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1.
Front Immunol ; 15: 1386243, 2024.
Article in English | MEDLINE | ID: mdl-38835757

ABSTRACT

Introduction: Current vaccines against COVID-19 administered via parenteral route have limited ability to induce mucosal immunity. There is a need for an effective mucosal vaccine to combat SARS-CoV-2 virus replication in the respiratory mucosa. Moreover, sex differences are known to affect systemic antibody responses against vaccines. However, their role in mucosal cellular responses against a vaccine remains unclear and is underappreciated. Methods: We evaluated the mucosal immunogenicity of a booster vaccine regimen that is recombinant protein-based and administered intranasally in mice to explore sex differences in mucosal humoral and cellular responses. Results: Our results showed that vaccinated mice elicited strong systemic antibody (Ab), nasal, and bronchiole alveolar lavage (BAL) IgA responses, and local T cell immune responses in the lung in a sex-biased manner irrespective of mouse genetic background. Monocytes, alveolar macrophages, and CD103+ resident dendritic cells (DCs) in the lungs are correlated with robust mucosal Ab and T cell responses induced by the mucosal vaccine. Discussion: Our findings provide novel insights into optimizing next-generation booster vaccines against SARS-CoV-2 by inducing spike-specific lung T cell responses, as well as optimizing mucosal immunity for other respiratory infections, and a rationale for considering sex differences in future vaccine research and vaccination practice.


Subject(s)
Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Immunity, Mucosal , Immunogenicity, Vaccine , SARS-CoV-2 , Vaccines, Subunit , Animals , Female , Mice , SARS-CoV-2/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , COVID-19/immunology , COVID-19/virology , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Male , Antibodies, Viral/immunology , Antibodies, Viral/blood , Lung/immunology , Lung/virology , T-Lymphocytes/immunology , Spike Glycoprotein, Coronavirus/immunology , Mice, Inbred C57BL , Administration, Intranasal , Sex Factors , Immunoglobulin A/immunology , Dendritic Cells/immunology , Immunization, Secondary , Immunity, Humoral
2.
Expert Rev Vaccines ; 23(1): 498-509, 2024.
Article in English | MEDLINE | ID: mdl-38695310

ABSTRACT

BACKGROUND: Vaccination remains the cornerstone of defense against COVID-19 globally. This study aims to assess the safety and immunogenicity profile of innovative vaccines LYB001. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, parallel-controlled trial, in 100 healthy Chinese adults (21 to 72 years old). Three doses of 30 or 60 µg of SARS-CoV-2 RBD-based VLP vaccine (LYB001), or the SARS-CoV-2 RBD-based protein subunit vaccine (ZF2001, control group) were administered with a 28-day interval. Differences in the incidence of adverse events (AEs) and indicators of humoral and cellular immunity among the different groups were measured. RESULTS: No severe adverse events were confirmed to be vaccine-related, and there was no significant difference in the rate of adverse events between the LYB001 and control group or the age subgroups (p > 0.05). The LYB001 groups had significantly higher or comparable levels of seroconversion rates, neutralization antibody, S protein-binding antibody, and cellular immunity after whole vaccination than the control group. CONCLUSIONS: Our findings support that LYB001 developed on the VLP platform is safe and well tolerated with favorable immunogenicity for fundamental vaccination in healthy adults. Therefore, further larger-scale clinical studies are warranted. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT05552573).


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Humans , Adult , Middle Aged , Double-Blind Method , COVID-19 Vaccines/immunology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/administration & dosage , Male , Female , Antibodies, Viral/blood , Aged , Young Adult , Antibodies, Neutralizing/blood , SARS-CoV-2/immunology , COVID-19/prevention & control , COVID-19/immunology , Immunogenicity, Vaccine , Vaccines, Virus-Like Particle/immunology , Vaccines, Virus-Like Particle/adverse effects , Vaccines, Virus-Like Particle/administration & dosage , Immunity, Cellular , China , Immunity, Humoral , Spike Glycoprotein, Coronavirus/immunology , Vaccination/methods , Vaccines, Subunit/immunology , Vaccines, Subunit/adverse effects , Vaccines, Subunit/administration & dosage , East Asian People
3.
Front Immunol ; 15: 1383476, 2024.
Article in English | MEDLINE | ID: mdl-38799439

ABSTRACT

None of the typhoid Vi Polysaccharide (ViPS) subunit vaccines incorporate adjuvants, and the immunogenicity of ViPS vaccines (e.g. Typbar TCV® and Typhim Vi®) is in part due to associated TLR4 ligands such as endotoxin present in these vaccines. Since endotoxin content in vaccines is variable and kept very low due to inherent toxicity, it was hypothesized that incorporating a defined amount of a non-toxic TLR4-ligand such as monophosphoryl lipid A in ViPS vaccines would improve their immunogenicity. To test this hypothesis, a monophosphoryl lipid A-based adjuvant formulation named Turbo was developed. Admixing Turbo with Typbar TCV® (ViPS-conjugated to tetanus toxoid) increased the levels of anti-ViPS IgM, IgG1, IgG2b, IgG2a/c, and IgG3 in inbred and outbred mice. In infant mice, a single immunization with Turbo adjuvanted Typbar TCV® resulted in a significantly increased and durable IgG response and improved the control of bacterial burden compared to mice immunized without Turbo. Similarly, when adjuvanted with Turbo, the antibody response and control of bacteremia were also improved in mice immunized with Typhim Vi®, an unconjugated vaccine. The immunogenicity of unconjugated ViPS is inefficient in young mice and is lost in adult mice when immunostimulatory ligands in ViPS are removed. Nevertheless, when adjuvanted with Turbo, poorly immunogenic ViPS induced a robust IgG response in young and adult mice, and this was observed even under antigen-limiting conditions. These data suggest that incorporation of Turbo as an adjuvant will make typhoid vaccines more immunogenic regardless of their intrinsic immunogenicity or conjugation status and maximize the efficacy across all ages.


Subject(s)
Adjuvants, Immunologic , Antibodies, Bacterial , Lipid A , Toll-Like Receptor 4 , Typhoid Fever , Typhoid-Paratyphoid Vaccines , Vaccines, Subunit , Animals , Typhoid-Paratyphoid Vaccines/immunology , Typhoid-Paratyphoid Vaccines/administration & dosage , Mice , Toll-Like Receptor 4/immunology , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Antibodies, Bacterial/blood , Antibodies, Bacterial/immunology , Adjuvants, Immunologic/administration & dosage , Lipid A/analogs & derivatives , Lipid A/immunology , Typhoid Fever/prevention & control , Typhoid Fever/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Female , Ligands , Polysaccharides, Bacterial/immunology , Immunogenicity, Vaccine , Adjuvants, Vaccine , Salmonella typhi/immunology , Mice, Inbred BALB C
4.
J Immunother Cancer ; 12(5)2024 May 23.
Article in English | MEDLINE | ID: mdl-38782542

ABSTRACT

BACKGROUND: Neoantigens can serve as targets for T cell-mediated antitumor immunity via personalized neopeptide vaccines. Interim data from our clinical study NCT03715985 showed that the personalized peptide-based neoantigen vaccine EVX-01, formulated in the liposomal adjuvant, CAF09b, was safe and able to elicit EVX-01-specific T cell responses in patients with metastatic melanoma. Here, we present results from the dose-escalation part of the study, evaluating the feasibility, safety, efficacy, and immunogenicity of EVX-01 in addition to anti-PD-1 therapy. METHODS: Patients with metastatic melanoma on anti-PD-1 therapy were treated in three cohorts with increasing vaccine dosages (twofold and fourfold). Tumor-derived neoantigens were selected by the AI platform PIONEER and used in personalized therapeutic cancer peptide vaccines EVX-01. Vaccines were administered at 2-week intervals for a total of three intraperitoneal and three intramuscular injections. The study's primary endpoint was safety and tolerability. Additional endpoints were immunological responses, survival, and objective response rates. RESULTS: Compared with the base dose level previously reported, no new vaccine-related serious adverse events were observed during dose escalation of EVX-01 in combination with an anti-PD-1 agent given according to local guidelines. Two patients at the third dose level (fourfold dose) developed grade 3 toxicity, most likely related to pembrolizumab. Overall, 8 out of the 12 patients had objective clinical responses (6 partial response (PR) and 2 CR), with all 4 patients at the highest dose level having a CR (1 CR, 3 PR). EVX-01 induced peptide-specific CD4+ and/or CD8+T cell responses in all treated patients, with CD4+T cells as the dominating responses. The magnitude of immune responses measured by IFN-γ ELISpot assay correlated with individual peptide doses. A significant correlation between the PIONEER quality score and induced T cell immunogenicity was detected, while better CRs correlated with both the number of immunogenic EVX-01 peptides and the PIONEER quality score. CONCLUSION: Immunization with EVX-01-CAF09b in addition to anti-PD-1 therapy was shown to be safe and well tolerated and elicit vaccine neoantigen-specific CD4+and CD8+ T cell responses at all dose levels. In addition, objective tumor responses were observed in 67% of patients. The results encourage further assessment of the antitumor efficacy of EVX-01 in combination with anti-PD-1 therapy.


Subject(s)
Antigens, Neoplasm , Cancer Vaccines , Melanoma , Precision Medicine , Adult , Aged , Female , Humans , Male , Middle Aged , Antigens, Neoplasm/immunology , Cancer Vaccines/therapeutic use , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Melanoma/drug therapy , Melanoma/immunology , Neoplasm Metastasis , Precision Medicine/methods , Vaccines, Subunit/therapeutic use , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage
5.
PLoS One ; 19(5): e0294998, 2024.
Article in English | MEDLINE | ID: mdl-38713688

ABSTRACT

Tularemia is a zoonotic disease caused by the facultative intracellular gram-negative bacterium Francisella tularensis. F. tularensis has a very low infection dose by the aerosol route which can result in an acute, and potentially lethal, infection in humans. Consequently, it is classified as a Category A bioterrorism agent by the US Centers for Disease Control (CDC) and is a pathogen of concern for the International Biodefence community. There are currently no licenced tularemia vaccines. In this study we report on the continued assessment of a tularemia subunit vaccine utilising ß-glucan particles (GPs) as a vaccine delivery platform for immunogenic F. tularensis antigens. Using a Fischer 344 rat infection model, we demonstrate that a GP based vaccine comprising the F. tularensis lipopolysaccharide antigen together with the protein antigen FTT0814 provided partial protection of F344 rats against an aerosol challenge with a high virulence strain of F. tularensis, SCHU S4. Inclusion of imiquimod as an adjuvant failed to enhance protective efficacy. Moreover, the level of protection afforded was dependant on the challenge dose. Immunological characterisation of this vaccine demonstrated that it induced strong antibody immunoglobulin responses to both polysaccharide and protein antigens. Furthermore, we demonstrate that the FTT0814 component of the GP vaccine primed CD4+ and CD8+ T-cells from immunised F344 rats to express interferon-γ, and CD4+ cells to express interleukin-17, in an antigen specific manner. These data demonstrate the development potential of this tularemia subunit vaccine and builds on a body of work highlighting GPs as a promising vaccine platform for difficult to treat pathogens including those of concern to the bio-defence community.


Subject(s)
Bacterial Vaccines , Disease Models, Animal , Francisella tularensis , Rats, Inbred F344 , Tularemia , Vaccines, Subunit , Animals , Tularemia/prevention & control , Tularemia/immunology , Rats , Bacterial Vaccines/immunology , Bacterial Vaccines/administration & dosage , Francisella tularensis/immunology , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Glucans/immunology , Glucans/pharmacology , T-Lymphocytes/immunology , Female , Antigens, Bacterial/immunology
6.
Lancet Rheumatol ; 6(6): e352-e360, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38710192

ABSTRACT

BACKGROUND: The adjuvanted herpes zoster subunit vaccine has shown good efficacy and safety in the general population. However, its effectiveness has not been comprehensively assessed in patients with systemic lupus erythematosus (SLE). This study aimed to evaluate the immunogenicity and safety of the adjuvanted herpes zoster subunit vaccine in patients with SLE. METHODS: This single-centre, randomised, double-blind, placebo-controlled, trial was done at the rheumatology outpatient clinic at Seoul National University Hospital, South Korea. Patients (aged ≥19 years) with clinically stable SLE and previous exposure (≥4 weeks) to immunosuppressive drugs were randomly assigned (4:1) via a central interactive web response system to receive herpes zoster subunit vaccine or placebo (0·5 mL intramuscular injection) at weeks 0 and 8. Investigators and participants were masked to intervention and group assignment. Anti-glycoprotein E antibody titres and glycoprotein E-specific cell-mediated vaccine responses were evaluated at baseline and at week 8 after the first dose, and at week 4, week 26, and week 52 after the second dose using enzyme-linked immunosorbent assay and flow cytometry, respectively. Reactogenicity, SLE disease activity, including Systemic Lupus Erythematosus Disease Activity Index 2000 and British Isles Lupus Assessment Group-flare rate, were examined. The primary outcome was the proportion of patients with a positive humoral vaccine response 4 weeks after the second dose. The primary and safety analyses were done in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT06001606. FINDINGS: Between June 14, and July 19, 2023, 65 patients with SLE were enrolled, of whom 52 were randomly assigned to the herpes zoster subunit vaccine and 13 to placebo. 49 patients in the vaccine group and 11 patients in the placebo group were included in the modified intention-to-treat population. 56 (93%) of 60 patients were women and four (7%) were men. Mean age was 48·7 years (SD 11·4). The proportion of participants with a humoral vaccine response at 4 weeks after the second dose was significantly higher in the vaccine group (48 [98%] of 49 participants) than the placebo group (none [0%] of 11 patients; p<0·0001). More patients in the vaccine group than placebo group reported injection site reactions (42 patients vs two patients), fever (ten vs none), and fatigue (26 vs two). There were no differences in Systemic Lupus Erythematosus Disease Activity Index 2000 and British Isles Lupus Assessment Group-flare rates between the groups. There were no treatment-related deaths. INTERPRETATION: The herpes zoster subunit vaccine induces humoral and cellular immunity against herpes zoster with a good safety profile in patients with SLE. A larger study is warranted to assess the efficacy of vaccines to prevent herpes zoster in patients with SLE. FUNDING: Ministry of Science and ICT, The Government of the Republic of Korea.


Subject(s)
Herpes Zoster Vaccine , Lupus Erythematosus, Systemic , Vaccines, Subunit , Humans , Lupus Erythematosus, Systemic/immunology , Female , Double-Blind Method , Male , Herpes Zoster Vaccine/immunology , Herpes Zoster Vaccine/administration & dosage , Herpes Zoster Vaccine/adverse effects , Republic of Korea/epidemiology , Adult , Middle Aged , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/adverse effects , Vaccines, Subunit/therapeutic use , Herpes Zoster/prevention & control , Herpes Zoster/immunology , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/adverse effects , Immunogenicity, Vaccine , Antibodies, Viral/blood
7.
Front Immunol ; 15: 1372349, 2024.
Article in English | MEDLINE | ID: mdl-38698863

ABSTRACT

Pseudomonas aeruginosa (Pa) is an opportunistic bacterial pathogen responsible for severe hospital acquired infections in immunocompromised and elderly individuals. Emergence of increasingly drug resistant strains and the absence of a broad-spectrum prophylactic vaccine against both T3SA+ (type III secretion apparatus) and ExlA+/T3SA- Pa strains worsen the situation in a post-pandemic world. Thus, we formulated a candidate subunit vaccine (called ExlA/L-PaF/BECC/ME) against both Pa types. This bivalent vaccine was generated by combining the C-terminal active moiety of exolysin A (ExlA) produced by non-T3SA Pa strains with our T3SA-based vaccine platform, L-PaF, in an oil-in-water emulsion. The ExlA/L-PaF in ME (MedImmune emulsion) was then mixed with BECC438b, an engineered lipid A analogue and a TLR4 agonist. This formulation was administered intranasally (IN) to young and elderly mice to determine its potency across a diverse age-range. The elderly mice were used to mimic the infection seen in elderly humans, who are more susceptible to serious Pa disease compared to their young adult counterparts. After Pa infection, mice immunized with ExlA/L-PaF/BECC/ME displayed a T cell-mediated adaptive response while PBS-vaccinated mice experienced a rapid onset inflammatory response. Important genes and pathways were observed, which give rise to an anti-Pa immune response. Thus, this vaccine has the potential to protect aged individuals in our population from serious Pa infection.


Subject(s)
Emulsions , Pseudomonas Infections , Pseudomonas Vaccines , Pseudomonas aeruginosa , Vaccines, Subunit , Animals , Pseudomonas aeruginosa/immunology , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Mice , Pseudomonas Infections/immunology , Pseudomonas Infections/prevention & control , Pseudomonas Vaccines/immunology , Pseudomonas Vaccines/administration & dosage , Female , Vaccine Development , Humans , Antibodies, Bacterial/immunology , Antibodies, Bacterial/blood , Disease Models, Animal , Bacterial Proteins/immunology , Bacterial Proteins/genetics
8.
Vaccine ; 42(13): 3172-3179, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38616438

ABSTRACT

BACKGROUND: Bivalent RSV prefusion F subunit vaccine (RSVpreF), comprised of equal quantities of stabilized prefusion F antigens from the major circulating subgroups (RSV A, RSV B), is licensed for prevention of RSV-associated lower respiratory tract illness (LRTI) in older adults and for maternal vaccination for prevention of RSV-associated LRTI in infants. To support licensure and large-scale manufacturing, this lot consistency study was conducted to demonstrate equivalence in immunogenicity across 3 RSVpreF lots. METHODS: This phase 3, multicenter, parallel-group, placebo-controlled, randomized (1:1:1:1), double-blind study evaluated immunogenicity, safety, and tolerability of RSVpreF in healthy 18-49-year-old adults. Participants received a single 120-µg injection of 1 of 3RSVpreF lots or placebo. Geometric mean ratio (GMR) of RSV serum 50 % neutralizing geometric mean titers obtained 1 month after vaccination were compared between each vaccine lot for RSV A and RSV B, separately. Equivalence between lots was defined using a 1.5-fold criterion (GMR 95 % CIs for every lot pair within the 0.667-1.5 interval). Safety and tolerability were assessed. RESULTS: Of 992participants vaccinated, 948 were included in the evaluable immunogenicity population. All 3 RSVpreF lots elicited strong immune responses, meeting the 1.5-fold equivalence criterion for all between-lot comparisons for both RSV A and RSV B. Across the 3 lots, RSV A and RSV B 50 % neutralizing geometric mean titers substantially increased from baseline (RSV A, 1671-1795; RSV B 1358-1429) to 1 month after RSVpreF vaccination (RSV A, 24,131-25,238; RSV B, 19,238-21,702), corresponding to ≥14-fold increases in 50 % neutralizing titers for both RSV A and RSV B from before to 1 month after vaccination. Single doses of RSVpreF were safe and well tolerated, with similar safety profiles across the 3 RSVpreF lots. CONCLUSIONS: These findings support the reproducibility of RSVpreF vaccine manufacturing with similar safety and reactogenicity profiles (NCT05096208).


Subject(s)
Antibodies, Viral , Immunogenicity, Vaccine , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus Vaccines , Respiratory Syncytial Virus, Human , Humans , Respiratory Syncytial Virus Vaccines/immunology , Respiratory Syncytial Virus Vaccines/administration & dosage , Respiratory Syncytial Virus Vaccines/adverse effects , Female , Male , Adult , Double-Blind Method , Young Adult , Adolescent , Antibodies, Viral/blood , Middle Aged , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus, Human/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/adverse effects , Healthy Volunteers , Vaccination/methods , Viral Fusion Proteins/immunology
9.
Biochem Biophys Res Commun ; 711: 149919, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38608435

ABSTRACT

Subunit vaccines are among the most useful vaccine modalities; however, their low immunogenicity necessitates the addition of adjuvants. Although adjuvants improve immune responses induced by vaccines, they often cause adverse reactions. To address this, we developed an adjuvant-free subunit vaccine platform that uses pre-existing antibodies generated from past infections or vaccinations as carriers for the delivery of vaccine antigens. Although we have confirmed the usefulness of this platform for nasal vaccines, its suitability as a parenterally injectable vaccine remains uncertain. Here, we verified the potential of our vaccine platform to harness pre-existing immunity for parenterally injectable vaccines. We generated RBD-HA by combining the receptor binding domain (RBD) derived from SARS-CoV-2 as a vaccine antigen with hemagglutinin (HA) sourced from influenza viruses to serve as the carrier protein. We revealed that subcutaneous vaccination with RBD-HA effectively triggered strong RBD-specific IgG responses in mice previously infected with the influenza A virus, even in the absence of adjuvants, and conferred protection to mice against SARS-CoV-2 upon challenge. Furthermore, we revealed that vaccination with RBD-HA did not induce an inflammatory response, such as inflammatory cytokine production, swelling, and recruitment of inflammatory immune cells, whereas conventional vaccines combined with adjuvants induced these adverse reactions. In addition, we demonstrated the remarkable versatility of this platform using a vaccine antigen derived from Streptococcus pneumoniae. These findings indicate the potential of this adjuvant-free vaccine platform to enhance the efficacy of parenterally injectable subunit vaccines and reduce adverse reactions.


Subject(s)
COVID-19 Vaccines , COVID-19 , Immunoglobulin G , Mice, Inbred BALB C , SARS-CoV-2 , Animals , Immunoglobulin G/immunology , Immunoglobulin G/blood , Mice , SARS-CoV-2/immunology , COVID-19/prevention & control , COVID-19/immunology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Female , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Hemagglutinin Glycoproteins, Influenza Virus/administration & dosage , Humans , Antibodies, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Adjuvants, Immunologic/administration & dosage , Influenza A virus/immunology , Influenza Vaccines/immunology , Influenza Vaccines/administration & dosage
10.
Acta Trop ; 254: 107208, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38621620

ABSTRACT

The study aimed to elicit protective immune responses against murine schistosomiasis mansoni at the parasite lung- and liver stage. Two peptides showing amino acid sequence similarity to gut cysteine peptidases, which induce strong memory immune effectors in the liver, were combined with a peptide based on S. mansoni thioredoxin peroxidase (TPX), a prominent lung-stage schistosomula excretory-secretory product, and alum as adjuvant. Only one of the 2 cysteine peptidases-based peptides in a multiple antigenic peptide construct (MAP-3 and MAP-4) appeared to adjuvant protective immune responses induced by the TPX peptide in a MAP form. Production of TPX MAP-specific IgG1 serum antibodies, and increase in lung interleukin-1 (IL-1), uric acid, and reactive oxygen species (ROS) content were associated with significant (P < 0.05) 50 % reduction in recovery of lung-stage larvae. Increase in lung triglycerides and cholesterol levels appeared to provide the surviving worms with nutrients necessary for a stout double lipid bilayer barrier at the parasite-host interface. Surviving worms-released products elicited memory responses to the MAP-3 immunogen, including production of specific IgG1 antibodies and increase in liver IL-33 and ROS. Reduction in challenge worm burden recorded 45 days post infection did not exceed 48 % associated with no differences in parasite egg counts in the host liver and small intestine compared to unimmunized adjuvant control mice. Alum adjuvant assisted the second peptide, MAP-4, in production of IgG1, IgG2a, IgG2b and IgA specific antibodies and increase in liver ROS, but with no protective potential, raising doubt about the necessity of adjuvant addition. Accordingly, different vaccine formulas containing TPX MAP and 1, 2 or 3 cysteine peptidases-derived peptides with or without alum were used to immunize parallel groups of mice. Compared to unimmunized control mice, significant (P < 0.05 to < 0.005) 22 to 54 % reduction in worm burden was recorded in the different groups associated with insignificant changes in parasite egg output. The results together indicated that a schistosomiasis vaccine able to entirely prevent disease and halt its transmission still remains elusive.


Subject(s)
Adjuvants, Immunologic , Antibodies, Helminth , Immunoglobulin G , Liver , Lung , Schistosoma mansoni , Schistosomiasis mansoni , Vaccines, Subunit , Animals , Schistosoma mansoni/immunology , Schistosomiasis mansoni/prevention & control , Schistosomiasis mansoni/immunology , Schistosomiasis mansoni/parasitology , Lung/parasitology , Lung/immunology , Mice , Antibodies, Helminth/immunology , Antibodies, Helminth/blood , Liver/parasitology , Liver/immunology , Immunoglobulin G/blood , Adjuvants, Immunologic/administration & dosage , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Female , Antigens, Helminth/immunology , Disease Models, Animal , Alum Compounds/administration & dosage , Mice, Inbred BALB C , Protein Subunit Vaccines
11.
Sci Rep ; 14(1): 9830, 2024 04 29.
Article in English | MEDLINE | ID: mdl-38684712

ABSTRACT

We assessed S-268019-b, a recombinant spike protein vaccine with a squalene-based adjuvant, for superiority in its immunogenicity over ChAdOx1 nCoV-19 vaccine among adults in Japan. In this multicenter, randomized, observer-blinded, phase 3 study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naïve participants (aged ≥ 18 years, without prior infection or vaccination against SARS-CoV-2) were randomized (1:1) to receive either S-268019-b or ChAdOx1 nCoV-19 as two intramuscular injections given 28 days apart. Participants who provided consent for a booster administration received S-268019-b at Day 211. The primary endpoint was SARS-CoV-2 neutralizing antibody (NAb) titer on Day 57; the key secondary endpoint was the seroconversion rate for SARS-CoV-2 NAb titer on Day 57. Other endpoints included anti-SARS-CoV-2 S-protein immunoglobulin (Ig)G antibody titer and safety. The demographic and baseline characteristics were generally comparable between S-268019-b (n = 611) and ChAdOx1 nCoV-19 (n = 610) groups. S-268019-b showed superior immunogenicity over ChAdOx1 nCoV-19, based on their geometric mean titers (GMTs) and GMT ratios of SARS-CoV-2 NAb on Day 57 by cytopathic effect assay (GMT [95% confidence interval {CI}] 19.92 [18.68, 21.23] versus 3.63 [3.41, 3.87]; GMT ratio [95% CI] 5.48 [5.01, 6.00], respectively; two-sided p-values < 0.0001). Additionally, NAb measured using a cell viability assay also showed similar results (GMT [95% CI] 183.25 [168.04, 199.84] versus 24.79 [22.77, 27.00]; GMT ratio [95% CI] 7.39 [6.55, 8.35] for S-268019-b versus ChAdOx1 nCoV-19, respectively; p < 0.0001). The GMT of anti-SARS-CoV-2 S-protein IgG antibody was 370.05 for S-268019-b versus 77.92 for ChAdOx1 nCoV-19 on Day 57 (GMT ratio [95% CI] 4.75 [4.34, 5.20]). Notably, immune responses were durable through the end of the study. S-268019-b elicited T-helper 1 skewed T-cell response, comparable to that of ChAdOx1 nCoV-19. After the first dose, the incidence of solicited systemic treatment-related adverse events (TRAEs) was higher in the ChAdOx1 nCoV-19 group, but after the second dose, the incidence was higher in the S-268019-b group. Headache, fatigue, and myalgia were the most commonly reported solicited systemic TRAEs, while pain at the injection site was the most frequently reported solicited local TRAE following both doses in both groups. No serious treatment-related adverse serious TRAEs events were reported in the two groups. S-268019-b was more immunogenic than ChAdOx1 nCoV-19 vaccine and was well tolerated (jRCT2051210151).


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Spike Glycoprotein, Coronavirus , Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antibodies, Viral/immunology , ChAdOx1 nCoV-19 , COVID-19/prevention & control , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , East Asian People , Immunoglobulin G/blood , Immunoglobulin G/immunology , Japan , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/immunology , Vaccines, Synthetic/immunology , Vaccines, Synthetic/administration & dosage
12.
Int J Biol Macromol ; 266(Pt 2): 131289, 2024 May.
Article in English | MEDLINE | ID: mdl-38570002

ABSTRACT

Intranasal vaccination offers crucial protection against influenza virus pandemics. However, antigens, especially subunit antigens, often fail to induce effective immune responses without the help of immune adjuvants. Our research has demonstrated that a polyelectrolyte complex, composed of curdlan sulfate/O-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (CS/O-HTCC), effectively triggers both mucosal and systemic immune responses when administrated intranasal. In this study, stable nanoparticles formed by curdlan-O-HTCC conjugate (CO NP) were prepared and characterized. Furthermore, the efficacy of CO NP was evaluated as a mucosal adjuvant in an intranasal influenza H1N1 subunit vaccine. The results revealed that CO NP exhibits uniform and spherical morphology, with a size of 190.53 ± 4.22 nm, and notably, it remains stable in PBS at 4 °C for up to 6 weeks. Biological evaluation demonstrated that CO NP stimulates the activation of antigen-presenting cells (APCs), including macrophages and dendritic cells (DCs), both in vitro and in vivo. Furthermore, intranasal administration of CO NP effectively elicits cellular and humoral immune responses, notably enhancing mucosal immunity. Thus, CO NP emerges as a promising mucosal adjuvant for influenza subunit vaccines.


Subject(s)
Adjuvants, Immunologic , Administration, Intranasal , Chitosan , Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Nanoparticles , Vaccines, Subunit , beta-Glucans , Influenza A Virus, H1N1 Subtype/immunology , Chitosan/chemistry , Nanoparticles/chemistry , Influenza Vaccines/immunology , Influenza Vaccines/chemistry , Influenza Vaccines/administration & dosage , beta-Glucans/chemistry , beta-Glucans/pharmacology , beta-Glucans/administration & dosage , Animals , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/administration & dosage , Mice , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Immunity, Mucosal/drug effects , Mice, Inbred BALB C , Female , Dendritic Cells/immunology , Orthomyxoviridae Infections/prevention & control , Orthomyxoviridae Infections/immunology
13.
J Virol ; 98(5): e0021224, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38591886

ABSTRACT

Porcine rotaviruses (PoRVs) cause severe economic losses in the swine industry. P[7] and P[23] are the predominant genotypes circulating on farms, but no vaccine is yet available. Here, we developed a bivalent subunit PoRV vaccine using truncated versions (VP4*) of the VP4 proteins from P[7] and P[23]. The vaccination of mice with the bivalent subunit vaccine elicited more robust neutralizing antibodies (NAbs) and cellular immune responses than its components, even at high doses. The bivalent subunit vaccine and inactivated bivalent vaccine prepared from strains PoRVs G9P[7] and G9P[23] were used to examine their protective efficacy in sows and suckling piglets after passive immunization. The immunized sows showed significantly elevated NAbs in the serum and colostrum, and the suckling piglets acquired high levels of sIgA antibodies from the colostrum. Challenging subunit-vaccinated or inactivated-vaccinated piglets with homologous virulent strains did not induce diarrhea, except in one or two piglets, which had mild diarrhea. Immunization with the bivalent subunit vaccine and inactivated vaccine also alleviated the microscopic lesions in the intestinal tissues caused by the challenge with the corresponding homologous virulent strain. However, all the piglets in the challenged group displayed mild to watery diarrhea and high levels of viral shedding, whereas the feces and intestines of the piglets in the bivalent subunit vaccine and inactivated vaccine groups had lower viral loads. In summary, our data show for the first time that a bivalent subunit vaccine combining VP4*P[7] and VP4*P[23] effectively protects piglets against the diarrhea caused by homologous virulent strains.IMPORTANCEPoRVs are the main causes of diarrhea in piglets worldwide. The multisegmented genome of PoRVs allows the reassortment of VP4 and VP7 genes from different RV species and strains. The P[7] and P[23] are the predominant genotypes circulating in pig farms, but no vaccine is available at present in China. Subunit vaccines, as nonreplicating vaccines, are an option to cope with variable genotypes. Here, we have developed a bivalent subunit candidate vaccine based on a truncated VP4 protein, which induced robust humoral and cellular immune responses and protected piglets against challenge with homologous PoRV. It also appears to be safe. These data show that the truncated VP4-protein-based subunit vaccine is a promising candidate for the prevention of PoRV diarrhea.


Subject(s)
Rotavirus Vaccines , Vaccines, Subunit , Animals , Female , Mice , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Capsid Proteins/immunology , Capsid Proteins/genetics , Diarrhea/prevention & control , Diarrhea/virology , Diarrhea/veterinary , Diarrhea/immunology , Genotype , Immunity, Cellular , Mice, Inbred BALB C , Rotavirus/immunology , Rotavirus Infections/prevention & control , Rotavirus Infections/veterinary , Rotavirus Infections/immunology , Rotavirus Infections/virology , Rotavirus Vaccines/immunology , Rotavirus Vaccines/administration & dosage , Swine , Swine Diseases/prevention & control , Swine Diseases/virology , Swine Diseases/immunology , Vaccination , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Vaccines, Synthetic/immunology , Vaccines, Synthetic/administration & dosage
14.
Vaccine ; 42(14): 3355-3364, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38631949

ABSTRACT

To better understand the role of pHsp90 adjuvant in immune response modulation, we proposed the use of the Receptor Binding Domain (RBD) of the Spike protein of SARS-CoV2, the principal candidate in the design of subunit vaccines. We evaluated the humoral and cellular immune responses against RBD through the strategy "protein mixture" (Adjuvant + Antigen). The rRBD adjuvanted with rAtHsp81.2 group showed a higher increase of the anti-rRBD IgG1, while the rRBD adjuvanted with rNbHsp90.3 group showed a significant increase in anti-rRBD IgG2b/2a. These results were consistent with the cellular immune response analysis. Spleen cell cultures from rRBD + rNbHsp90.3-immunized mice showed significantly increased IFN-γ production. In contrast, spleen cell cultures from rRBD + rAtHsp81.2-immunized mice showed significantly increased IL-4 levels. Finally, vaccines adjuvanted with rNbHsp90.3 induced higher neutralizing antibody responses compared to those adjuvanted with rAtHsp81.2. To know whether both chaperones must form complexes to generate an effective immune response, we performed co-immunoprecipitation (co-IP) assays. The results indicated that the greater neutralizing capacity observed in the rRBD adjuvanted with rNbHsp90.3 group would be given by the rRBD-rNbHsp90.3 interaction rather than by the quality of the immune response triggered by the adjuvants. These results, together with our previous results, provide a comparative benchmark of these two novel and safe vaccine adjuvants for their capacity to stimulate immunity to a subunit vaccine, demonstrating the capacity of adjuvanted SARS-CoV2 subunit vaccines. Furthermore, these results revealed differences in the ability to modulate the immune response between these two pHsp90s, highlighting the importance of adjuvant selection for future rational vaccine and adjuvant design.


Subject(s)
Adjuvants, Immunologic , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , HSP90 Heat-Shock Proteins , Immunoglobulin G , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Animals , Spike Glycoprotein, Coronavirus/immunology , Mice , Adjuvants, Immunologic/administration & dosage , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/blood , HSP90 Heat-Shock Proteins/immunology , Antibodies, Viral/immunology , Antibodies, Viral/blood , COVID-19 Vaccines/immunology , SARS-CoV-2/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Female , COVID-19/prevention & control , COVID-19/immunology , Mice, Inbred BALB C , Immunity, Cellular , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Adjuvants, Vaccine , Immunity, Humoral , Humans
15.
Vet Microbiol ; 293: 110088, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38640639

ABSTRACT

Orf virus (ORFV), a member of the genus Parapoxvirus, possesses an excellent immune activation capability, which makes it a promising immunomodulation agent. In this study, we evaluated ORFV as a novel adjuvant to enhance the immune response of mice to a subunit vaccine using porcine circovirus type 2 (PCV2) capsid (Cap) protein as a model. Our results showed that both inactivated and live attenuated ORFV activated mouse bone marrow-derived dendritic cells and increased expression of immune-related cytokines interleukin (IL)-1ß, IL-6, and TNF-α. Enhanced humoral and cellular immune responses were induced in mice immunized with PCV2 Cap protein combined with inactivated or live attenuated ORFV adjuvant compared with the aluminum adjuvant. Increased secretion of Th1 and Th2 cytokines by splenic lymphocytes in immunized mice further indicated that the ORFV adjuvant promoted a mixed Th1/Th2 immune response. Moreover, addition of the ORFV adjuvant to the PCV2 subunit vaccine significantly reduced the viral load in the spleen and lungs of PCV2-challenged mice and prevented pathological changes in lungs. This study demonstrates that ORFV enhances the immunogenicity of a PCV2 subunit vaccine by improving the adaptive immune response, suggesting the potential application of ORFV as a novel adjuvant.


Subject(s)
Adjuvants, Immunologic , Circoviridae Infections , Circovirus , Cytokines , Orf virus , Vaccines, Subunit , Viral Vaccines , Animals , Circovirus/immunology , Mice , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Viral Vaccines/immunology , Viral Vaccines/administration & dosage , Circoviridae Infections/prevention & control , Circoviridae Infections/veterinary , Circoviridae Infections/immunology , Circoviridae Infections/virology , Adjuvants, Immunologic/administration & dosage , Cytokines/immunology , Orf virus/immunology , Capsid Proteins/immunology , Female , Immunity, Cellular , Dendritic Cells/immunology , Viral Load , Antibodies, Viral/blood , Immunity, Humoral , Swine , Adjuvants, Vaccine , Mice, Inbred BALB C , Th1 Cells/immunology
16.
Med ; 5(5): 401-413.e4, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38574739

ABSTRACT

BACKGROUND: The recently circulating Omicron variants BA.2.86 and JN.1 were identified with more than 30 amino acid changes on the spike protein compared to BA.2 or XBB.1.5. This study aimed to comprehensively assess the immune escape potential of BA.2.86, JN.1, EG.5, and EG.5.1. METHODS: We collected human and murine sera to evaluate serological neutralization activities. The participants received three doses of coronavirus disease 2019 (COVID-19) vaccines or a booster dose of the ZF2022-A vaccine (Delta-BA.5 receptor-binding domain [RBD]-heterodimer immunogen) or experienced a breakthrough infection (BTI). The ZF2202-A vaccine is under clinical trial study (ClinicalTrials.gov: NCT05850507). BALB/c mice were vaccinated with a panel of severe acute respiratory syndrome coronavirus 2 RBD-dimer proteins. The antibody evasion properties of these variants were analyzed with 41 representative human monoclonal antibodies targeting the eight RBD epitopes. FINDINGS: We found that BA.2.86 had less neutralization evasion than EG.5 and EG.5.1 in humans. The ZF2202-A booster induced significantly higher neutralizing titers than BTI. Furthermore, BA.2.86 and JN.1 exhibited stronger antibody evasion than EG.5 and EG.5.1 on RBD-4 and RBD-5 epitopes. Compared to BA.2.86, JN.1 further lost the ability to bind to several RBD-1 monoclonal antibodies and displayed further immune escape. CONCLUSIONS: Our data showed that the currently dominating sub-variant, JN.1, showed increased immune evasion compared to BA.2.86 and EG.5.1, which is highly concerning. This study provides a timely risk assessment of the interested sub-variants and the basis for updating COVID-19 vaccines. FUNDING: This work was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, the Beijing Life Science Academy, the Bill & Melinda Gates Foundation, and the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (CPSF).


Subject(s)
Antibodies, Monoclonal , Antibodies, Neutralizing , COVID-19 Vaccines , COVID-19 , Mice, Inbred BALB C , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccines, Subunit , Humans , Animals , Antibodies, Monoclonal/immunology , SARS-CoV-2/immunology , Mice , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/blood , COVID-19/prevention & control , COVID-19/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/chemistry , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Female , Antibodies, Viral/blood , Antibodies, Viral/immunology , Betacoronavirus/immunology , Male , Immune Sera/immunology , Adult , Immune Evasion , Neutralization Tests , Epitopes/immunology
17.
J Control Release ; 369: 687-695, 2024 May.
Article in English | MEDLINE | ID: mdl-38575073

ABSTRACT

Extracts of the Chilean soapbark tree, Quillaja Saponaria (QS) are the source of potent immune-stimulatory saponin compounds. This study compared the adjuvanticity and toxicity of QS-18 and QS-21, assessing the potential to substitute QS-18 in place of QS-21 for vaccine development. QS-18, the most abundant QS saponin fraction, has been largely overlooked due to safety concerns. We found that QS-18 spontaneously inserted into liposomes, thereby neutralizing hemolytic activity, and following administration did not induce local reactogenicity in a footpad swelling test in mice. With high-dose intramuscular administration, transient weight loss was minor, and QS-18 did not induce significantly more weight loss compared to a liposome vaccine adjuvant system lacking it. Two days after administration, no elevation of inflammatory cytokines was detected in murine serum. In a formulation including cobalt-porphyrin-phospholipid (CoPoP) for short peptide sequestration, QS-18 did not impact the formation of peptide nanoparticles. With immunization, QS-18 peptide particles induced higher levels of cancer neoepitope-specific and tumor-associated antigen-specific CD8+ T cells compared to QS-21 particles, without indication of greater toxicity based on mouse body weight. T cell receptor sequencing of antigen-specific CD8+ T cells showed that QS-18 induced significantly more T cell transcripts. In two murine cancer models, vaccination with QS-18 peptide particles induced a similar therapeutic effect as QS-21 particles, without indication of increased toxicity. Antigen-specific CD8+ T cells in the tumor microenvironment were found to express the exhaustion marker PD-1, pointing to the rationale for exploring combination therapy. Taken together, these data demonstrate that QS-18, when formulated in liposomes, can be a safe and effective adjuvant to induce tumor-inhibiting cellular responses in murine models with potential to facilitate or diminish costs of production for vaccine adjuvant systems. Further studies are warranted to assess liposomal QS-18 immunogic, reactogenic and toxicological profiles in mice and other animal species.


Subject(s)
Adjuvants, Immunologic , Cancer Vaccines , Liposomes , Quillaja , Animals , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Quillaja/chemistry , Adjuvants, Immunologic/administration & dosage , Female , Mice, Inbred C57BL , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/immunology , Mice , Quillaja Saponins , Cytokines , Saponins/administration & dosage , Saponins/pharmacology , Cell Line, Tumor , Protein Subunit Vaccines
18.
J Control Release ; 369: 556-572, 2024 May.
Article in English | MEDLINE | ID: mdl-38580136

ABSTRACT

Vaccines represent one of the most powerful and cost-effective innovations for controlling a wide range of infectious diseases caused by various viruses and bacteria. Unlike mRNA and DNA-based vaccines, subunit vaccines carry no risk of insertional mutagenesis and can be lyophilized for convenient transportation and long-term storage. However, existing adjuvants are often associated with toxic effect and reactogenicity, necessitating expanding the repertoire of adjuvants with better biocompatibility, for instance, designing self-adjuvating polymeric carriers. We herein report a novel subunit vaccine delivery platform constructed via in situ free radical polymerization of C7A (2-(Hexamethyleneimino) ethyl methacrylate) and acrylamide around the surface of individual protein antigens. Using ovalbumin (OVA) as a model antigen, we observed substantial increases in both diameter (∼70 nm) and surface potential (-1.18 mV) following encapsulation, referred to as n(OVA)C7A. C7A's ultra pH sensitivity with a transition pH around 6.9 allows for rapid protonation in acidic environments. This property facilitates crucial processes such as endosomal escape and major histocompatibility complex (MHC)-I-mediated antigen presentation, culminating in the substantial CD8+ T cell activation. Additionally, compared to OVA nanocapsules without the C7A components and native OVA without modifications, we observed heightened B cell activation within the germinal center, along with remarkable increases in serum antibody and cytokine production. It's important to note that mounting evidence suggests that adjuvant effects, particularly its targeted stimulation of type I interferons (IFNs), can contribute to advantageous adaptive immune responses. Beyond its exceptional potency, the nanovaccine also demonstrated robust formation of immune memory and exhibited a favorable biosafety profile. These findings collectively underscore the promising potential of our nanovaccine in the realm of immunotherapy and vaccine development.


Subject(s)
Mice, Inbred C57BL , Ovalbumin , T-Lymphocytes, Cytotoxic , Animals , Ovalbumin/immunology , Ovalbumin/administration & dosage , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/drug effects , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/chemistry , Female , Methacrylates/chemistry , Polymers/chemistry , Polymers/administration & dosage , Nanoparticles/chemistry , Nanoparticles/administration & dosage , Mice , Vaccines/administration & dosage , Vaccines/immunology , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/immunology , Nanovaccines
19.
Int J Pharm ; 656: 124076, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38569976

ABSTRACT

Vaccines represent a pivotal health advancement for preventing infection. However, because carrier systems with repeated administration can invoke carrier-targeted immune responses that diminish subsequent immune responses (e.g., PEG antibodies), there is a continual need to develop novel vaccine platforms. Zinc carnosine microparticles (ZnCar MPs), which are composed of a one-dimensional coordination polymer formed between carnosine and the metal ion zinc, have exhibited efficacy in inducing an immune response against influenza. However, ZnCar MPs' limited suspendability hinders clinical application. In this study, we address this issue by mixing mannan, a polysaccharide derived from yeast, with ZnCar MPs. We show that the addition of mannan increases the suspendability of this promising vaccine formulation. Additionally, since mannan is an adjuvant, we illustrate that the addition of mannan increases the antibody response and T cell response when mixed with ZnCar MPs. Mice vaccinated with mannan + OVA/ZnCar MPs had elevated serum IgG and IgG1 levels in comparison to vaccination without mannan. Moreover, in the mannan + OVA/ZnCar MPs vaccinated group, mucosal washes demonstrated increased IgG, IgG1, and IgG2c titers, and antigen recall assays showed enhanced IFN-γ production in response to MHC-I and MHC-II immunodominant peptide restimulation, compared to the vaccination without mannan. These findings suggest that the use of mannan mixed with ZnCar MPs holds potential for subunit vaccination and its improved suspendability further promotes clinical translation.


Subject(s)
Carnosine , Mannans , Vaccines, Subunit , Zinc , Mannans/chemistry , Mannans/administration & dosage , Mannans/immunology , Animals , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/immunology , Zinc/chemistry , Zinc/administration & dosage , Carnosine/administration & dosage , Carnosine/chemistry , Female , Immunoglobulin G/blood , Mice , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/chemistry , Ovalbumin/immunology , Ovalbumin/administration & dosage , Mice, Inbred C57BL , Polymers/chemistry , Polymers/administration & dosage , Mice, Inbred BALB C , Drug Carriers/chemistry
20.
Poult Sci ; 103(5): 103569, 2024 May.
Article in English | MEDLINE | ID: mdl-38447310

ABSTRACT

Non-typhoidal Salmonella infection is a significant health and economic burden in poultry industry. Developing an oral vaccine to induce robust mucosal immunity in the intestines of birds, especially cross protection against different Salmonella serotypes is challenging. Therefore, a potent oral vaccine platform that can mitigate different serotypes of Salmonella is warranted for the poultry industry. We reported earlier that the Salmonella enteritidis (SE) immunogenic outer membrane proteins (OMPs) and flagellin (FLA) entrapped in mannose chitosan nanoparticles (OMPs-FLA-mCS NPs) administered prime-boost (d-3 and 3-wk later) by oral inoculation elicits mucosal immunity and reduces challenge SE colonization by over 1 log10 CFU in birds. In this study, we sought to evaluate whether the SE antigens containing OMPs-FLA-mCS NPs vaccine induces cross-protection against Salmonella typhimurium (ST) in broilers. Our data indicated that the OMPs-FLA-mCS NPs vaccine induced higher cross-protective antibody responses compared to commercial Poulvac ST vaccine (contains a modified-live ST bacterium). Particularly, OMPs-FLA-mCS-NP vaccine elicited OMPs and FLA antigens specific increased production of secretory IgA and IgY antibodies in samples collected at both post-vaccination and post-challenge timepoints compared to commercial vaccine group. Notably, the vaccine reduced the challenge ST bacterial load by 0.8 log10 CFU in the cecal content, which was comparable to the outcome of Poulvac ST vaccination. In conclusion, our data suggested that orally administered OMPs-FLA-mCS-NP SE vaccine elicited cross protective mucosal immune responses against ST colonization in broilers. Thus, this candidate vaccine could be a viable option replacing the existing both live and killed Salmonella vaccines for birds.


Subject(s)
Chickens , Chitosan , Cross Protection , Nanoparticles , Poultry Diseases , Salmonella Infections, Animal , Salmonella Vaccines , Salmonella enteritidis , Salmonella typhimurium , Animals , Chickens/immunology , Salmonella enteritidis/immunology , Poultry Diseases/prevention & control , Poultry Diseases/immunology , Salmonella Infections, Animal/prevention & control , Salmonella Infections, Animal/immunology , Chitosan/administration & dosage , Chitosan/pharmacology , Salmonella Vaccines/immunology , Salmonella Vaccines/administration & dosage , Nanoparticles/administration & dosage , Salmonella typhimurium/immunology , Administration, Oral , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/immunology
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