Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial
Leigh M. HowardKristen L. HoekJohannes B. GollParimal SamirAllison C. GalassieTara M. AllosXinnan NiuLaura E. GordyC. Buddy CreechNripesh PrasadTravis L. JensenHeather HillShawn LevySebastian JoyceAndrew J. LinkKathryn M. Edwards
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Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood.We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination.Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination.Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.ClinicalTrials.gov NCT01573312.Keywords:
Antibody titer
SummaryThe development of adjuvant 65 has added a new dimension to the prospects for the control of influenza by vaccine. Previous studies with the adjuvant revealed heightened antibody response of...
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Vaccine adjuvant
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Direct immunogenicity comparison of adjuvants from various sources and with different mechanisms of action for inactivated influenza vaccines.Groups of mice were immunized intramuscularly twice with an inactivated whole-virion influenza vaccine based on A/California/07/2009 X-179A (H1N1) strain. The following adjuvants were added to the vaccine (10 in total): aluminium hydroxide, oligonucleotide CpG, complete Freund's adjuvant, poly(lactide-coglycolide) microparticles, monophosphoryl lipid A and polyoxidonium, as well as 2 adjuvants based on characterized chitosan substances with different physical/chemical properties and 2 experimental complex formulations (a multi-component adjuvant and an oil-in-water emulsion based on squalene and tocopherol). Immuogenicity was determined by HAI and MN (MDCK) sera antibodies.Different adjuvants increased immunogenicity of the vaccine against the homologous strain in varying patterns. Experimental complex formulations were the most immunogenic (antibody titer increase reached 48 - 96 times compared with unadjuvanted vaccines). Chitosan based adjuvants showed high immunogenicity. Not all the adjuvants significantly increased immunogenicity, and in some cases even an immunogenicity decrease was noted with the addition of certain adjuvants.Research and development of chitosan based adjuvants with characterization and standardization issues addressed, as well as complex adjuvants, both multi-component and emulsion based, are the most promising approaches that could lead to next generation vaccines against influenza and other human and animal infectious diseases.
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Chitosan-based adjuvants combine effectiveness, safety and economic feasibility and thus are quite promising for enhancement of influenza control via vaccination, however, problems of characterization and reproducibility remain unresolved; data on relations between physical-chemical characteristics (PCC) of the polymer and immunogenicity of chitosan-based adjuvants, as well as comparative evaluation with other adjuvants are needed. Groups of mice were immunized intramuscularly with inactivated influenza vaccines based on A/California/07/2009 (H1N1) strain with characterized adjuvants based on chitosan with varying PCC (molecular mass 700 and 10 kDa, deacetylation degree 85%; HMC and LMC, respectively) and its derivative (succinylated chitosan (SC)). Experimental formulations were also studied: an «oil-in-water» emulsion (ME) and a multi-component adjuvant (MS). Different adjuvants increased immunogenicity of the inactivated influenza vaccines by hemagglutinin inhibiting sera antibodies in varying patterns. HMC was more immunogenic than LMC, whereas SC even reduced immunogenicity of the vaccine. HMC was comparable to MS by immunogenicity, and LMC - to ME. PCC of chitosan and its derivatives play an important role in immunogenicity of the respective adjuvants, and perspective and characterized chitosan-based adjuvants are comparable or even more immunogenic than adjuvants from other groups.
Inactivated vaccine
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Recombinant IL-2 expressed in prokaryotic was injected with oil vaccine to study the effects on four in one oil adjuvant inactivited vaccine.The experiment had five groups,ten chickens for each group.The control group was immunized only with oil adjuvant vaccine,the other four groups were injected with IL-2 at dose of 0.05 mg,0.10 mg,0.15 mg,0.20 mg, respectively at the same time. The experiment groups and the control group were all inoculated with 0.5 mL oil adjuvant vaccine , respectively. The antibody titers of newcastle disease and avian influenza were detected by HA and HI assay. The results indicated that the recombinant IL-2 had strong effect on oil adjuvant vaccine, and the titers of antibodies increased by 2.4~2.8 titers and 2.3~3.0 titers, respectively.During the whole experiment periods, the toxic effect was not found.The results confirmed that recobmbinant IL-2 was effective in enhancing the immune antibody titers.
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Newcastle Disease
Immunopotentiator
Vaccine adjuvant
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Combined DNA vaccine encoding Ag85B, MPT64 and MPT83 of Mycobacterium tuberculosis were formulated into DDA and MPL to immunize mice and then the immunogenicity and protective efficacy of each group were evaluated. The DDA and MPL groups induced a much more enhanced Th1-type cellular response indicated by the higher levels of IFN-γ compared with that without any adjuvant. In DDA group, antigens specific IFN-γ for Ag85B, MPT64, MPT83 are (265.37±79.2) U/ml,(185.31±58.3) U/ml,(108.13±54.4) U/ml respectively which are 16 U/ml,45 U/ml,2 U/ml higher than that of the non-adjuvant group. The bacterial CFU in lungs and spleens of the DDA group was reduced 1/5 and 1/4 respectively relative to the same combined vaccine with MPL and without adjubvants. The pathological lungs slices of adjuvant groups gave consistent result that showed less damage than non-adjuvant group due to influx of epithelioid macrophages and less neutrophils. In conclusion, DDA is more efficacious than MPL as adjuvants to enhance immune efficacy of combined DNA vaccine in mice.
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Pneumolysin
Alum
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Aim. Evaluate specific immunogenic activity of a prototype vaccine against hepatitis E (HE). Materials and methods. Non-linear mice, male (n=170), were immunized once intraperitoneally by a prototype vaccine against HE at 5,10 and 20 pg per animal. Anti-HEV IgG were determined by ELISA using species-specific conjugate at days 7,14,21 and 28 after immunization. Experimental samples of the vaccine preparation containing 20 pg of the antigen and compositions of adjuvants based on aluminium hydroxide and immune modulators polyoxidonium and glutoxim were administered to 250 mice split into 25 groups (10 animals per group) to optimize vaccine immuno-genicity. Anti-HEV were determined in mice sera samples at day 28 after the immunization, and mean immunization dose (Ш50) for each composition of the vaccine preparation was calculated. Results. Increase of immunogenicity for the same standard antigen dose (20 pg) for glutoxim adjuvant at 10 mg/ml in aluminium hydroxide solution (0,5 mg/ml) was 51.4%. A non-significant increase of immunogenicity was also observed for vaccine composition with polyoxidonium (1.0 mg/ml), however, it was statistically non-significant when compared with standard adjuvant (aluminium hydroxide at 0,5 mg/ml). Conclusion. The data obtained give evidence regarding high immunogenicity of the vaccine preparation against hepatitis E. Use of glutoxim immune modulator in the composition of the experimental vaccine against hepatitis E ensures highest immunogenicity.
Hepatitis B vaccine
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Influenza is a major threat to public health. Vaccination is an effective strategy to control influenza; however, the current inactivated influenza vaccine has mild immunogenicity and exhibits suboptimal efficacy in clinical use. Vaccine efficacy can be improved by the addition of adjuvants, but few adjuvants have been approved for human use. To explore novel and effective adjuvants for influenza vaccines, here we screened 145 compounds from food additives approved in Japan. Of these 145 candidates, we identified 41 compounds that enhanced the efficacy of the split influenza hemagglutinin (HA) vaccine against lethal virus challenge in a mouse model. These 41 compounds included 18 novel adjuvant candidates and 15 compounds with previously reported adjuvant effects for other antigens but not for the influenza vaccine. Our results are of value to the development of novel and effective adjuvanted influenza or other vaccines for human use.
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Vaccine efficacy
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Design of an effective and safe vaccine against pathogenic streptococci is still on the agenda, in spite of numerous attempts in this area undertaken by different laboratories. In order to improve immunogenicity of recombinant vaccine preparations, a selection of effective adjuvants is necessary. Previously, two recombinant GBS polypeptides P6 and ScaAB were found to be immunogenic, and their injection in separate preparations or mixed manner boosted production of specific and protective antibodies with high affinity. Four different adjuvants (Freund adjuvant, aluminum hydroxide, Bestim and Interleukine-1β) have been tested for immunization of mice with single polypeptides, or with their mixtures. As a result of vaccination, it was demonstrated that aluminum hydroxide was providing the most desirable immunological parameters of immune response among the adjuvants tested. A mixture of polypeptides containing aluminum hydroxide was found to produce specific antibodies with better opsonizing activity against group B streptococci. (Med. Immunol., 2008, vol. 10, N 2-3, pp 215-222) .
Streptococcus Pyogenes
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