A Multistage Subunit Vaccine Effectively Protects Mice Against Primary Progressive Tuberculosis, Latency and Reactivation

Ma, Jilei; Teng, Xiaochun; Wang, Xiaochun; Fan, Xionglin; Wu, Yongjiang; Tian, Man; Zhou, Zhongqiang; Li, Longmeng

doi:10.1016/j.ebiom.2017.07.005

Cited by 32 publications

(71 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12 weeks after infection, the protection afforded by RR-CDG and the ESAT-6/Ag85B fusion protein was equivalent to 5Ag/RR-CDG (Figure S2). Thus, when combined with TB proteins, RR-CDG provides significant protective efficacy against M. tuberculosis challenge that is as effective as any other adjuvant tested in the context of an M. tuberculosis protein subunit vaccine to date (Skeiky et al, 2004; Bertholet et al, 2010; Aagaard et al, 2011; Baldwin et al, 2012; Billeskov et al, 2012; Ma et al, 2017). …”

Section: Resultsmentioning

confidence: 99%

STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium tuberculosis Infection

et al. 2018

View full text Add to dashboard Cite

SUMMARY There are a limited number of adjuvants that elicit effective cell-based immunity required for protection against intracellular bacterial pathogens. Here, we report that STING-activating cyclic dinucleotides (CDNs) formulated in a protein subunit vaccine elicit long-lasting protective immunity to Mycobacterium tuberculosis in the mouse model. Subcutaneous administration of this vaccine provides equivalent protection to that of the live attenuated vaccine strain Bacille Calmette-Guérin (BCG). Protection is STING dependent but type I IFN independent and correlates with an increased frequency of a recently described subset of CXCR3-expressing T cells that localize to the lung parenchyma. Intranasal delivery results in superior protection compared with BCG, significantly boosts BCG-based immunity, and elicits both Th1 and Th17 immune responses, the latter of which correlates with enhanced protection. Thus, a CDN-adjuvanted protein subunit vaccine has the capability of eliciting a multi-faceted immune response that results in protection from infection by an intracellular pathogen.

show abstract

Section: Resultsmentioning

confidence: 99%

STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium tuberculosis Infection

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Aagaard et al ( 19 ) and Lin et al ( 27 ) confirmed that the multiple Mtb antigens combining the early and late stage Mtb antigens would be better than a single Mtb protein, as the multiple Mtb antigens were not only capable of preventing Mtb infection but also able to control late-stage infection and reactivation. Other studies also indicated that the protective immunity of antigen proteins fusion of different infectious stage related antigens were better than the individual antigen ( 28 – 30 ). However, whether multistage-fusion epitopes have the same effect is worth exploring further.…”

Section: Discussionmentioning

confidence: 97%

Heterologous Boosting With Listeria-Based Recombinant Strains in BCG-Primed Mice Improved Protection Against Pulmonary Mycobacterial Infection

et al. 2020

View full text Add to dashboard Cite

While Baccillus Calmette-Guerin (BCG) is used worldwide, tuberculosis (TB) is still a global concern due to the poor efficacy of BCG. Novel vaccine candidates are therefore urgently required. In this study, two attenuated recombinant Listeria strains, LMΔ -msv and LIΔ -msv were constructed by deletion of actA and plcB and expression of a fusion protein consisting of T cell epitopes from four Mycobacterium tuberculosis ( Mtb ) antigens ( Rv2460c, Rv2660c, Rv3875 , and Rv3804c ). The safety and immunogenicity of the two recombinant strains were evaluated in C57BL/6J mice. After intravenous immunization individually, both recombinant strains entered liver and spleen but eventually were eliminated from these organs after several days. Simultaneously, they induced antigen-specific cell-mediated immunity, indicating that the recombinant Listeria strains were immunogenic and safe in vivo . LMΔ -msv immunization induced stronger cellular immune responses than LIΔ -msv immunization, and when boosted with LIΔ -msv , antigen-specific IFN-γ CD8 + T cell responses were notably magnified. Furthermore, we evaluated the protection conferred by the vaccine candidates against mycobacterial infection via challenging the mice with 1 × 10 7 CFU of BCG. Especially, we tested the feasibility of application of them as heterologous BCG supplement vaccine by immunization of mice with BCG firstly, and boosted with LMΔ -msv and LIΔ -msv sequentially before challenging. Combination immune strategy (LMΔ -msv prime-LIΔ -msv boost) conferred comparable protection efficacy as BCG alone. More importantly, BCG-vaccinated mice acquired stronger resistance to Mycobacterial challenge when boosted with LMΔ -msv and LIΔ -msv sequentially. Our results inferred that heterologous immunization with Listeria -based recombinant strains boosted BCG-primed protection against pulmonary mycobacterial infection.

show abstract

“…Mice models of primary infection and late persistent TB infection were established as previously described ( 8 , 9 ). Vaccinated mice were infected i.n.…”

Section: Methodsmentioning

confidence: 99%

“…The lung from three mice in each group was fixed in 4% paraformaldehyde solution, embedded in paraffin, sectioned and stained with hematoxylin and eosin (HE) and acid-fast (AF) staining. Lung histopathological scores of three mice in different groups were evaluated as previously described ( 9 ).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we reported that a regimen of BCG prime and DMT (DDA-MPLA-TDB) adjuvanted multistage subunit protein WH121 showed a stronger ability to protect mice against M. tuberculosis post-exposure infection than BCG alone or BCG repeat vaccination in mice ( 8 ). Furthermore, subunit vaccine CMFO in adjuvant of DMT enhanced the BCG vaccine to thwart the reactivation of LTBI ( 9 ). Therefore, whether heterologous boost regimens are more efficacious to prevent against LTBI than primary infection remains to be investigated.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Heterologous Boost Following Mycobacterium bovis BCG Reduces the Late Persistent, Rather Than the Early Stage of Intranasal Tuberculosis Challenge Infection

Cai

et al. 2018

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Adults are the leading population affected by tuberculosis (TB) epidemic and death. Developing an effective vaccine against adult TB is urgently needed. Mycobacterium bovis Bacillus Calmette-Guerin (BCG) prime-heterologous boost strategy has been explored extensively to protect adults against primary TB infection, but the majority of experimental regimens have not improved the protection primed by the BCG vaccine. The reason attributed to the failure remains unknown. In this study, CTT3H-based vaccines, namely DMT adjuvanted CTT3H subunit or DNA vaccine (pCTT3H-DMT), and recombinant adenovirus rAdCTT3H were constructed. Protective efficacy and immunogenicity of BCG prime-CTT3H based boosters were compared in C57BL/c mice models of primary or late persistent TB infection. Similar protective efficacy against early intranasal infection was provided by different CTT3H-based vaccines alone in vaccinated mice, and their protection was inferior to that of the BCG vaccine. In addition, CTT3H-based heterologous boosters did not enhance the protection conferred by the BCG vaccine against primary infection. However, all of these three boosters provided stronger protection against late persistent TB infection than BCG alone, regardless of vaccine types. Although BCG prime-boosters elicited Th1-biased responses to the antigen CTT3H, the number of CTT3H-sepcific IFN-γ-expressing TEM (CD62LloCD44hi) and IL-2-expressing TCM (CD62LhiCD44hi) cells in the spleen was not improved before exposure to Mycobacterium tuberculosis infection. In contrast, IFN-γ+ TEM and IL-2+ TCM cells in spleens, especially in lungs were significantly increased in BCG prime-boosters after exposure vaccination. Our results indicate that BCG prime-boost strategy might be a promising measure for the prevention against late persistent TB infection by induction of IFN-γ+ TEM and IL-2+ TCM cells in the lung, which can be used as alternative biomarkers for guiding the clinical practice and future development of TB vaccine for adults.

show abstract

A Multistage Subunit Vaccine Effectively Protects Mice Against Primary Progressive Tuberculosis, Latency and Reactivation

Cited by 32 publications

References 39 publications

STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium tuberculosis Infection

STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium tuberculosis Infection

Heterologous Boosting With Listeria-Based Recombinant Strains in BCG-Primed Mice Improved Protection Against Pulmonary Mycobacterial Infection

Heterologous Boost Following Mycobacterium bovis BCG Reduces the Late Persistent, Rather Than the Early Stage of Intranasal Tuberculosis Challenge Infection

Contact Info

Product

Resources

About