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Despite advances in critical care medicine, infection remains a significant problem that continues to be complicated with the challenge of antibiotic resistance. Immunocompromised patients are highly susceptible to development of severe infection which often progresses to the life-threatening condition of sepsis. Thus, immunotherapies aimed at boosting host immune defenses are highly attractive strategies to ward off infection and protect patients. Recently there has been mounting evidence that activation of the innate immune system can confer long-term functional reprogramming whereby innate leukocytes mount more robust responses upon secondary exposure to a pathogen for more efficient clearance and host protection, termed trained immunity. Toll-like receptor (TLR) agonists are a class of agents which have been shown to trigger the phenomenon of trained immunity through metabolic reprogramming and epigenetic modifications which drive profound augmentation of antimicrobial functions. Immunomodulatory TLR agonists are also highly beneficial as vaccine adjuvants. This review provides an overview on TLR signaling and our current understanding of TLR agonists which show promise as immunotherapeutic agents for combating infection. A brief discussion on our current understanding of underlying mechanisms is also provided. Although an evolving field, TLR agonists hold strong therapeutic potential as immunomodulators and merit further investigation for clinical translation. [ABSTRACT FROM AUTHOR]

A range of cationic delivery systems have been investigated as vaccine adjuvants, though few direct comparisons exist. To investigate the impact of the delivery platform, we prepared four cationic systems (emulsions, liposomes, polymeric nanoparticles and solid lipid nanoparticles) all containing equal concentrations of the cationic lipid dimethyldioctadecylammonium bromide in combination with the Neisseria adhesin A variant 3 subunit antigen. The formulations were physicochemically characterized and their ability to associate with cells and promote antigen processing (based on degradation of DQ-OVA, a substrate for proteases which upon hydrolysis is fluorescent) was compared in vitro and their vaccine efficacy (antigen-specific antibody responses and IFN-γ production) and biodistribution (antigen and adjuvant) were evaluated in vivo. Due to their cationic nature, all delivery systems gave high antigen loading (> 85%) with liposomes, lipid nanoparticles and emulsions being <200 nm, whilst polymeric nanoparticles were larger (~350 nm). In vitro, the particulate systems tended to promote cell uptake and antigen processing, whilst emulsions were less effective. Similarly, whilst the particulate delivery systems induced a depot (of both delivery system and antigen) at the injection site, the cationic emulsions did not. However, out of the systems tested the cationic emulsions induced the highest antibody responses. These results demonstrate that while cationic lipids can have strong adjuvant activity, their formulation platform influences their immunogenicity. Unlabelled Image [ABSTRACT FROM AUTHOR]

Aluminum salts still remain as the most popular adjuvants in marketed human prophylactic vaccines due to their capability to trigger humoral immune responses with a good safety record. However, insufficient induction of cellular immune responses limits their further applications. In this study, we prepare a library of silicon (Si)- or calcium (Ca)-doped aluminum oxyhydroxide (AlOOH) nanoadjuvants. They exhibit well-controlled physicochemical properties, and the dopants are homogeneously distributed in nanoadjuvants. By using Hepatitis B surface antigen (HBsAg) as the model antigen, doped AlOOH nanoadjuvants mediate higher antigen uptake and promote lysosome escape of HBsAg through lysosomal rupture induced by the dissolution of the dopant in the lysosomes in bone marrow-derived dendritic cells (BMDCs). Additionally, doped nanoadjuvants trigger higher antigen accumulation and immune cell activation in draining lymph nodes. In HBsAg and varicella-zoster virus glycoprotein E (gE) vaccination models, doped nanoadjuvants induce high IgG titer, activations of CD4 + and CD8 + T cells, cytotoxic T lymphocytes, and generations of effector memory T cells. Doping of aluminum salt-based adjuvants with biological safety profiles and immunostimulating capability is a potential strategy to mediate robust humoral and cellular immunity. It potentiates the applications of engineered adjuvants in the development of vaccines with coordinated immune responses.

Monophosphoryl lipid A (MPL®) is the first non-alum vaccine adjuvant to achieve widespread clinical and market acceptance, a remarkable achievement given that it is manufactured from a Salmonella enterica endotoxin. To understand how MPL® successfully balanced the dual mandate of vaccine design—low reactogenicity with high efficacy—clinical- and research-grade MPL was evaluated in human and mouse cell systems. Stimulatory dose response curves revealed that most preparations of MPL are much more active in mouse than in human cell systems, and that the limited efficacy observed in human cells correlated with TLR4 inhibitory activity that resulted in a partial agonist profile. Further analysis of the major components of MPL® adjuvant prepared synthetically identified two structural variants that functioned as competitive antagonists of human TLR4. A partial agonist profile could be recapitulated and manipulated by spiking synthetic agonists with synthetic antagonists to achieve a broad dose range over which TLR4 stimulation could be constrained below a desired threshold. This report thus identifies mixed agonist–antagonist activity as an additional mechanism by which MPL® adjuvant is detoxified, relative to its parental LPS, to render it safe for use in prophylactic vaccines.

Treatment modalities for systemic mycoses are still limited. Currently, the main antifungal therapeutics include polyenes, azoles, and echinocandins. However, even in the setting of appropriate administration of antifungals, mortality rates remain unacceptably high. Moreover, antifungal therapy is expensive, treatment periods can range from weeks to years, and toxicity is also a serious concern. In recent years, the increased number of immunocompromised individuals has contributed to the high global incidence of systemic fungal infections. Given the high morbidity and mortality rates, the complexity of treatment strategies, drug toxicity, and the worldwide burden of disease, there is a need for new and efficient therapeutic means to combat invasive mycoses. One promising avenue that is actively being pursued is nanotechnology, to develop new antifungal therapies and efficient vaccines, since it allows for a targeted delivery of drugs and antigens, which can reduce toxicity and treatment costs. The goal of this review is to discuss studies using nanoparticles to develop new therapeutic options, including vaccination methods, to combat systemic mycoses caused by Candida sp., Cryptococcus sp., Paracoccidioides sp., Histoplasma sp., Coccidioides sp., and Aspergillus sp., in addition to providing important information on the use of different types of nanoparticles, nanocarriers and their corresponding mechanisms of action.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory illness, particularly in infants, the elderly, and immunocompromised adults. There is no licensed commercial vaccine against RSV. Importantly, formalin-inactivated RSV vaccines mediate enhanced respiratory disease. RSV fusion (F) protein with pre-fusion conformation is a promising candidate subunit vaccine. However, some problems remain to be solved, such as low immunogenicity and humoral immunity bias. Adjuvants can effectively enhance and adjust vaccine immune responses. In this study, we formulated pre-fusion RSV-F protein with the adjuvants, Alhydrogel, MF59, AS03, AS02, and glycol chitosan (GCS). We then conducted head-to-head comparisons of vaccine-induced immune responses in BALB/c mice. All adjuvanted vaccines enhanced antigen-specific and neutralizing antibody titers and viral clearance and gave an order of adjuvant activity: AS02 > AS03, MF59 > GCS, and Alhydrogel. Among them, AS02 elicited the highest antibody expression, which persisted until week 18. Moreover, AS02 significantly enhanced Th1 type immune response in immunized mice. Mice in the AS02 group also showed faster recovery from viral attacks in challenge tests. Further transcriptome analysis revealed that AS02 regulates immune balance by activating TLR-4 and promotes Th1-type immune responses. These results suggest that AS02 may be an excellent candidate adjuvant for RSV-F subunit vaccines. This study also provides valuable information regarding the effect of other adjuvants on immune responses of RSV-F subunit vaccines.

Mycobacterium abscessus is a prevalent pathogenic mycobacterium in cystic fibrosis (CF) patients and one of the most highly drug resistant mycobacterial species to antimicrobial agents. It possesses the property to transition from a smooth (S) to a rough (R) morphotype, thereby influencing the host innate immune response. This transition from the S to the R morphotype takes place in patients with an exacerbation of the disease and a persistence of M. abscessus. We have previously shown that the exacerbation of the Toll-like receptor 2 (TLR2)-mediated inflammatory response, following this S to R transition, is essentially due to overproduction of bacilli cell envelope surface compounds, which we were able to extract by mechanical treatment and isolation by solvent partition in a fraction called interphase. Here, we set up a purification procedure guided by bioactivity to isolate a fraction from the R variant of M. abscessus cells which exhibits a high TLR2 stimulating activity, referred to as TLR2-enriched fraction (TLR2eF). As expected, TLR2eF was found to contain several lipoproteins and proteins known to be stimuli for TLR2. Vaccination with TLR2eF showed no protection toward an M. abscessus aerosol challenge, but provided mild protection in ΔF508 mice and their FVB littermates when intravenously challenged by M. abscessus. Interestingly however, antibodies against TLR2eF compounds were detected during disease in CF patients. In conclusion, we show the potential for compounds in TLR2eF as vaccine and diagnostic candidates, in order to enhance diagnosis, prevent and/or treat M. abscessus-related infections.

The development of cervical cancer has been shown to involve both viral and host factors. The host factors are those that determine the specific response to human papillomavirus (HPV) infection by the patient's immune system. The immune responses to vaccines have been shown to be influenced by polymorphisms in genes involved in innate and adaptive immunity. The specific genetic variants that may influence the immune responses to HPV vaccine which may contribute to persistence of immunity (POI) have not been widely studied yet. In order to address the question as to “is it right to vaccinate all children, and all with equal dose?” we have critically examined the knowledge of common immunogenetic and immunogenomic variations that may influence the HPV vaccine POI across various populations. We have also identified a number of specific research questions that need to be addressed in future research into host molecular genetic variations and HPV vaccine POI in order to afford life-long protection against the development of cervical cancer. This work informs future insights for improved HPV vaccine designs based on common host molecular genetic variations.

Our previous study has recorded that the recombinant protein of Nile tilapia (Oreochromis niloticus) galectin-2 (rOnGal-2) can enhance immune response against Streptococcus agalactiae (S.agalactiae) infection in vitro. In this study, we further explored the effects of OnGal-2 in immune response against bacterial infection in vivo. The administration of rOnGal-2 could improve serum antibacterial activity (ALKP, ACP, and LZM) and antioxidant capacity (CAT, POD, and SOD). After S. agalactiae infection, rOnGal-2 injection could reduce bacterial burden and decrease tissue damage in head kidney, spleen, and liver of tilapia. Also, rOnGal-2 regulated the inflammatory-related genes expression including IL-6 , IL-8 and IL-10 during bacterial infection. Furthermore, rOnGal-2 administration could increase the relative percentage survival of tilapia infected with S.agalactiae. Taken together, our results indicate that OnGal-2 can protect fish from bacterial infection through reducing bacterial burden, impairing tissue damage and modulating anti-bacterial immune response, which also can be applied as a potential vaccine adjuvant in O.niloticus culture. • The administration of rOnGal-2 in vivo improved Nile tilapia serum antibacterial activity and antioxidant capacity. • rOnGal-2 treatment could reduce bacterial burden and decrease tissue damage post S.agalactiae infection. • rOnGal-2 could regulate the inflammatory-related genes expression during bacterial infection. • rOnGal-2 administration could increase the relative percentage survival of tilapia infected with S.agalactiae. [ABSTRACT FROM AUTHOR]

Background: Patients with inflammatory bowel disease (IBD) are at increased risk of developing herpes zoster. In October 2017, the FDA approved a two-dose adjuvanted, recombinant herpes zoster vaccine (RZV). There is a theoretical concern that vaccine adjuvants may cause flares in patients with immune-mediated diseases. We aimed to assess the rates of IBD flare and adverse reactions after administration of RZV in a cohort of patients with IBD.Methods: We conducted a prospective observational study of patients with IBD who received RZV between February 2018 and July 2019 at a tertiary IBD referral center. IBD activity scores were collected from patients during office visit or phone call after vaccination. The primary outcome was rate of IBD flare, defined as an increase in IBD activity, resulting in escalation of medical therapy, following vaccination. The secondary outcomes were rates of local and systemic adverse reactions after vaccination.Results: We identified 67 patients (28 with ulcerative colitis and 39 with Crohn's disease) who received at least one dose of RZV. The two-dose vaccine series was completed by 55 patients (82%). Median duration of follow-up after vaccination was 207 days. One case of IBD flare was identified. No cases of herpes zoster were identified. Local and systemic adverse reactions were reported in 74.6% and 56.7% of patients, respectively.Conclusions: In this cohort of 67 patients, a low rate of IBD flare (1.5%) was observed after RZV administration. Rates of local and systemic adverse reactions were comparable to those seen in the RZV clinical trials. [ABSTRACT FROM AUTHOR]

Malaria is a tropical human disease, caused by protozoan parasites, wherein a significant number of the world's population is at risk. Annually, more than 219 million new cases are reported. Although there are prevention treatments, there are no highly and widely effective licensed anti-malarial vaccines available for use. Opportunities for utilization of plant-based vaccines as novel platforms for developing safe, reliable, and affordable treatments offer promise for developing such a vaccine against malaria. In this study, a Malchloroplast candidate vaccine was designed, composed of segments of AMA1 and MSP1 proteins, two epitopes of Plasmodium falciparum, along with a GK1 peptide from Taenia solium as adjuvant, and this was expressed in tobacco chloroplasts. Transplastomic tobacco lines were generated using biolistic transformation, and these were confirmed to carry the synthetic gene construct. Expression of the synthetic GK1 peptide was confirmed using RT-PCR and Western blots. Furthermore, the GK1 peptide was detected by HPLC at levels of up to 6 µg g−1 dry weight of tobacco leaf tissue. The plant-derived Malchloroplast candidate vaccine was subsequently tested in BALB/c female mice following subcutaneous administration, and was found to elicit specific humoral responses. Furthermore, components of this candidate vaccine were recognized by antibodies in Plasmodium falciparum malaria patients and were immunogenic in test mice. Thus, this study provided a 'proof of concept' for a promising plant-based candidate subunit vaccine against malaria. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory illness, particularly in infants, the elderly, and immunocompromised adults. There is no licensed commercial vaccine against RSV. Importantly, formalin-inactivated RSV vaccines mediate enhanced respiratory disease. RSV fusion (F) protein with pre-fusion conformation is a promising candidate subunit vaccine. However, some problems remain to be solved, such as low immunogenicity and humoral immunity bias. Adjuvants can effectively enhance and adjust vaccine immune responses. In this study, we formulated pre-fusion RSV-F protein with the adjuvants, Alhydrogel, MF59, AS03, AS02, and glycol chitosan (GCS). We then conducted head-to-head comparisons of vaccine-induced immune responses in BALB/c mice. All adjuvanted vaccines enhanced antigen-specific and neutralizing antibody titers and viral clearance and gave an order of adjuvant activity: AS02 > AS03, MF59 > GCS, and Alhydrogel. Among them, AS02 elicited the highest antibody expression, which persisted until week 18. Moreover, AS02 significantly enhanced Th1 type immune response in immunized mice. Mice in the AS02 group also showed faster recovery from viral attacks in challenge tests. Further transcriptome analysis revealed that AS02 regulates immune balance by activating TLR-4 and promotes Th1-type immune responses. These results suggest that AS02 may be an excellent candidate adjuvant for RSV-F subunit vaccines. This study also provides valuable information regarding the effect of other adjuvants on immune responses of RSV-F subunit vaccines. [ABSTRACT FROM AUTHOR]

Treatment modalities for systemic mycoses are still limited. Currently, the main antifungal 18 therapeutics include polyenes, azoles, and echinocandins. However, even in the setting of 19 appropriate administration of antifungals, mortality rates remain unacceptably high. Moreover, 20 antifungal therapy is expensive, treatment periods can range from weeks to years, and toxicity 21 is also a serious concern. In recent years, the increased number of immunocompromised 22 individuals has contributed to the high global incidence of systemic fungal infections. Given 23 the high morbidity and mortality rates, the complexity of treatment strategies, drug toxicity, 24 and the worldwide burden of disease, there is a need for new and efficient therapeutic means 25 to combat invasive mycoses. One promising avenue that is actively being pursued is 26 nanotechnology, to develop new antifungal therapies and efficient vaccines, since it allows for 27 a targeted delivery of drugs and antigens, which can reduce toxicity and treatment costs. The 28 goal of this review is to discuss studies using nanoparticles to develop new therapeutic options, 29 including vaccination methods, to combat systemic mycoses caused by Candida sp., 30 Cryptococcus sp., Paracoccidioides sp., Histoplasma sp., Coccidioides sp., and Aspergillus sp., 31 in addition to providing important information on the use of different types of nanoparticles, 32 nanocarriers and their corresponding mechanisms of action. [ABSTRACT FROM AUTHOR]

Mycobacterium abscessus is a prevalent pathogenic mycobacterium in cystic fibrosis (CF) patients and one of the most highly drug resistant mycobacterial species to antimicrobial agents. It possesses the property to transition from a smooth (S) to a rough (R) morphotype, thereby influencing the host innate immune response. This transition from the S to the R morphotype takes place in patients with an exacerbation of the disease and a persistence of M. abscessus. We have previously shown that the exacerbation of the Toll-like receptor 2 (TLR2)-mediated inflammatory response, following this S to R transition, is essentially due to overproduction of bacilli cell envelope surface compounds, which we were able to extract by mechanical treatment and isolation by solvent partition in a fraction called interphase. Here, we set up a purification procedure guided by bioactivity to isolate a fraction from the R variant of M. abscessus cells which exhibits a high TLR2 stimulating activity, referred to as TLR2-enriched fraction (TLR2eF). As expected, TLR2eF was found to contain several lipoproteins and proteins known to be stimuli for TLR2. Vaccination with TLR2eF showed no protection toward an M. abscessus aerosol challenge, but provided mild protection in ΔF508 mice and their FVB littermates when intravenously challenged by M. abscessus. Interestingly however, antibodies against TLR2eF compounds were detected during disease in CF patients. In conclusion, we show the potential for compounds in TLR2eF as vaccine and diagnostic candidates, in order to enhance diagnosis, prevent and/or treat M. abscessus -related infections. [ABSTRACT FROM AUTHOR]

Vaccine is one of the most effective strategies for preventing and controlling infectious diseases and some noninfectious diseases, especially cancers. Adjuvants and carriers have been appropriately added to the vaccine formulation to improve the immunogenicity of the antigen and induce long-lasting immunity. However, there is an urgent need to develop new all-purpose adjuvants because some adjuvants approved for human use have limited functionality. Graphene oxide (GO), widely employed for the delivery of biomolecules, excels in loading and delivering antigen and shows the potentiality of activating the immune system. However, GO aggregates in biological liquid and induces cell death, and it also exhibits poor biosolubility and biocompatibility. To address these limitations, various surface modification protocols have been employed to integrate aqueous compatible substances with GO to effectively improve its biocompatibility. More importantly, these modifications render functionalized-GO with superior properties as both carriers and adjuvants. Herein, the recent progress of physicochemical properties and surface modification strategies of GO for its application as both carriers and adjuvants is reviewed. Due to its unique physicochemical properties, graphene oxide is widely employed in medicine for purposes of photothermal treatment of cancer, drug delivery, antibacterial therapy, and medical imaging. Our work describes the surface modification of graphene oxide and for the first time summarizes that functionalized graphene oxide serves as a vaccine carrier and shows significant adjuvant activity in activating cellular and humoral immunity. In the future, it is expected to be introduced into vaccine research to improve the efficacy of vaccines. Image, graphical abstract [ABSTRACT FROM AUTHOR]

• The synthesized novel PPV vaccine (PPV/N-2-HACC) had good storage stability and high safety. • PPV/N-2-HACC elicited the effectually humoral immune responses and maintained higher antibody levels for a long time. • PPV/N-2-HACC vaccine protected sows from PPV challenge. • N-2-HACC is a safe, stable and effective adjuvants with the ability to enhance the immune responses of inactive immunogens. Porcine parvovirus (PPV) is one of the most common and important virus causes of infectious infertility in swine throughout the world. Inactivated PPV vaccine is broadly used, however, there is no appropriate immunomodulatory adjuvant for enhancing present vaccines and developing new ones. Therefore, in this study, the water-soluble N -2-Hydroxypropyl trimethyl ammonium chloride chitosan (N-2-HACC) was synthesized, the adjuvant potential of chitosan derivative was evaluated in inactivated PPV vaccine. Twenty adult healthy sows were assigned to four groups and vaccinated with synthesized PPV/N-2-HACC, commercial inactivated vaccine, N-2-HACC adjuvant and PBS. After insemination, all sows were challenged with the homologous PPV-H strain. In vivo immunization showed that sows immunized with the PPV/N-2-HACC induced more long-lasting HI antibodies and strong immune responses. Importantly, immunization of PPV/N-2-HACC significantly protected sows from homologous PPV-H strain infection. However, immunization of PPV/N-2-HACC didn't change the level of IL-2, IL-4 and IFN-γ and the production of CD4+, CD8 + T lymphocyte. The results indicated that PPV/N-2-HACC protect PPV infection mainly through enhancing the humoral immunity rather than cellular immunity. In addition, the mummified fetuses were observed from the control groups, but neither of the two vaccine groups. In conclusion, these results suggest that N-2-HACC can be exploited as an effective adjuvant for vaccine development, and the PPV/N-2-HACC are potent immunization candidates against PPV infection. [ABSTRACT FROM AUTHOR]

A vaccine that induces broadly neutralizing antibodies (bnAbs) against the human immunodeficiency virus (HIV) would be instrumental in controlling the disease. The membrane proximal external region (MPER) peptide is an appealing antigen candidate since it is conserved and is the target of several human bnAbs, such as 2F5. We previously found that liposomes containing cobalt porphyrin-phospholipid (CoPoP) can bind to a his-tagged MPER peptide, resulting in biomimetic antigen presentation on a lipid bilayer. The present study generated various his-tagged, synthetic MPER fragments, which were bound to liposomes containing CoPoP and a synthetic monophosphoryl lipid A (MPLA) and assessed for immunogenicity in mice. MPER peptides with amino acids stretches originating from the membrane insertion point that were at least 25 amino acids in length, had greater 2F5 reactivity and induced stronger antibody responses, compared to shorter ones. Immunization with the lipid-presented MPER elicited stronger antibody responses compared to Alum and Montanide adjuvants, which could recognize recombinant gp41 and gp140 proteins that contained MPER sequences. The induced antibodies neutralized a tier 1A virus that is sensitive to neutralizing antibodies (W61D(TCLA)0.71), but not another tier 1A nor a tier 2 strain. Co-formulation of the MPER peptide with an unrelated malaria protein antigen (Pfs25) that is effectively adjuvanted with liposomes containing CoPoP and MPLA resulted in elicitation of higher MPER antibody levels, but did not improve neutralization, possibly due to interference with proper peptide presentation in the membrane. Murine hybridomas were generated that produced MPER antibodies, but they were non-neutralizing. These results do not show that bnAbs could be generated with MPER peptides and CoPoP liposomes, but do not rule out this possibility with additional improvements to the approach. [ABSTRACT FROM AUTHOR]

The development of cervical cancer has been shown to involve both viral and host factors. The host factors are those that determine the specific response to human papillomavirus (HPV) infection by the patient's immune system. The immune responses to vaccines have been shown to be influenced by polymorphisms in genes involved in innate and adaptive immunity. The specific genetic variants that may influence the immune responses to HPV vaccine which may contribute to persistence of immunity (POI) have not been widely studied yet. In order to address the question as to "is it right to vaccinate all children, and all with equal dose?" we have critically examined the knowledge of common immunogenetic and immunogenomic variations that may influence the HPV vaccine POI across various populations. We have also identified a number of specific research questions that need to be addressed in future research into host molecular genetic variations and HPV vaccine POI in order to afford life-long protection against the development of cervical cancer. This work informs future insights for improved HPV vaccine designs based on common host molecular genetic variations. [ABSTRACT FROM AUTHOR]

Introduction: From its earliest days, the US. military has embraced the use of vaccines to fight infectious diseases. The Army Liposome Formulation (ALF) has been a pivotal innovation as a vaccine adjuvant that provides excellent safety and potency and could lead to dual-use military and civilian benefits. For protection of personnel against difficult disease threats found in many areas of the world, Army vaccine scientists have created novel liposome-based vaccine adjuvants. Areas covered: ALF consists of liposomes containing saturated phospholipids, cholesterol, and monophosphoryl lipid A (MPLA) as an immunostimulant. ALF exhibited safety and strong potency in many vaccine clinical trials. Improvements based on ALF include: ALF adsorbed to aluminum hydroxide (ALFA); ALF containing QS21 saponin (ALFQ); and ALFQ adsorbed to aluminum hydroxide (ALFQA). Preclinical safety and efficacy studies with ALF, LFA, ALFQ, and ALFQA are discussed in preparation for upcoming vaccine trials targeting malaria, HIV-1, bacterial diarrhea, and opioid addiction. Expert opinion: The introduction of ALF in the 1980s stimulated commercial interest in vaccines to infectious diseases, and therapeutic vaccines to cancer, and Alzheimer's disease. It is likely that ALF, ALFA, and ALFQ, will provide momentum for new types of modern vaccines with improved efficacy and safety. [ABSTRACT FROM AUTHOR]

[Display omitted] • Glucan particles interact differently with immune cells based on particle size and chemical composition. • Glucan particles have the capacity to induce both phenotypic and functional maturation of DCs. • Dendritic cells matured by glucan particles can accelerate T cell proliferation. • Glucan particles induce upregulation of Dectin-1 in monocytes. The immunomodulatory properties of β-glucans have sparked interest among various medical fields. As vaccine adjuvants, glucan particles offer additional advantages as antigen delivery systems. This study reported the immunomodulatory properties of glucan particles with different size and chemical composition. The effect of glucan microparticles (GPs) and glucan nanoparticles (Glu 130 and 355 NPs) was evaluated on human immune cells. While GPs and Glu 355 NPs demonstrated substantial interaction with Dectin-1 receptor on monocytes, Glu 130 NPs exhibited reduced activation of this receptor. This observation was substantiated by blocking Dectin-1, resulting in inhibition of reactive oxygen species production induced by GPs and Glu 355 NPs. Notably, monocyte-derived dendritic cells (moDCs) stimulated by Glu 355 NPs exhibited phenotypic and functional maturation, essential for antigen cross-presentation. The immunomodulatory efficacy was investigated using an autologous mixed lymphocyte reaction (AMLR), resulting in considerable rates of lymphocyte proliferation and an intriguing profile of cytokine and chemokine release. Our findings highlight the importance of meticulously characterizing the size and chemical composition of β-glucan particles to draw accurate conclusions regarding their immunomodulatory activity. This in vitro model mimics the human cellular immune response, and the results obtained endorse the use of β-glucan-based delivery systems as future vaccine adjuvants. [ABSTRACT FROM AUTHOR]

• Clay nanosheet adjuvants are easy to prepare without organic solvents. • The lyophilization process cannot affect antigen loading on the nanosheets. • Nanosheet adjuvant induces a strong cellular immune response. • Nanosheet vaccine leads 13-fold higher EBV neutralizing antibody titers to aluminum. The experience of fighting COVID-19 shows the growing importance of vaccine-induced cellular immunity, whereas aluminum adjuvants fail to meet this medical requirement. Herein, with very simple processing, we prepared a narrow lateral size of monolayer clay nanosheets from montmorillonite, a FDA-approved generally recognized as safe (GARS) material. The nanosheets adsorbed antigen ovalbumin (OVA) through hydrophilic and electrostatic interactions, while utilizing nanosheets to expose more octahedral Al-OH and tetrahedral Si-OH residues to complete the adsorption of mannose (Man) targeting antigen presentation cells, leading to the production of nanosheet vaccines. In additional, the lyophilization process did not significantly affect the loading of OVA and Man on the nanosheets. The obtained nanosheet vaccines induced a strong cellular immune response in addition to a potent humoral immune response. Inspired by the results, the prophylactic nanosheet adjuvant vaccine against Epstein-Barr virus (EBV) was developed, which induced a 13-fold increase in EBV-neutralizing antibody titers compared to aluminum adjuvant vaccine, and efficiently blocked EBV infection of target cells. Based on the simple formulation process, remarkable immune response effect and excellent safety profile, montmorillonite nanosheets have the potential to replace aluminum adjuvant as a vaccine platform for inducing effective immune responses. [ABSTRACT FROM AUTHOR]

This study describes a polymer potentially used as a vaccine adjuvant. We first synthesized a novel polyacrylic acid modified by perfluorinated butanol—a bioactive compound that is biocompatible. The main aim was to functionalize the polyacrylic acid by fluorine. This functionalization could offer a permanent graft by an esterification reaction. The chemical structure of the polymer has been characterized by the hydrogen nuclear magnetic resonance spectrum (1H-NMR) and fourier transform infrared spectrum (FT-IR). Thermal analysis showed that the esterification reaction was successful on the polyacrylic acid. Viscosity testing showed that the viscosity of the sample aqueous solution increases along with esterification. The surface tension of the polymer was also tested. The results show that the surface tension of the polyacrylic acid markedly decreased when modified by fluorine. Finally, the interaction of these materials with macrophages was tested on cell test. Results showed that the modified polyacrylic acid performed better improve the activation effect than pure polyacrylic acid in 1L-1β.

Porcine parvovirus (PPV) is the most important infectious agent causing infertility in pigs, which can be prevented by routine vaccination. Successful vaccination depends on the association with potent adjuvants that can enhance the immunogenicity of antigen and activate the immune system. Polysaccharide adjuvant has low toxicity and high safety, and they can enhance the humoral, cellular and mucosal immune responses. In the present study, we prepared the VP2 protein subunit vaccine against PPV (PPV/VP2/N-2-HACC) using water-soluble N-2-Hydroxypropyl trimethyl ammonium chloride chitosan (N-2-HACC) as the vaccine adjuvant, and the ability of the PPV/VP2/N-2-HACC to induce immune responses and protect sows from PPV infection was evaluated. In vivo immunization showed that the sows immunized with the PPV/VP2/N-2-HACC by intramuscular injection produced higher HI antibody levels and long-term immune protection compared with the other groups, while the subunit vaccine did not stimulate the proliferation of CD4+ and CD8+ T lymphocytes to trigger the secretion of higher levels of IL-2, IL-4, IFN-α, IFN-β, and IFN-γ, indicating that the PPV/VP2/N-2-HACC mainly induced humoral immunity rather than cellular immunity. PPV was not detected in the viscera of the sows immunized with the PPV/VP2/N-2-HACC, and the protective efficacy was 100%. Collectively, our findings suggested that the N-2-HACC was a potential candidate adjuvant, and the PPV/VP2/N-2-HACC had immense application value for the control of PPV.

Cyclic dinucleotides (CDNs), originally discovered as bacterial second messengers, play critical roles in bacterial signal transduction, cellular processes, biofilm formation, and virulence. The finding that CDNs can trigger the innate immune response in eukaryotic cells through the stimulator of interferon genes (STING) signalling pathway has prompted the extensive research and development of CDNs as potential immunostimulators and novel molecular adjuvants for induction of systemic and mucosal innate and adaptive immune responses. In this review, we summarize the chemical structure, biosynthesis regulation, and the role of CDNs in enhancing the crosstalk between host innate and adaptive immune responses. We also discuss the strategies to improve the efficient delivery of CDNs and the recent advance and future challenges in the development of CDNs as potential adjuvants in prophylactic vaccines against infectious diseases and in therapeutic vaccines against cancers.

Pattern recognition receptors (PRRs) play a central role in the inflammation that ensues following microbial infection by their recognition of molecular patterns present in invading microorganisms but also following tissue damage by recognising molecules released during disease states. Such receptors are expressed in a variety of cells and in various compartments of these cells. PRR binding of molecular patterns results in an intracellular signalling cascade and the eventual activation of transcription factors and the release of cytokines, chemokines, and vasoactive molecules. PRRs and their accessory molecules are subject to tight regulation in these cells so as to not overreact or react in unnecessary circumstances. They are also key to reacting to infection and in stimulating the immune system when needed. Therefore, targeting PRRs offers a potential therapeutic approach for chronic inflammatory disease, infections and as vaccine adjuvants. In this review, the current knowledge on anti-viral PRRs and their signalling pathways is reviewed. Finally, compounds that target PRRs and that have been tested in clinical trials for chronic infections and as adjuvants in vaccine trials are discussed.

Nobutaka Hanagata,1,2 Xianglan Li,1 Min-Hua Chen,1 Jie Li,1 Shinya Hattori1 1Nanotechnology Innovation Station, National Institute for Materials Science, Tsukuba, 2Graduate School of Life Science, Hokkaido University, Sapporo, Japan Abstract: Conventional class B cytosine-guanine (CpG) (CpG-B) oligodeoxynucleotide (ODNs) consisting of a single-stranded (ss) phosphorothioate (PT) backbone (ss CpG-B-PT) is converted from a proinflammatory cytokine inducer to a type-I interferon (IFN) inducer when complexed with cationic materials. In this study, we designed ss CpG-B and double-stranded (ds) CpG-B ODNs with a phosphodiester (PD) backbone (ss CpG-B-PD and ds CpG-B-PD, respectively) that became type-I IFN inducers upon complexation with Lipofectamine 2000 (Lipo), a cationic liposome. The ds CpG-B-PD complex induced higher IFN-β expression in mouse macrophage-like RAW264 cells than ss CpG-B-PD and ss CpG-B-PT complexes. The fold induction of IFN-β increased with the number of CpG motifs in ds CpG-B-PD, and a complex of ds CpG-B-PD consisting of 72 base pairs with nine CpG motifs (ds CpG-B72-PD) and Lipo showed the highest capacity to induce IFN-β. The materials and method used for complexation influenced the degree of IFN-β induction: ds CpG-B72-PD entrapped by calcium phosphate (CaP) (ds CpG-B72-PD/CaP) showed a higher induction capacity than ds CpG-B72-PD adsorbed onto the CaP surface. Entrapment of ds CpG-B72-PD by CaP also enhanced the induction of the proinflammatory cytokine interleukin-12. Vaccinating mice with ds CpG-B72-PD/CaP in conjunction with ovalbumin (OVA) increased the ratios of OVA-specific CD8+ T cells to total CD8+ T cells in peripheral blood and of OVA-specific IgG2a associated with helper T (Th)1 cells to OVA-specific IgG1 associated with Th2 cells. These results indicate that ds CpG-B72-PD/CaP is an effective vaccine adjuvant that can activate both cellular and Th1-type humoral immune responses. Keywords: CpG oligodeoxynucleotide, calcium phosphate, vaccine adjuvant, cellular immunity, humoral immunity

Introduction: Adjuvants are essential components in vaccine formulations to induce robust immunity against pathogens. The most widely used adjuvants in human vaccines are aluminum salts, that can effectively elicit a T helper type-2 (Th2)-biased humoral immune response for producing a high antibody titer but with a limited cellular immune response. Biocompatible calcium phosphate nanoparticles (CaP-NPs) with tunable characteristics have potentials to function as adjuvants for inducing more balanced T helper type-1 (Th1) and Th2 immune responses. Areas covered: Here we review the preparation procedures and characteristics of CaP-NPs. The process can be well-controlled and readily scaled up. Antigen loading can take place as encapsulation during the particle formation or as passive adsorption post particle formation. Different modalities of immunogens were tested with CaP-NPs as adjuvants. The possible mechanisms of the CaP-NP-based adjuvants are discussed. Expert commentary: With good adjuvant effects and safety profiles, CaP-NPs have the potentials to be a new generation vaccine adjuvant. A more in-depth understanding of the mechanisms of their adjuvanticity could facilitate the process optimization for making adjuvants with preferred characteristics. Interdisciplinary collaborations are essential for testing the biocompatible CaP-NPs in human vaccines for clinical development and eventually for use in marketed vaccines.

The use of a good vaccine adjuvant may induce a higher immunogenicity profile of vaccine antigens. Here, we developed a new adjuvant by combining poly-γ-glutamic acid (γ-PGA) with alum (PGA/Alum) and investigated its ability to enhance the immunogenicity and the cross-reactive efficacy of pandemic H1N1 (pH1N1) influenza vaccine antigen. PGA/Alum enhanced antigen delivery to draining lymph nodes and antigen-specific immunogenicity in mice using OVA as a model antigen. It also greatly increased OVA-specific antibody production, cytotoxic T lymphocyte (CTL) activity, and antibody-dependent cellular cytotoxicity (ADCC). These abilities of PGA/Alum improved the protective efficacy of pH1N1 vaccine antigen by increasing hemagglutination-inhibition titers, enhancing ADCC and CTL activity, and speeding viral clearance following homologous viral challenge. Importantly, the cross-protective efficacy of pH1N1 vaccine against heterologous viruses [A/Puerto Rico/8/34 (H1N1) and A/Hong Kong/1/1968 (H3N2)] was significantly enhanced by PGA/Alum, and cross-reactive ADCC and CTL activities were observed. Together, our results strongly suggest that PGA/Alum may be a promising vaccine adjuvant for preventing influenza and other infectious diseases.

Vaccination is the most cost-effective and sustainable way to prevent and eliminate infectious diseases. Compared with traditional vaccines, novel vaccines have better stability, longer duration and require less antigen usage. In addition, novel vaccines have better immune effects and significantly less toxic side effects. However, both novel vaccines and traditional vaccines require carrier molecules or adjuvants to produce an optimal immune response. There is an increasing demand for vaccine adjuvants and delivery systems that can induce stronger immune response whilst reducing production cost and the dose of vaccine. In recent years, nanotechnology has played an important role in the development of novel vaccine adjuvants and nano-delivery systems. Biodegradable materials have also received a lot of attention in medical science because they have excellent biocompatibility, biodegradability and low toxicity, which can protect antigens from degradation, increase antigen stability and provide slow release; resulting in enhanced immunogenicity. Therefore, biodegradable nanoparticles have attracted much attention in the formulation of vaccines. In this review, we outline some key features of biodegradable nanomaterials in the developing safer and more effective vaccines. The properties, structural characteristics, advantages and disadvantage of the biodegradable nanomaterials will be systematically reviewed. Additionally, applications, research progress and future prospects of biodegradable nanomaterials are discussed. This review will be help in future research work directed at developing biodegradable vaccine adjuvants or delivery carriers. [ABSTRACT FROM AUTHOR]

Monophosphoryl lipid A (MPLA) species, including MPL (a trade name of GlaxoSmithKline) and GLA (a trade name of Immune Design, a subsidiary of Merck), are widely used as an adjuvant in vaccines, allergy drugs, and immunotherapy to boost the immune response. Even though MPLA is a derivative of lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, bacterial strains producing MPLA have not been found in nature nor engineered. In fact, MPLA generation involves expensive and laborious procedures based on synthetic routes or chemical transformation of precursors isolated from Gram-negative bacteria. Here, we report the engineering of an Escherichia coli strain for in situ production and accumulation of MPLA. Furthermore, we establish a succinct method for purifying MPLA from the engineered E. coli strain. We show that the purified MPLA (named EcML) stimulates the mouse immune system to generate antigen-specific IgG antibodies similarly to commercially available MPLA, but with a dramatically reduced manufacturing time and cost. Our system, employing the first engineered E. coli strain that directly produces the adjuvant EcML, could transform the current standard of industrial MPLA production. • Monophosphoryl lipid A (MPLA) is a safe and effective adjuvant. • Engineering lipopolysaccharide biosynthetic pathway enables to produce MPLA. • Employing lipid A 1-phosphatase from Aquifex dephosphorylates lipid A in vivo. • The succinct purification method of MPLA (EcML) is developed. • EcML purified from the engineered strain effectively functions as an adjuvant. [ABSTRACT FROM AUTHOR]

To increase vaccine immunogenicity, modern vaccines incorporate adjuvants, which serve to enhance immune cross-protection, improve humoral and cell-mediated immunity, and promote antigen dose sparing. Pattern recognition receptors (PRRs), including the Toll-like receptor (TLR) family are promising targets for development of agonist formulations for use as vaccine adjuvants. Combinations of co-delivered TLR4 and TLR7/8 ligands have been demonstrated to have synergistic effects on innate and adaptive immune response. Here, we create liposomes that stably co-encapsulate CRX-601, a synthetic TLR4 agonist, and UM-3004, a lipidated TLR7/8 agonist, within the liposomal bilayer in order to achieve co-delivery, allow tunable physical properties, and induce in vitro and in vivo immune synergy. Co-encapsulation demonstrates a synergistic increase in IL-12p70 cytokine output in vitro from treated human peripheral blood mononuclear cells (hPBMCs). Further, co-encapsulated formulations give significant improvement of early IgG2a antibody titers in BALB/c mice following primary vaccination when compared to single agonist or dual agonists delivered in separate liposomes. This work demonstrates that co-encapsulation of TLR4 and lipidated TLR7/8 agonists within the liposomal bilayer leads to innate and adaptive immune synergy which biases a Th1 immune response. Thus, liposomal co-encapsulation may be a useful and flexible tool for vaccine adjuvant formulation containing multiple TLR agonists. [ABSTRACT FROM AUTHOR]

Cardiolipins (CLs) are tetra-acylated diphosphatidylglycerols found in bacteria, yeast, plants, and animals. In healthy mammals, CLs are unsaturated, whereas saturated CLs are found in blood cells from Barth syndrome patients and in some Gram-positive bacteria. Here, we show that unsaturated but not saturated CLs block LPS-induced NF-κB activation, TNF-α and IP-10 secretion in human and murine macrophages, as well as LPS-induced TNF-α and IL-1β release in human blood mononuclear cells. Using HEK293 cells transfected with Toll-like receptor 4 (TLR4) and its co-receptor Myeloid Differentiation 2 (MD2), we demonstrate that unsaturated CLs compete with LPS for binding TLR4/MD2 preventing its activation, whereas saturated CLs are TLR4/MD2 agonists. As a consequence, saturated CLs induce a pro-inflammatory response in macrophages characterized by TNF-α and IP-10 secretion, and activate the alternative NLRP3 inflammasome pathway in human blood-derived monocytes. Thus, we identify that double bonds discriminate between anti- and pro-inflammatory properties of tetra-acylated molecules, providing a rationale for the development of TLR4 activators and inhibitors for use as vaccine adjuvants or in the treatment of TLR4-related diseases. [ABSTRACT FROM AUTHOR]

Liposomes containing cholesterol and monophosphoryl lipid A (such as ALFQ and AS01B) are vaccine adjuvants. During construction of the formulations, addition of QS21 to nano-size (50–100 nm) liposomes resulted in extremely large (up to ∼30 µm) liposomes in ALFQ, but AS01B liposomes remained small nano-vesicles. Here, we show that saturation of phospholipid chains is essential for production of large liposomes by QS21. [ABSTRACT FROM AUTHOR]

The use of a good vaccine adjuvant may induce a higher immunogenicity profile of vaccine antigens. Here, we developed a new adjuvant by combining poly-γ-glutamic acid (γ-PGA) with alum (PGA/Alum) and investigated its ability to enhance the immunogenicity and the cross-reactive efficacy of pandemic H1N1 (pH1N1) influenza vaccine antigen. PGA/Alum enhanced antigen delivery to draining lymph nodes and antigen-specific immunogenicity in mice using OVA as a model antigen. It also greatly increased OVA-specific antibody production, cytotoxic T lymphocyte (CTL) activity, and antibody-dependent cellular cytotoxicity (ADCC). These abilities of PGA/Alum improved the protective efficacy of pH1N1 vaccine antigen by increasing hemagglutination-inhibition titers, enhancing ADCC and CTL activity, and speeding viral clearance following homologous viral challenge. Importantly, the cross-protective efficacy of pH1N1 vaccine against heterologous viruses [A/Puerto Rico/8/34 (H1N1) and A/Hong Kong/1/1968 (H3N2)] was significantly enhanced by PGA/Alum, and cross-reactive ADCC and CTL activities were observed. Together, our results strongly suggest that PGA/Alum may be a promising vaccine adjuvant for preventing influenza and other infectious diseases. [ABSTRACT FROM AUTHOR]

Developing effective mucosal subunit vaccine for the Streptococcus pneumoniae has been unsuccessful mainly because of their poor immunogenicity with insufficient memory T and B cell responses. We thus address whether such limitation can be overcome by introducing effective adjuvants that can enhance immunity and show here that polysorbitol transporter (PST) serves as a mucosal adjuvant for a subunit vaccine against the Streptococcus pneumoniae. Pneumococcal surface protein A (PspA) with PST adjuvant induced protective immunity against S. pneumoniae challenge, especially long-term T and B cell immune responses. Moreover, we found that the PST preferentially induced T helper (Th) responses toward Th2 or T follicular helper (Tfh) cells and, importantly, that the responses were mediated through antigen-presenting cells via activating a peroxisome proliferator-activated receptor gamma (PPAR-γ) pathway. Thus, these data indicate that PST can be used as an effective and safe mucosal vaccine adjuvant against S. pneumoniae infection. In this study, we suggested the nanoparticle forming adjuvant, PST works as an effective adjuvant for the pneumococcal vaccine, PspA. The PspA subunit vaccine together with PST adjuvant efficiently induced protective immunity, even in the long-term memory responses, against Streptococcus pneumoniae lethal challenge. We found that PspA with PST adjuvant induced dendritic cell activation followed by follicular helper T cell responses through PPAR-γ pathway resulting long-term memory antibody-producing cells. Consequently, in this paper, we suggest the mechanism for safe nanoparticle forming subunit vaccine adjuvant against pneumococcal infection. [ABSTRACT FROM AUTHOR]

Résumé Les adjuvants vaccinaux potentialisent de façon non spécifique la réponse immunitaire. Ils permettent d'obtenir des titres plus élevés d'anticorps avec une quantité plus faible d'antigène et un plus petit nombre de doses. De ce fait, ils favorisent la diminution du coût de la vaccination. Ils ont également une activité immunostimulante sans être immunogène. Summary Vaccine adjuvants boost the immune response in a non-specific way. They allow higher antibody titers with a smaller quantity of antigens and a lower number of doses. Consequently, they help to reduce the cost of the vaccine. They are also immunostimulating without being immunogenic. [ABSTRACT FROM AUTHOR]

Highlights • Arabinofuranans are rapidly prepared by stereo- and regiocontrolled polymerization. • Incorporation of a linker and polymerization are done in a single step. • A versatile amine linker facilitates protein conjugation. • Glycan conjugation improves in vivo immune responses of the vaccine tetanus toxoid. Abstract A rapid synthesis of the α(1→5) arabinofuranan polysaccharides, found on the outer surface of Mycobacterium tuberculosis (Mtb), is achieved by a regio- and stereocontrolled ring opening polymerization of β- d -arabinofuranose-1,2,5-orthobenzoate. The robust polymerization reaction allows the incorporation of an amine linker, which was used to conjugate with protein tetanus toxoid (TT) to further investigate its adjuvant activities. The synthetic arabinan, which is the glycan on the non-reducing end of Mtb lipoarabinomannan (LAM), was evaluated for its immunological properties in vitro and in vivo. Systemic inflammation and the promotion of innate immune response were observed in macrophages treated with the synthetic arabinan as an adjuvant through an increase in the production of TNF-α and IL-12. In vivo evaluation of IFN-γ, IL-2, and TNF-α productions in mice pre-immunized with the synthetic arabinan conjugated TT indicated great enhancements of the immunological responses when compared to that of TT alone. [ABSTRACT FROM AUTHOR]

Adjuvant CIA09, composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-based cationic liposomes and the toll-like receptor 4 agonist de-O-acylated lipooligosaccharide (dLOS), has been shown to enhance antibody and cellular immune responses to varicella-zoster virus (VZV) glycoprotein E (gE), recombinant tuberculosis vaccine antigen, and inactivated Japanese encephalitis vaccine. In this study, we investigated its modes of action using VZV gE as a model antigen. Liposomes adsorbed gE and cooperatively with dLOS promoted endocytosis-mediated cellular uptake of gE by mouse dendritic cells in vitro. CIA09 increased the stability and cellular uptake of the antigen at the muscle site of injection, and induced immune cell recruitment and cytokine and chemokine production, which led to efficient antigen delivery to draining lymph nodes. Mouse bone marrow-derived dendritic cells, pulsed with CIA09-adjuvanted gE, efficiently presented gE to antigen-specific T cells, inducing Th1-type biased immunity, as shown by high IFN-γ production. The data indicate that liposomes and dLOS cooperate in the adjuvant activity of CIA09 by promoting antigen uptake and delivery to lymph nodes as well as antigen presentation to T cells.

Archaeosomes, composed of sulfated lactosyl archaeol (SLA) glycolipids, have been proven to be an effective vaccine adjuvant in multiple preclinical models of infectious disease or cancer. SLA archaeosomes are a promising adjuvant candidate due to their ability to strongly stimulate both humoral and cytotoxic immune responses when simply admixed with an antigen. In the present study, we evaluated whether the adjuvant effects of SLA archaeosomes could be further enhanced when combined with other adjuvants. SLA archaeosomes were co-administered with five different Toll-like Receptor (TLR) agonists or the saponin QS-21 using ovalbumin as a model antigen in mice. Both humoral and cellular immune responses were greatly enhanced compared to either adjuvant alone when SLA archaeosomes were combined with either the TLR3 agonist poly(I:C) or the TLR9 agonist CpG. These results were also confirmed in a separate study using Hepatitis B surface antigen (HBsAg) and support the further evaluation of these adjuvant combinations.

Newcastle disease (ND) and infectious bronchitis (IB) are important diseases, which cause respiratory diseases in chickens, resulting in severely economic losses in the poultry industry. In this study, N-2-hydroxypropyl trimethyl ammonium chloride chitosan (N-2-HACC) and N,O-carboxymethyl chitosan (CMC) were synthesized as adjuvant and delivery carrier for vaccine antigens. N-2-HACC-CMC/NDV/IBV nanoparticles (NPs) (NDV/La Sota and IBV/H120 encapsulated in N-2-HACC-CMC NPs) and N-2-HACC-CMC/NDV-IBV NPs (the mixing of N-2-HACC-CMC/NDV NPs and N-2-HACC-CMC/IBV NPs in a ratio of 1:1) were prepared by the polyelectrolyte composite method, respectively. Both nanoparticles exhibited lower cytotoxicity and higher stability. Their bioactivities were maintained when they were stored at 37 °C for three weeks. Release assay in vitro showed that both NDV and IBV could be sustainably released from the nanoparticles after an initial burst release. In vivo immunization of chickens showed that N-2-HACC-CMC/NDV/IBV NPs or N-2-HACC-CMC/NDV-IBV NPs intranasally induced higher titers of IgG and IgA antibodies, significantly promoted proliferation of lymphocytes and induced higher levels of interleukine-2 (IL-2), IL-4 and interferon-γ (IFN-γ) than the commercially combined attenuated live vaccine did. This is the first study in the field of animal vaccines demonstrating that intranasal administration of chickens with antigens (NDV and IBV) encapsulated with chitosan derivative could induce humoral, cellular, and mucosal immune responses, which protected chickens from the infection of highly virulent NDV and IBV. This study indicated that N-2-HACC-CMC could be used as an efficient adjuvant and delivery carrier for further development of mucosal vaccines and drugs and could have an immense application potential in medicine.

Interleukin 33 (IL-33), a member of the IL-1 family, is constitutively expressed in epithelial and in endothelial cells at barrier sites, acting as a danger signal and adjuvanting the immune response following tissue damage and infection. Originally implicated in allergy, IL-33 is also known to be involved in innate and adaptive immune responses by enhancing natural killer, Th1, and CD4 and CD8 T-cell functions. The nature of the antiviral immune response orchestrated by IL-33 depends on the site of infection, the duration of the disease and the cytokine milieu. In this review, we focus on the distinctive contribution of IL-33 as an anti-infective and proinflammatory cytokine in response to cell death and viral infections. The dynamic role of IL-33 in the acute and chronic phases of infection with HIV, hepatitis B and C viruses, and with CMV is highlighted. This review will also discuss the potential immunotherapeutic and adjuvant roles of IL-33. Search Strategy and Selection Criteria: English language, indexed publications in PubMed were searched using combinations of following key words: “interleukin-33”, “IL-33”, “suppression of tumorigenicity 2”, ST2”, “sST2”, “HIV”, “HBV”, “HCV”, “CMV”, “HPV”, “immunotherapy” and “vaccine”. Except for seminal studies, only articles published between 2010 and 2016 were included.

The present study compared the differential functions of two groups of adjuvants, Montanide incomplete Seppic adjuvant (ISA) series and Quil A, cholesterol, dimethyl dioctadecyl ammonium bromide, and Carbopol (QCDC) formulations, in chicken by analyzing published microarray data associated with each type of vaccine adjuvants. In the biological function analysis for differentially expressed genes altered by two different adjuvant groups, ISA series and QCDC formulations showed differential effects when chickens were immunized with a recombinant immunogenic protein of Eimeria. Among the biological functions, six categories were modified in both adjuvant types. However, with respect to “Response to stimulus”, no biological process was modified by the two adjuvant groups at the same time. The QCDC adjuvants showed effects on the biological processes (BPs) including the innate immune response and the immune response to the external stimulus such as toxin and bacterium, while the ISA adjuvants modified the BPs to regulate cell movement and the response to stress. In pathway analysis, ISA adjuvants altered the genes involved in the functions related with cell junctions and the elimination of exogenous and endogenous macromolecules. The analysis in the present study could contribute to the development of precise adjuvants based on molecular signatures related with their immunological functions.