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Use of highly purified antigens to improve vaccine safety has led to reduced immunogenicity and efficacy, resulting in the need for adjuvants to increase and/or modulate the immunogenicity of the vaccine. Despite the need for potent and safe vaccine adjuvants, currently, there are still very few adjuvants in licensed human vaccines. Advances in immunology and molecular biology, especially in the last decade, have allowed researchers to understand better how the adjuvants work and enhance immune responses. While aluminum salts are still the most widely used adjuvants, research has shifted toward the rational design of adjuvant systems containing immunostimulatory molecules. Application of systems biology, which is based on high-throughput technologies using mathematical and computational modeling, has provided a deeper understanding of the biological events elicited by vaccination as well as the influence of other factors such as sex, age, microbiota, genetics and metabolism on the immune response. By this means, it became possible to tailor potential vaccine adjuvants more precisely for a successful vaccine with enhanced efficacy, safety and protection. In this review, after describing the mechanism of action of the adjuvants, current adjuvants in licensed vaccines, as well as those under clinical development will be mentioned in detail. Finally, new approaches in vaccine adjuvant development using systems biology and artificial intelligence will be reviewed, and future directions in vaccine research in regard to efficacy, safety and quality aspects will be discussed.

Since the early 1990s, vaccinologists have worked to use adjuvants targeting toll-like receptors in the development of new vaccines. At the forefront of these efforts is the progress made with the toll-like receptor 4 agonist monophosphoryl lipid A which has now been incorporated into different adjuvant systems. These have led to the first vaccines against malaria and respiratory syncytial virus, and improved vaccines for hepatitis B, human papilloma virus, and shingles. In addition to monophosphoryl lipid A, next-generation toll-like receptor 4 adjuvants are under development with potential improvements in manufacturing, efficacy, and tolerability. This review provides a summary of the field of toll-like receptor 4 vaccine adjuvants to date, highlighting their considerable success and the new adjuvants currently under development. •TLR-4 agonist MPL is present in vaccine adjuvant systems AS01 and AS04.•AS01 facilitated the first vaccines against malaria and respiratory syncytial virus.•AS01 is also present in improved vaccines for shingles.•AS04 is present in improved vaccines for hepatitis B and human papilloma virus.•Next generation synthetic TLR-4 agonists are now in advanced clinical stages.•Success achieved from co-formulation of TLR-4 agonists with secondary adjuvants.

Vaccine adjuvants, as key components in enhancing vaccine immunogenicity, play a vital role in modern vaccinology. This review systematically examines the historical evolution and mechanisms of vaccine adjuvants, with particular emphasis on innovative advancements in aluminum-based adjuvants, emulsion-based adjuvants, and nucleic acid adjuvants (e.g., CpG oligonucleotides). Specifically, aluminum adjuvants enhance immune responses through particle formation/antigen adsorption, inflammatory cascade activation, and T-cell stimulation. Emulsion adjuvants amplify immunogenicity via antigen depot effects and localized inflammation, while nucleic acid adjuvants like CpG oligonucleotides directly activate B cells and dendritic cells to promote Th1-type immune responses and memory T-cell generation. The article further explores the prospective applications of these novel adjuvants in combating emerging pathogens (including influenza and SARS-CoV-2), particularly highlighting their significance in improving vaccine potency and durability. Moreover, this review underscores the critical importance of adjuvant development in next-generation vaccine design and provides theoretical foundations for creating safer, effective adjuvant.

Immunotherapies are effective for cancer treatment but are limited in ‘cold’ tumor microenvironments due to a lack of infiltrating CD8 + T cells, key players in the anti-cancer immune response. The onset of the COVID-19 pandemic sparked the widespread use of mRNA-formulated vaccines and is well documented that vaccination induces a Th1-skewed immune response. Here, we evaluated the effects of an intratumoral injection of the mRNA COVID-19 vaccine in subcutaneous melanoma tumor mouse models. Tumor growth and survival studies following a single intratumoral injection of the COVID-19 vaccine showed significant tumor suppression and prolonged survival in established B16F10 subcutaneous tumor-bearing mice. mRNA vaccine treatment resulted in a significant increase in CD8 + T cell infiltration into the tumor microenvironment, as observed using intravital imaging and flow cytometry. Further tumor growth suppression was achieved using additional mRNA vaccine treatments. Combination administration of mRNA vaccine with immune checkpoint therapies demonstrated enhanced effects, further delaying tumor growth and improving the survival time of tumor-bearing mice. This study demonstrates that mRNA vaccines may be used as adjuvants for immunotherapies.

Respiratory infections are a major public health concern caused by pathogens that colonize and invade the respiratory mucosal surface. Nasal vaccines have the advantage of providing protection at the primary site of pathogen infection, as they induce higher levels of mucosal secretory IgA antibodies and antigen-specific T and B cell responses. Adjuvants are crucial components of vaccine formulation that enhance the immunogenicity of the antigen to confer long-term and effective protection. Saponins, natural glycosides derived from plants, shown potential as vaccine adjuvants, as they can activate the mammalian immune system. Several licensed human vaccines containing saponins-based adjuvants administrated through intramuscular injection have demonstrated good efficacy and safety. Increasing evidence suggests that saponins can also be used as adjuvants for nasal vaccines, owing to their safety profile and potential to augment immune response. In this review, we will discuss the structure-activity-relationship of saponins, their important role in nasal vaccines, and future prospects for improving their efficacy and application in nasal vaccine for respiratory infection.

Mucosal secretory IgA (SIgA) produced by subepithelial plasma cells in the lamina propria is the major antigen-specific defense mechanism against mucosal infections. We investigated if a retinoic acid (RA)-containing adjuvant in parenteral immunization, can induce vaccine-specific SIgA in the jejunal lumen in a dose-dependent manner in neonatal pigs immunized with a Chlamydia hybrid antigen. To accurately quantify SIgA responses in mucosal secretions, an antigen-specific ELISA method with secondary detection of porcine secretory component rather than IgA was developed. RA facilitated a stronger (or faster) IgG, IgA, IgM and SIgA response in serum after primary immunization, and a more than 10-fold significantly increased level of vaccine-specific SIgA in jejunum at termination 2 weeks after the secondary boost, whereas IgA or SIgA responses in bronchoalveolar lavage (BAL) were not significantly increased after immunization with RA. Analyses of different isotype responses to vaccination and different sampling sites, revealed significant correlations between IgG and IgA responses in serum, and between IgG in serum and jejunum, while IgA in jejunum was neither correlated with IgA in serum nor with IgG in jejunum. This is indicative of IgG in jejunum being primarily a transudate from serum, while IgA is not. Jejunum SIgA correlated significantly with jejunum IgA and with both serum SIgA and IgA. Our results thus support the use of SC-specific reagents for mucosal SIgA responses, although IgA reagents to a lesser extent also reflects local antibodies. Although the IgA and SIgA levels in BAL were not significantly different with or without RA, we observed a significant correlation of vaccine-specific SIgA in jejunum and BAL, indicating a level of commonality in the regulation of mucosal antibodies in gut and respiratory system. In conclusion, an adjuvant with high concentration of RA was shown to increase the local intestinal mucosal antibody response after parenteral immunization in pigs. •Secretory IgA antibody responses were measured in the jejunum mucosa.•Vaccine adjuvants were formulated with increasing doses of retinoic acid (RA).•Vaccine-specific SIgA develop in jejunum after parenteral vaccination with RA.•RA facilitated a stronger (or faster) IgG, IgA, IgM and SIgA response in serum.

The SARS-CoV-2 pandemic caused a massive health and societal crisis, although the fast development of effective vaccines reduced some of the impact. To prepare for future respiratory virus pandemics, a pan-viral prophylaxis could be used to control the initial virus outbreak in the period prior to vaccine approval. The liposomal vaccine adjuvant CAF®09b contains the TLR3 agonist polyinosinic:polycytidylic acid, which induces a type I interferon (IFN-I) response and an antiviral state in the affected tissues. When testing CAF09b liposomes as a potential pan-viral prophylaxis, we observed that intranasal administration of CAF09b liposomes to mice resulted in an influx of innate immune cells into the nose and lungs and upregulation of IFN-I-related gene expression. When CAF09b liposomes were administered prior to challenge with mouse-adapted influenza A/Puerto Rico/8/1934 virus, it protected from severe disease, although the virus was still detectable in the lungs. However, when CAF09b liposomes were administered after influenza challenge, the mice had a similar disease course to controls. In conclusion, CAF09b may be a suitable candidate as a pan-viral prophylactic treatment for epidemic viruses, but must be administered prior to virus exposure to be effective.

The ulvans are sulfated heteropolysaccharides that can stimulate the immune response in vitro. Using a human cell model, this study aimed to characterize and evaluate the immunostimulatory properties of crude ulvans extracted from Ulva spp., collected in Algarrobo, Chile. The crude ulvans, characterized by spectrophotometric methods, are composed of 47.6% total sugars, 14.3% uronic acids, and 8.9% sulfates, with an average molecular weight of 40.000 kDa. The FTIR spectrum showed bands related to uronic acids, rhamnose, and sulfate groups. GCMS analysis confirmed the presence of rhamnose, xylose, glucose, and galactose, with a predominance of the disaccharides U3s and B3s. HL60 cells differentiated into macrophages were cultured with three concentrations of crude ulvans (25, 50, and 100 μg/mL), with cell viability remaining above 90% at the lower concentrations. The crude ulvan activated CD86 co-stimulatory molecules and promoted the release of IL-6, IL-10, IL-4, and nitric oxide cytokines. The results suggest that ulvan is non-toxic and can activate inflammatory pathways, making it a potential candidate for studies as a vaccine adjuvant.

Background 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. Methods 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. Results 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. Conclusions 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. Graphical Abstract

There is a need for mucosal vaccines that can fight pathogens at the site of infection. At present, there are no approved adjuvants for mucosal vaccines. Among different immunization routes, oral delivery is the natural choice because of its ease of administration. However, oral administration has two main drawbacks: proteolytic digestion and immune tolerance. In this study, a systematic screening of putative protease inhibitors (PIs) from bacteria to identify novel oral vaccine adjuvants was conducted. Selected candidates were then evaluated for their ability to inhibit gastrointestinal proteases and to stimulate murine dendritic cells. Finally, promising candidates were incorporated as adjuvants into oral vaccine formulations containing model (OVA) or real antigens, such as the cholera toxin B subunit (CTB) and tetanus toxoid and tested in experiments. In addition, a proteomic analysis to assess their effects on dendritic cells was performed. This approach led to the selection of 11 PIs from human pathogenic bacteria, representing diverse families of PIs. These proteins were then expressed in E. coli; five of them demonstrated soluble expression and efficient purification. Three candidates -Ecotin from Salmonella, APRin from Pseudomonas, and STA (staphostatin A) from Staphylococcus aureus- exhibited both protease inhibition and TLR4-independent dendritic-cell activation. studies demonstrated that Ecotin, APRin, and STA enhanced immune responses when orally co-administered with OVA, promoting T-cell proliferation and antibody production. Further evaluation with real antigens, confirmed their adjuvant effect by inducing mucosal and systemic immunity. Proteomic analysis of dendritic cells treated with these proteins revealed significant enrichment in immune-related pathways, including interferon and TNF-signaling, as well as metabolic pathways linked to immune activation. These results demonstrate that three protease inhibitors from bacteria: Ecotin, APRin, and STA function as novel oral mucosal adjuvants capable of modulating immune responses and enhancing antigen immunogenicity.