CpG7909 adjuvant enhanced immunogenicity efficacy in mice immunized with ESAT6-Ag85A fusion protein, but does not confer significant protection against <i>Mycobacterium tuberculosis</i>
 infection

Hu, Song; Chen, H.; Ma, Jilei; Chen, Q.; Deng, Hepu; Gong, Feili; Huang, Hailin; Shi, Chunwei

doi:10.1111/jam.12315

Cited by 7 publications

(9 citation statements)

References 30 publications

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“…In our previous work, CpG7909 was used as adjuvant of an anti-tuberculosis subunit vaccine. CpG7909 was able to enhance Th1-type immunity induced by subunit vaccine [38]. In the current work, it was determined that, as immunostimulant, CpG7909 induced M1 polarization of U937 cells, however, M. tb infection suppressed CpG7909-evoked M1 polarization.…”

Section: Discussionmentioning

confidence: 77%

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IRAK-M alters the polarity of macrophages to facilitate the survival of Mycobacterium tuberculosis

Shen

et al. 2017

BMC Microbiol

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BackgroundIntracellular bacterium, Mycobacterium tuberculosis (M. tb), infects specifically macrophages as host cells. IRAK-M, a member of IRAK family, is a negative regulator in TLR signaling and specifically expresses in monocytes and macrophages. The role of IRAK-M in intracellular growth of M. tb and macrophage polarization was explored, for deeply understanding the pathogenesis of M. tb, the significance of IRAK-M to innate immunity and pathogen-host interaction.MethodsIRAK-M expression was detected in M. tb infected macrophages and in human lung tissue of pulmonary tuberculosis with immunofluorescence staining, Western blot and immunohistochemistry. IRAK-M knock-down and over-expressing cell strains were constructed and intracellular survival of M. tb was investigated by acid-fast staining and colony forming units. Molecular markers of M1-type (pSTAT1 and iNOS) and M2-type (pSTAT6 and Arg-1) macrophages were detected using Western blot in IRAK-M knockdown U937 cells infected with M. tb H37Rv. U937 cells were stimulated with immunostimulant CpG7909 into M1 status and then infected with M. tb H37Rv. Expression of IRAK-M, IRAK-4 and iNOS was detected with immunofluorescence staining and Western blot, to evaluate the effect of IRAK-M to CpG directed M1-type polarization of macrophages during M. tb infection. Molecules related with macrophage’s bactericidal ability such as Hif-1 and phosphorylated ERK1/2 were detected with immunohistochemistry and Western blot.ResultsIRAK-M increased in M. tb infected macrophage cells and also in human lung tissue of pulmonary tuberculosis. IRAK-M over-expression resulted in higher bacterial load, while IRAK-M interference resulted in lower bacterial load in M. tb infected cells. During M. tb infection, IRAK-M knockdown induced M1-type, while inhibited M2-type polarization of macrophage. M1-type polarization of U937 cells induced by CpG7909 was inhibited by M. tb infection, which was reversed by IRAK-M knockdown in U937 cells. IRAK-M affected Hif-1 and MAPK signaling cascade during M. tb infection.ConclusionsConclusively, IRAK-M might alter the polarity of macrophages, to facilitate intracellular survival of M. tb and affect Th1-type immunity of the host, which is helpful to understanding the pathogenesis of M. tb.

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Section: Discussionmentioning

confidence: 77%

“…We have previously reported that CpG7909 was able to enhance the ability of subunit vaccine to induced Th1-type immunity, however, CpG7909 was not able to improve its protective effects against M. tb infection [38]. The negative regulatory role of IRAK-M might contribute to this phenomenon.…”

Section: Discussionmentioning

confidence: 92%

IRAK-M alters the polarity of macrophages to facilitate the survival of Mycobacterium tuberculosis

Shen

et al. 2017

BMC Microbiol

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“…The adjuvants used for enhancing the immunogenicity and protective efficacy of Ag85A are DDA, CpG7909. Studies show that CpG7909 is able to enhance the immunological effects of Ag85A (Hu et al, 2013), but it does not confer significant protective efficacy against infection with M. tuberculosis. In contrast, Brandt's research has shown that DDA-MPL can induce similarly high levels of immunity as BCG (Brandt et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Enhanced immune responses in mice to combined immunization with Mycobacterium tuberculosis Ag85A and DDA/MPL

Zhao¹,

Tan²,

Xu³

et al. 2014

Afr. J. Microbiol. Res.

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The tuberculosis (TB) Bacillus Calmette-Guerin (BCG) vaccine, which is based on Mycobacterium bovis, has variable protective efficacy in humans; therefore, safe and effective vaccines are urgently required to prevent this disease. The antigen 85A from Mycobacterium tuberculosis (M. tuberculosis) is a prime target for immunity in the early phase of tuberculosis in various animal models. The purpose of this study was to confirm whether Ag85A could elicit protective immune responses in mice. Dimethyldioctadecylammonium (DDA), an adjuvant with Th1-promoting activities and monophosphoryl lipid A (MPL), an immunostimulatory component that has strong adjuvant activity for both cellular and humoral immune responses, has been used as the adjuvant to study the biological and immunological characteristics of tuberculosis proteins in the researches previously. The gene coding Ag85A (fbpA), was cloned into a pET-30a(+) prokaryotic expression vector, and the induced amino acid sequence corresponds to a 33 kDa protein, which was confirmed by mass spectrometry and western blots. Mice were subcutaneously immunized with Ag85A protein emulsified with DDA and MPL and the results showed that the 85A antigen, when combined with these adjuvants, elicited strong Ag85A-specific T-cell responses and humoral responses as compared with vaccination with BCG. Based on the fact that this vaccine combination induced strong antigen-specific immune responses, it is a prime candidate as a component of a future TB vaccine.

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“…Preclinical studies have been conducted with CPG 7909-adjuvanted vaccine candidates against diseases caused by Plasmodium , Pseudomonas , and Mycobacterium species. 1-3 These studies showed induction of an innate cellular and humoral immune response, consistent with TLR9 activation, characterized by the production of pro-inflammatory cytokines which in turn may enhance the vaccine efficacy. 4 Similarly, CPG 7909 enhanced immunogenicity and efficacy of anthrax vaccines in mice, guinea pigs, and nonhuman primates.…”

Section: Introductionmentioning

confidence: 89%

Evaluation of the AV7909 Anthrax Vaccine Toxicity in Sprague Dawley Rats Following Three Intramuscular Administrations

Rao

Godin²,

Lacy

et al. 2021

Int J Toxicol

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AV7909 is a next-generation anthrax vaccine under development for post-exposure prophylaxis following suspected or confirmed Bacillus anthracis exposure, when administered in conjunction with the recommended antibacterial regimen. AV7909 consists of the FDA-approved BioThrax® vaccine (anthrax vaccine adsorbed) and an immunostimulatory Toll-like receptor 9 agonist oligodeoxynucleotide adjuvant, CPG 7909 . The purpose of this study was to evaluate the potential systemic and local toxicity of AV7909 when administered via repeat intramuscular injection to the right thigh muscle (biceps femoris) to male and female Sprague Dawley rats. The vaccine was administered on Days 1, 15, and 29 and the animals were assessed for treatment-related effects followed by a 2-week recovery period to evaluate the persistence or reversibility of any toxic effects. The AV7909 vaccine produced no apparent systemic toxicity based on evaluation of clinical observations, body weights, body temperature, clinical pathology, and anatomic pathology. Necrosis and inflammation were observed at the injection sites as well as in regional lymph nodes and adjacent tissues and were consistent with immune stimulation. Antibodies against B. anthracis protective antigen (PA) were detected in rats treated with the AV7909 vaccine, confirming relevance of this animal model for the assessment of systemic toxicity of AV7909. In contrast, sera of rats that received saline or soluble CPG 7909 alone were negative for anti-PA antibodies. Overall, 3 intramuscular immunizations of Sprague Dawley rats with AV7909 were well tolerated, did not induce mortality or any systemic adverse effects, and did not result in any delayed toxicity.

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CpG7909 adjuvant enhanced immunogenicity efficacy in mice immunized with ESAT6-Ag85A fusion protein, but does not confer significant protection against Mycobacterium tuberculosis infection

Cited by 7 publications

References 30 publications

IRAK-M alters the polarity of macrophages to facilitate the survival of Mycobacterium tuberculosis

IRAK-M alters the polarity of macrophages to facilitate the survival of Mycobacterium tuberculosis

Enhanced immune responses in mice to combined immunization with Mycobacterium tuberculosis Ag85A and DDA/MPL

Evaluation of the AV7909 Anthrax Vaccine Toxicity in Sprague Dawley Rats Following Three Intramuscular Administrations

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