The combination of Mycobacterium tuberculosis fusion proteins LT33 and LT28 induced strong protective immunity in mice
Pu HeJuan WangD. S. K. TanLina HuYanlin MaYoujun MiFei LiTingting ZhangYunjie DuWenhua ZhangJun LiLei JiaoBingdong Zhu
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Effective subunit vaccines for tuberculosis (TB) must target antigenic components at various stages of infection. In this study, we constructed fusion proteins using secreted antigens from Mycobacterium tuberculosis ( M. tuberculosis ), specifically ESAT6, CFP10, MPT64, and Rv2645 from the proliferation stage, along with latency-associated antigens Rv1738 and Rv1978. The resulting fusion proteins, designated LT33 (ESAT6-CFP10-Rv1738) and LT28 (MPT64 61-170 -Rv1978 8-60 -Rv2645 21-80 ), were combined with an adjuvant containing dimethyldioctadecylammonium bromide (DDA), polyriboinosinic polyribocytidylic acid (PolyI:C), and cholesterol to construct subunit vaccines. We evaluated the subunit vaccine effect in C57BL/6 mice and revealed that LT33 and LT28 exhibited strong immunogenicity and induced protective efficacy against aerosol challenge with M. tuberculosis H37Rv. Notably, the combination of LT33 and LT28 led to a significant reduction of 0.77 log10 colony-forming units (CFU) of H37Rv in the lungs compared to the adjuvant control group, highlighting their potential as promising candidates for subunit vaccine against M. tuberculosis infection.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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Tumor immunology
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This chapter contains sections titled: Introduction Immunogenicity of Therapeutic Proteins Immune Mechanisms Related to Protein Immunogenicity Aggregates and Immunogenicity Conclusions References
Human proteins
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This chapter contains sections titled: Introduction How the Immune System Responds to Protein Therapeutics Risk Factors for Inducing Immunogenicity Methods for Identifying an Immune Response Strategic Approach for Monitoring Immunogenicity Consequences of an Immune Response to a Therapeutic Protein Nonclinical Immunogenicity Testing Summary
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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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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.
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Abstract An antigen refers to a molecule that is able to bind to the cells of the immune system. If an antigen can also stimulate an immune response, it is termed an immunogen. Immunogenicity is a measure of this ability to activate the immune response: that is, the B and T cells underlying humoral and cell‐mediated immunity. Understanding the concept of immunogenicity is therefore vital in understanding the field of immunology as a whole. The determinants of immunogenicity are complex, but much research has been conducted in this area in the context of vaccination and protein therapeutics, where understanding immunogenicity is of key clinical significance. While obtaining accurate measures of immunogenicity is difficult, a range of techniques to both predict the immunogenicity of a substance and to measure immunogenicity based on B and T cell activation have been developed. Key Concepts Immunogenicity is defined as the ability of a substance to elicit an adaptive immune response. The immunogenicity of a substance depends on multiple factors relating to the properties of the substance itself, the biological system, and how the substance is delivered to the biological system. Immunogenicity is necessary for our body to respond to and destroy pathogens, as well as to remove tumourogenic and dying cells. Understanding immunogenicity is important for pharmaceutical development, where it is sometimes necessary to either increase (vaccination) or decrease (protein therapeutics) the immunogenicity of a product. Experimental model systems, and more recently, computational tools, are being developed to predict immunogenicity. Immunogenicity can be measured empirically by assessing the numbers of activated T or B cells, or antibody levels during a response to the substance.
Immunogen
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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) .
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