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Vaccines Jun 2024This study focuses on the development and characterization of an intranasal vaccine platform using adjuvanted nanoparticulate delivery of swine influenza A virus...
This study focuses on the development and characterization of an intranasal vaccine platform using adjuvanted nanoparticulate delivery of swine influenza A virus (SwIAV). The vaccine employed whole inactivated H1N2 SwIAV as an antigen and STING-agonist ADU-S100 as an adjuvant, with both surface adsorbed or encapsulated in mannose-chitosan nanoparticles (mChit-NPs). Optimization of mChit-NPs included evaluating size, zeta potential, and cytotoxicity, with a 1:9 mass ratio of antigen to NP demonstrating high loading efficacy and non-cytotoxic properties suitable for intranasal vaccination. In a heterologous H1N1 pig challenge trial, the mChit-NP intranasal vaccine induced cross-reactive sIgA antibodies in the respiratory tract, surpassing those of a commercial SwIAV vaccine. The encapsulated mChit-NP vaccine induced high virus-specific neutralizing antibody and robust cellular immune responses, while the adsorbed vaccine elicited specific high IgG and hemagglutinin inhibition antibodies. Importantly, both the mChit-NP vaccines reduced challenge heterologous viral replication in the nasal cavity higher than commercial swine influenza vaccine. In summary, a novel intranasal mChit-NP vaccine platform activated both the arms of the immune system and is a significant advancement in swine influenza vaccine design, demonstrating its potential effectiveness for pig immunization.
PubMed: 38932376
DOI: 10.3390/vaccines12060647 -
Vaccines Jun 2024Introducing new recombinant protein antigens to existing pediatric combination vaccines is important in improving coverage and affordability, especially in low- and...
Evaluating the Compatibility of New Recombinant Protein Antigens (Trivalent NRRV) with a Mock Pentavalent Combination Vaccine Containing Whole-Cell Pertussis: Analytical and Formulation Challenges.
Introducing new recombinant protein antigens to existing pediatric combination vaccines is important in improving coverage and affordability, especially in low- and middle-income countries (LMICs). This case-study highlights the analytical and formulation challenges encountered with three recombinant non-replicating rotavirus vaccine (NRRV) antigens (t-NRRV formulated with Alhydrogel adjuvant, AH) combined with a mock multidose formulation of a pediatric pentavalent vaccine used in LMICs. This complex formulation contained (1) vaccine antigens (i.e., whole-cell pertussis (wP), diphtheria (D), tetanus (T), (Hib), and hepatitis B (HepB), (2) a mixture of aluminum-salt adjuvants (AH and Adju-Phos, AP), and (3) a preservative (thimerosal, TH). Selective, stability-indicating competitive immunoassays were developed to monitor binding of specific mAbs to each antigen, except wP which required the setup of a mouse immunogenicity assay. Simple mixing led to the desorption of t-NRRV antigens from AH and increased degradation during storage. These deleterious effects were caused by specific antigens, AP, and TH. An AH-only pentavalent formulation mitigated t-NRRV antigen desorption; however, the Hib antigen displayed previously reported AH-induced instability. The same rank-ordering of t-NRRV antigen stability (P[8] > P[4] > P[6]) was observed in mock pentavalent formulations and with various preservatives. The lessons learned are discussed to enable future multidose, combination vaccine formulation development with new vaccine candidates.
PubMed: 38932338
DOI: 10.3390/vaccines12060609 -
Vaccines May 2024During the multi-dose formulation development of recombinant vaccine candidates, protein antigens can be destabilized by antimicrobial preservatives (APs). The...
A Combined LC-MS and Immunoassay Approach to Characterize Preservative-Induced Destabilization of Human Papillomavirus Virus-like Particles Adsorbed to an Aluminum-Salt Adjuvant.
During the multi-dose formulation development of recombinant vaccine candidates, protein antigens can be destabilized by antimicrobial preservatives (APs). The degradation mechanisms are often poorly understood since available analytical tools are limited due to low protein concentrations and the presence of adjuvants. In this work, we evaluate different analytical approaches to monitor the structural integrity of HPV16 VLPs adsorbed to Alhydrogel™ (AH) in the presence and absence of APs (i.e., destabilizing m-cresol, MC, or non-destabilizing chlorobutanol, CB) under accelerated conditions (pH 7.4, 50 °C). First, in vitro potency losses displayed only modest correlations with the results from two commonly used methods of protein analysis (SDS-PAGE, DSC). Next, results from two alternative analytical approaches provided a better understanding of physicochemical events occurring under these same conditions: (1) competitive ELISA immunoassays with a panel of mAbs against conformational and linear epitopes on HPV16 VLPs and (2) LC-MS peptide mapping to evaluate the accessibility/redox state of the 12 cysteine residues within each L1 protein comprising the HPV16 VLP (i.e., with 360 L1 proteins per VLP, there are 4320 Cys residues per VLP). These methods expand the limited analytical toolset currently available to characterize AH-adsorbed antigens and provide additional insights into the molecular mechanism(s) of AP-induced destabilization of vaccine antigens.
PubMed: 38932309
DOI: 10.3390/vaccines12060580 -
Viruses May 2024Humans continue to be at risk from the Zika virus. Although there have been significant research advancements regarding Zika, the absence of a vaccine or approved...
Humans continue to be at risk from the Zika virus. Although there have been significant research advancements regarding Zika, the absence of a vaccine or approved treatment poses further challenges for healthcare providers. In this study, we developed a microparticulate Zika vaccine using an inactivated whole Zika virus as the antigen that can be administered pain-free via intranasal (IN) immunization. These microparticles (MP) were formulated using a double emulsion method developed by our lab. We explored a prime dose and two-booster-dose vaccination strategy using MPL-A and Alhydrogel as adjuvants to further stimulate the immune response. MPL-A induces a Th1-mediated immune response and Alhydrogel (alum) induces a Th2-mediated immune response. There was a high recovery yield of MPs, less than 5 µm in size, and particle charge of -19.42 ± 0.66 mV. IN immunization of Zika MP vaccine and the adjuvanted Zika MP vaccine showed a robust humoral response as indicated by several antibodies (IgA, IgM, and IgG) and several IgG subtypes (IgG1, IgG2a, and IgG3). Vaccine MP elicited a balance Th1- and Th2-mediated immune response. Immune organs, such as the spleen and lymph nodes, exhibited a significant increase in CD4 helper and CD8 cytotoxic T-cell cellular response in both vaccine groups. Zika MP vaccine and adjuvanted Zika MP vaccine displayed a robust memory response (CD27 and CD45R) in the spleen and lymph nodes. Adjuvanted vaccine-induced higher Zika-specific intracellular cytokines than the unadjuvanted vaccine. Our results suggest that more than one dose or multiple doses may be necessary to achieve necessary immunological responses. Compared to unvaccinated mice, the Zika vaccine MP and adjuvanted MP vaccine when administered via intranasal route demonstrated robust humoral, cellular, and memory responses. In this pre-clinical study, we established a pain-free microparticulate Zika vaccine that produced a significant immune response when administered intranasally.
Topics: Animals; Administration, Intranasal; Zika Virus Infection; Zika Virus; Mice; Antibodies, Viral; Viral Vaccines; Female; Immunization; Adjuvants, Immunologic; Disease Models, Animal; Adjuvants, Vaccine; Vaccination; Cytokines; Antibodies, Neutralizing
PubMed: 38932158
DOI: 10.3390/v16060865 -
Pharmaceutics Jun 2024Despite the high success rates of dental implants, peri-implantitis is currently the most common complication in dental implantology. Peri-implantitis has an... (Review)
Review
Despite the high success rates of dental implants, peri-implantitis is currently the most common complication in dental implantology. Peri-implantitis has an inflammatory nature, it is associated with the accumulation of plaque in the peri-implant tissues, and its evolution can be progressive depending on various factors, comorbidities, and poor oral health. Prophylaxis and different treatment methods have been widely discussed in recent decades, and surgical and non-surgical techniques present both advantages and disadvantages. In this work, a literature review of different studies on the application of adjuvant treatments, such as local and systemic antibiotics and antiseptic treatments, was conducted. Positive outcomes have been found in the short (up to one year after treatment) and long term (up to ten years after treatment) with combined therapies. However, there is still a need to explore new therapies based on the use of advanced drug delivery systems for the effective treatment of peri-implantitis in the long term and without relapses. Hence, micro- and nanoparticles, implants, and injectable hydrogels, among others, should be considered in future peri-implantitis treatment with the aim of enhancing overall therapy outcomes.
PubMed: 38931890
DOI: 10.3390/pharmaceutics16060769 -
Journal of Acquired Immune Deficiency... Aug 2024An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent (TV1.C and 1086.C glycoprotein 120) subtype C envelope protein combinations, adjuvanted with MF59 or AS01B.
METHODS
HIV Vaccine Trials Network (HVTN)108 was a randomized, placebo-controlled, double-blind, phase 1/2a trial conducted in the United States and South Africa. HIV-negative adults were randomly assigned to 1 of 7 intervention arms or placebo to assess DNA prime with DNA/protein/adjuvant boosts, DNA/protein/adjuvant co-administration, and low-dose protein/adjuvant regimens. HVTN111 trial participants who received an identical regimen were also included. Outcomes included safety and immunogenicity 2 weeks and 6 months after final vaccination.
RESULTS
From June 2016 to July 2018, 400 participants were enrolled (N = 334 HVTN108, N = 66 HVTN111); 370 received vaccine and 30 received placebo. There were 48 grade 3 and 3 grade 4 reactogenicity events among 39/400 (9.8%) participants, and 32 mild/moderate-related adverse events in 23/400 (5.8%) participants. All intervention groups demonstrated high IgG response rates (>89%) and high magnitudes to HIV-1 Env gp120 and gp140 proteins; response rates for AS01B-adjuvanted groups approached 100%. V1V2 IgG magnitude, Fc-mediated functions, IgG3 Env response rates, and CD4+ T-cell response magnitudes and rates were higher in the AS01B-adjuvanted groups. The AS01B-adjuvanted low-dose protein elicited greater IgG responses than the higher protein dose.
CONCLUSIONS
The vaccine regimens were generally well tolerated. Co-administration of DNA with AS01B-adjuvanted bivalent Env gp120 elicited the strongest humoral responses; AS01B-adjuvanted regimens elicited stronger CD4+ T-cell responses, justifying further evaluation.ClinicalTrials.gov registration: NCT02915016, registered 26 September 2016.
Topics: Humans; AIDS Vaccines; Vaccines, DNA; Female; Male; Adult; Squalene; Polysorbates; HIV Envelope Protein gp120; Adjuvants, Immunologic; HIV-1; HIV Infections; HIV Antibodies; Double-Blind Method; Middle Aged; Young Adult; Adjuvants, Vaccine; South Africa; Immunogenicity, Vaccine; Adolescent; United States
PubMed: 38916429
DOI: 10.1097/QAI.0000000000003438 -
Molecular Biology Research... 2024Silymarin is known for its anti-inflammatory and antioxidant properties. We investigated these effects on serum levels of CTRP3, Anti-CCP, and hs-CRP in individuals with...
Effects of silymarin as adjuvant drug on serum levels of CTRP3, anti-cyclic citrullinated peptide (CCP), and high-sensitivity C-reactive protein (hs-CRP) in rheumatoid arthritis patients.
Silymarin is known for its anti-inflammatory and antioxidant properties. We investigated these effects on serum levels of CTRP3, Anti-CCP, and hs-CRP in individuals with Rheumatoid arthritis (RA). In this study, 42 individuals with RA were recruited and their serum specimens were collected, serum levels of hs-CRP, AntiCCP antibodies, and CTRP3 were measured using ELISA. DNA was extracted and investigated for the existence of possible new mutations in the gene encoding CTRP3 using the PCR technique; the desired fragments were then amplified and sequenced. Another blood sample was collected from the case group after taking for three months (3 doses of 140 mg/day) and the tests were repeated. Anti-CCP Abs levels in the postintervention responding group decreased compared to preintervention (p<0.001) while in the non-responding group, the levels increased after the intervention compared to the levels before the intervention (p=0.019). Additionally, CTRP3 levels in the responding group increased postintervention (p=0.003), however, in the non-responding group the levels decreased postintervention when compared to preintervention (p=0.02). The responding group had significantly lower levels of hs-CRP when compared to that of preintervention (p=0.005) whereas the non-responding group had significantly higher levels of postintervention (p<0.001). Moreover, the results of sequencings of exon 6 on gene showed the presence of mutations in exon 6 (position 215:C>T, 338:G>A, 359:A>C, and 153:T>C). Silymarin could be used as an adjuvant in the treatment of rheumatoid arthritis.
PubMed: 38915456
DOI: 10.22099/mbrc.2024.48466.1876 -
Asian Journal of Pharmaceutical Sciences Jun 2024Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting cancer. However, the potential application of bacterial...
Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting cancer. However, the potential application of bacterial therapy is hindered by the presence of instability and susceptibility to infections within bacterial populations. Furthermore, monotherapy is ineffective in completely eliminating complex cancer with multiple contributing factors. In this study, based on our discovery that spore shell (SS) of exhibits excellent tumor-targeting ability and adjuvant activity, we develop a biomimetic spore nanoplatform to boost bacteria-mediated antitumor therapy, chemodynamic therapy and antitumor immunity for synergistic cancer treatment. In detail, SS is separated from probiotic spores and then attached to the surface of liposome (Lipo) that was loaded with hemoglobin (Hb), glucose oxidase (GOx) and JQ1 to construct SS@Lipo/Hb/GOx/JQ1. In tumor tissue, highly toxic hydroxyl radicals (•OH) are generated via sequential catalytic reactions: GOx catalyzing glucose into HO and Fe in Hb decomposing HO into •OH. The combination of •OH and SS adjuvant can improve tumor immunogenicity and activate immune system. Meanwhile, JQ1-mediated down-regulation of PD-L1 and Hb-induced hypoxia alleviation synergistically reshape immunosuppressive tumor microenvironment and potentiate immune response. In this manner, SS@Lipo/Hb/GOx/JQ1 significantly suppresses tumor growth and metastasis. To summarize, the nanoplatform represents an optimum strategy to potentiate bacteria-based cancer immunotherapy.
PubMed: 38903128
DOI: 10.1016/j.ajps.2024.100912 -
International Journal of Molecular... May 2024Dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) has been found to be beneficial in rodent rheumatoid arthritis models and human trials. However, the...
Dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) has been found to be beneficial in rodent rheumatoid arthritis models and human trials. However, the molecular targets of n-3 PUFAs and their beneficial effects on rheumatoid arthritis are under-researched. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor for n-3 PUFA. We aim to investigate whether FFA4 activation reduces collagen-induced rheumatoid arthritis (CIA) by using an FFA4 agonist, compound A (CpdA), in combination with DBA-1J gene wild-type (WT) and gene knock-out (KO) mice. CIA induced an increase in the arthritis score, foot edema, synovial hyperplasia, pannus formation, proteoglycan loss, cartilage damage, and bone erosion, whereas the administration of CpdA significantly suppressed those increases in WT mice but not gene KO mice. CIA increased mRNA expression levels of pro-inflammatory Th1/Th17 cytokines, whereas CpdA significantly suppressed those increases in WT mice but not gene KO mice. CIA induced an imbalance between Th1/Th17 and Treg cells, whereas CpdA rebalanced them in spleens from WT mice but not gene KO mice. In SW982 synovial cells, CpdA reduced the LPS-induced increase in pro-inflammatory cytokine levels. In summary, the present results suggest that the activation of FFA4 in immune and synovial cells could suppress the characteristics of rheumatoid arthritis and be an adjuvant therapy.
Topics: Animals; Arthritis, Experimental; T-Lymphocytes, Regulatory; Th17 Cells; Receptors, G-Protein-Coupled; Mice; Th1 Cells; Mice, Knockout; Mice, Inbred DBA; Arthritis, Rheumatoid; Male; Cytokines
PubMed: 38892051
DOI: 10.3390/ijms25115866 -
International Journal of Molecular... May 2024Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-β-activated kinase-1 (TAK1) activation, inflammatory...
Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-β-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1β. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines.
Topics: Animals; MAP Kinase Kinase Kinases; Muscular Atrophy; Mice; Cytokines; Muscle Weakness; Myostatin; Muscle Proteins; Tumor Necrosis Factor-alpha; NF-kappa B; Inflammation; Signal Transduction; Tripartite Motif Proteins; Disease Models, Animal; Interleukin-1beta; Phosphorylation; Muscle, Skeletal; Zearalenone
PubMed: 38891908
DOI: 10.3390/ijms25115715