and many diseases, such as cancer, autoimmune, cardiovascular, metabolic, hepatic, viral, and other infectious diseases. The lymphatic system is, therefore, an important treatment target site for a range of diseases. Lymph nodes (LNs), rich in T cells, B cells, dendritic cells, and macrophages, are also primary sites of action for vaccines and immunotherapies. Promoting the delivery of therapeutics and vaccines to LNs can, therefore, enhance treatment efficacy and facilitate avoidance of off-target side effects by enabling a reduction in therapeutic dose. Several nanoparticle (NP) based delivery systems, such as polymeric NPs, lipid NPs, liposomes, micelles, and dendrimers, have been reported to enhance the delivery of therapeutics and/or vaccines to LNs. Specific uptake into the lymph following injection into tissues is highly dependent on particle properties, particularly particle size, as small molecules are more likely to be taken up by blood capillaries due to higher blood flow rates, whereas larger molecules and NPs can be specifically transported via the lymphatic vessels to LNs as the initial lymphatic capillaries are more permeable than blood capillaries. Once NPs enter LNs, particle properties also have an important influence on their disposition within the node and association with immune cells, which has significant implications for the design of vaccines and immunotherapies. This review article focuses on the impact of NP properties, such as size, surface charge and modification, and route of administration, on lymphatic uptake, retention, and interactions with immune cells in LNs. We suggest that optimizing all these factors can enhance the efficacy of vaccines or therapeutics with targets in the lymphatics and also be helpful for the rational design of vaccines. STATEMENT OF SIGNIFICANCE: The lymphatic system plays an essential role in health and is an important treatment target site for a range of diseases. Promoting the delivery of immunotherapies and vaccines to immune cells in lymph nodes can enhance efficacy and facilitate avoidance of off-target side effects by enabling a reduction in therapeutic dose. One of the major approaches used to deliver therapeutics and vaccines to lymph nodes is via injection in nanoparticle delivery systems. This review aims to provide an overview of the impact of nanoparticle properties, such as size, surface charge, modification, and route of administration, on lymphatic uptake, lymph node retention, and interactions with immune cells in lymph nodes. This will inform the design of future improved nanoparticle systems for vaccines and immunotherapies.

Background/Objective: Cationic polymers were shown to assemble with negatively charged proteins yielding nanoparticles (NPs). Poly-diallyl-dimethyl-ammonium chloride (PDDA) combined with ovalbumin (OVA) yielded a stable colloidal dispersion (OVA/PDDA-NPs) eliciting significant anti-OVA immune response. Dendritic cells (DCs), as sentinels of foreign antigens, exert a crucial role in the antigen-specific immune response. Here, we aimed to evaluate the involvement of DCs in the immune response induced by OVA/PDDA. Methods: In vivo experiments were used to assess the ability of OVA/PDDA-NPs to induce anti-OVA antibodies by ELISA, as well as plasma cells and memory B cells using flow cytometry. Additionally, DC migration to draining lymph nodes following OVA/PDDA-NP immunization was evaluated by flow cytometry. In vitro experiments using bone marrow-derived DCs (BM-DCs) were used to analyze the binding and uptake of OVA/PDDA-NPs, DC maturation status, and their antigen-presenting capacity. Results: Our data confirmed the potent effect of OVA/PDDA-NPs inducing anti-OVA IgG1 and IgG2a antibodies with increased CD19+CD138+ plasma cells and CD19+CD38+CD27+ memory cells in immunized mice. OVA/PDDA-NPs induced DC maturation and migration to draining lymph nodes. The in vitro results showed higher binding and the uptake of OVA/PDDA-NPs by BM-DCs. In addition, the NPs were able to induce the upregulation of costimulatory and MHC-II molecules on DCs, as well as TNF-α and IL-12 production. Higher OVA-specific T cell proliferation was promoted by BM-DCs incubated with OVA/PDDA-NPs. Conclusions: The data showed the central role of DCs in the induction of antigen-specific immune response by OVA-PDDA-NPs, thus proving that these NPs are a potent adjuvant for subunit vaccine design.

To investigate the association between long-term exposure to PM2.5, PM10, NO2 and O3 with SARS-CoV-2 breakthrough infections and COVID-19 vaccine-induced antibody responses in a northern Italian population-based sample of older adults.

Within an ongoing prospective population-based study, we followed-up 1326 vaccinated individuals aged 65-83 years, with no prior SARS-CoV-2 infection, for their first positive SARS-CoV-2 swab until December 31st, 2022. We assessed spike IgG antibody levels in most participants (n = 1206). The 2019 annual mean levels of air pollutants derived from combined use of chemical-transport and random-Forest models (spatial resolution: 1Kmq) were individually assigned based on the latest residence address. We estimated multivariable-adjusted associations (per 1 interquartile range increase, IQR) of air pollutants with breakthrough infections using Cox models with time-dependent vaccine exposure; and with percent change in the IgG geometric mean using generalized additive models.

The mean (SD) age was 74.9 ± 4.1 years, and 50% were women. An IQR (1.2 μg/m3) increase in long-term PM2.5 exposure was associated with a 52% increase in breakthrough infection risk following a second vaccine and a 26% increase following a third vaccine. The effect vanished with the further increment of vaccination doses. Associations for NO2 were inconsistent. Ozone was negatively associated with breakthrough infection risk, but this association reversed in bi-pollutant models adjusting for PM2.5. PM2.5 was associated with a -7.3% (-13.9% to -0.2%) reduction in vaccine-induced IgG levels. The reduction became more pronounced as the time delay from vaccination increased, and with adjustment for NO2 co-exposure.

In our population of vaccinated older adults, fine particulate matter exposure was independently associated with a higher risk of SARS-CoV-2 breakthrough infection and a lower antibody response, both effects being influenced by timely and repeated vaccination schedule.

The U.S. opioid epidemic is an extraordinary public health crisis that started in 1990 and significantly accelerated in the last decade. Since 2020, over 100,000 fatal drug overdoses have been reported annually, and 75% of those involved fentanyl and its analogs (F/FA). Accelerating the translation of innovative, effective, and safe treatments is needed to augment existing measures to counteract such a crisis. Active immunization against F/FA and other opioids represents a promising therapeutic and prophylactic strategy for opioid use disorder (OUD) and opioid-induced overdose toxicity. Previously we demonstrated that the anti-fentanyl vaccine comprising a fentanyl-based hapten (F) conjugated to the diphtheria cross-reactive material (CRM), admixed with the novel lipidated toll-like receptor 7/8 (TLR7/8) agonist INI-4001 adsorbed on Alhydrogel ® (alum) induced high-affinity fentanyl-specific polyclonal antibodies that protected against fentanyl-induced pharmacological effects in mice, rats, and mini-pigs. Here, INI-4001 was formulated into liposomes with different surface charges, and their impact on F-CRM adsorption, INI-4001 adjuvanticity, and vaccine efficacy were explored. Additionally, as the role of innate immunity in mediating the efficacy of addiction vaccines is largely unknown, we tested these formulations on the activation of innate immunity in vitro . Cationic INI-4001 liposomes surpassed other liposomal and aluminum-based formulations of INI-4001 by enhancing the efficacy of fentanyl vaccines and protecting rats against bradycardia and respiratory depression by blocking the distribution of fentanyl to the brain. Fentanyl vaccines adjuvanted with either cationic INI-4001 liposomes or the aqueous INI-4001 adsorbed to alum induced significant surface expression of co-stimulatory molecules and maturation markers in a murine dendritic cell line (JAWS II), while the former was superior in enhancing the macrophages surface expression of CD40, CD86 and inducible nitric oxide synthase (iNOS), indicative of maturation and activation. These results warrant further investigation of liposome-based formulations of TLR7/8 agonists for improving the efficacy of vaccines targeting F/FA and other opioids of public health interest.

The current H3N2 influenza subunit vaccine exhibits weak immunogenicity, which limits its effectiveness in preventing and controlling influenza virus infections.

In this study, we aimed to develop a T4 phage-based nanovaccine designed to enhance the immunogenicity of two antigens by displaying the HA1 and M2e antigens of the H3N2 influenza virus on each phage nanoparticle. Specifically, we fused the Soc protein with the HA1 antigen and the Hoc protein with the M2e antigen, assembling them onto a T4 phage that lacks Soc and Hoc proteins (Soc-Hoc-T4), thereby constructing a nanovaccine that concurrently presents both HA1 and M2e antigens.

The analysis of the optical density of the target protein bands indicated that each particle could display approximately 179 HA1 and 68 M2e antigen molecules. Additionally, animal experiments demonstrated that this nanoparticle vaccine displaying dual antigen clusters induced a stronger specific immune response, higher antibody titers, a more balanced Th1/Th2 immune response, and enhanced CD4+ and CD8+ T cell effects compared to immunization with HA1 and M2e antigen molecules alone. Importantly, mice immunized with the T4 phage displaying dual antigen clusters achieved full protection (100% protection) against the H3N2 influenza virus, highlighting its robust protective efficacy.

In summary, our findings indicate that particles based on a T4 phage displaying antigen clusters exhibit ideal immunogenicity and protective effects, providing a promising strategy for the development of subunit vaccines against various viruses beyond influenza.

Vaccination stands as the paramount and cost-effective strategy for the prevention and management of animal infectious diseases. With the advances in biological technology, materials science and industrial optimization, substantial progress has been made in the development of innovative veterinary vaccines. A majority of the novel vaccines under current investigation tend to stimulate multiple immune pathways and to achieve long-term resistance against infectious diseases, yet it remains imperative to concentrate research efforts on the efficient utilization of vaccines, mitigating toxic side effects, and ensuring safe production processes. This article presents an overview of research progress in veterinary vaccines, encompassing comprehensive antigen design, adjuvant formulation advancements, preparation process optimization, and rigorous immune efficacy evaluation. It summarizes cutting-edge vaccines derived from in vitro synthesis and in vivo application, emphasizing immunogenic components and immune response mechanisms. It also highlights novel biological adjuvants that enhance immune efficacy, diversify raw materials, and possess targeted functions, while comprehensively exploring advancements in production methodologies and compatible vaccine products. By establishing a foundation for the integrated use of these innovative veterinary vaccines, this work facilitates future interdisciplinary cooperation in their advancement, aiming to accelerate the achievement of herd immunity through concerted efforts.

Subunit vaccines, significant in next-generation vaccine development, offer precise targeting of immune responses by focusing on specific antigens. However, this precision often comes at the cost of eliciting strong and durable immunity, posing a great challenge to vaccine design. To address this limitation, recent advancements in nanoparticles (NPs) are utilized to enhance antigen delivery efficiency and boost vaccine efficacy. This review examines how the physicochemical properties of NPs influence various stages of the immune response during vaccine delivery and analyzes how different NP types contribute to immune activation and enhance vaccine performance. It then explores the unique characteristics and immune activation mechanisms of these NPs, along with their recent advancements, and highlights their application in subunit vaccines targeting infectious diseases and cancer. Finally, it discusses the challenges in NP-based vaccine development and proposes future directions for innovation in this promising field.

The Swine Influenza Virus (SIV) is a major respiratory pathogen in swine, causing acute, febrile, and highly transmissible infections. This virus is widespread globally and poses significant risks to human health and social development. Traditional prevention strategies for SIV rely on the use of inactivated vaccines combined with Alum adjuvants. However, this method is limited by insufficient protection due to the lack of cellular immunity provided by Alum adjuvants. In this study, we investigated the effect of lovastatin, a specific inhibitor of the mevalonate pathway, on the immune response in mice vaccinated with the H1N1 vaccine. We focused on its impact on antibody production, as well as T-cell and B-cell development. Our findings reveal that the combination of lovastatin and H1N1 vaccine (Lov/H1N1) significantly enhances the production of H1N1-specific serum IgG and hemagglutination inhibition (HI) antibodies. Additionally, it promotes T-cell activation in both draining lymph nodes (dLNs) and the spleen. Analysis of cytokines produced after antigenic restimulation of splenic lymphocytes from immunized mice showed that the Lov/H1N1 combination induces both Th1-type (IFNγ, TNFα) and Th2-type (IL4, IL6) responses. Moreover, Lov/H1N1 facilitates the formation of germinal centers (GCs), which are crucial for the generation of memory B cells and long-lived plasma cells. These results indicate that lovastatin is a promising adjuvant candidate, capable of inducing robust cellular and humoral immune responses, thereby overcoming the limitations of Alum adjuvants. Our study provides a foundation for future research on combined vaccine strategies, highlighting Lovastatin's potential to enhance vaccine efficacy through improved immune responses.

In underdeveloped nations, tuberculosis (TB) continues to be a major source of morbidity and mortality. The currently available vaccine against tuberculosis in endemic areas is mainly ineffective, which triggers the need for a clinically effective vaccine against tuberculosis. In the present review, we emphasized the impact of genetic variations in the BCG strains, which influence the efficacy of BCG vaccines. We also discussed the current status of BCG vaccines and their potential mechanisms on the modulation of B cells and, thereby, humoral immunity, which trigger immune responses against various intracellular pathogens. Further, we also elaborated upon the pre-clinical and clinical studies demonstrating the efficacy and safety of the vaccines. Moreover, we also presented the putative novel targets such as polysaccharide-induced antibodies for the protection against Mtb, PGRS domain as an important target for Humoral immunity, HLA-E pathway-Target strategy for new TB vaccine, Coronin-1a - Novel player for Mycobacterial survival, IRGM, IFN-I3, an autophagy inducer with Irgm1 serving as a core part in the Tuberculosis vaccine development.

Immunological awareness plays a pivotal role in promoting adherence to health instructions during public health emergencies. This study assessed the influence of specialized immunology education on compliance behaviors among higher education students. To assess the influence of specialized immunology education on compliance behaviors toward health instructions and necessary vaccines during epidemics and pandemics among higher education students. A cross-sectional survey was conducted among 532 students at King Faisal University, Saudi Arabia using stratified random sampling. A validated questionnaire examined demographics, health awareness, and specific immunological knowledge. Regression analysis was performed to assess predictors of compliance with health instructions. Considerable knowledge gaps were found around fundamental immunological concepts despite fair awareness about vaccines. Marked disparities existed across gender and academic disciplines. Regression modeling established specialized immunology training as a significant predictor of compliance with guidelines like masking and vaccination during epidemics (p < .001). The findings highlight the need for customized immunology curricula targeting students from nonscientific backgrounds. Incorporating immunology training in continuing education programs for healthcare professionals and public officials can further promote compliance. Multifaceted public health campaigns combining immunology education with initiatives to address socio-cultural barriers are warranted. Further research should explore sustainable educational interventions to enhance long-term retention and integration of immunology knowledge into health behaviors.

Vaccine immunogenicity is affected by a variety of factors. Melatonin has been reported to affect immune responses to vaccines and infection. This was a randomized open-label trial - in which adults scheduled to receive the influenza vaccine were randomized to 5 mg melatonin or control to evaluate the effect of post-vaccination melatonin on humoral (hemagglutination-inhibition assays, HAI) and cellular (FluoroSpot) vaccine-specific cytokine responses 14-21 days post-vaccination. A total of 108 participants (melatonin treatment group: 53; control group: 55) completed the study. The groups were similar in baseline characteristics, including sleep as measured by the Pittsburgh Sleep Quality Index. Seroconversion rates or geometric mean fold rises (GMFR) in HAI titers did not vary by treatment group. There were also no statistically significant differences between pre- and post-vaccination levels of interferon gamma (IFN-γ) or granzyme B (GzB) by treatment; however, there was a significantly higher fold rise in the double secretor (IFN-γ + GzB) peripheral blood mononuclear cells for influenza vaccine in subjects taking daily melatonin (GMFR 1.7; 95% CI 1.3, 2.3) compared to those who did not (GMFR 0.9; 95% CI 0.7, 1.1) (p < .001). Daily melatonin for 14 days post-influenza vaccination significantly increased the cellular co-expression of IFN-γ + GzB; however, there were no other differences in the cellular or humoral responses. Future studies of the potential utility of melatonin for enhancing vaccine response with larger sample sizes may help elucidate candidate mechanisms for these limited effects, including any interactions with the circadian system.