Immunization With a Bivalent Adenovirus-vectored Tuberculosis Vaccine Provides Markedly Improved Protection Over Its Monovalent Counterpart Against Pulmonary Tuberculosis

Mu, Jingyu; Jeyanathan, Mangalakumari; Small, Cherrie-Lee; Zhang, Xizhong; Roediger, Elizabeth; Feng, Xueya; Chong, Duncan; Gauldie, Jack; Xing, Zhou

doi:10.1038/mt.2009.60

Cited by 34 publications

(18 citation statements)

References 34 publications

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“…As this antigen is expressed by BCG, M. tuberculosis and M. bovis, it may therefore represent an ideal candidate as a boost vaccine following BCG immunisation. Indeed, studies have reported the efficacy of multivalent adenoviral vaccines incorporating TB10.4 against both M. tuberculosis [16][17][18][19] [20]. Although murine studies predominantly demonstrate intranasal/respiratory delivery to be optimal, given the One Health approach of our research, and that respiratory vaccination remains a technical challenge in bovines, we wished to evaluate the potential of Ad expressing TB10.4 as an injectable BCG boost in a murine model of immunity against M. bovis.…”

Section: Introductionmentioning

confidence: 97%

Parenteral adenoviral boost enhances BCG induced protection, but not long term survival in a murine model of bovine TB

Kaveh¹,

García-Pelayo²,

Webb³

et al. 2016

Vaccine

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Boosting BCG using heterologous prime-boost represents a promising strategy for improved tuberculosis (TB) vaccines, and adenovirus (Ad) delivery is established as an efficacious boosting vehicle. Although studies demonstrate that intranasal administration of Ad boost to BCG offers optimal protection, this is not currently possible in cattle. Using Ad vaccine expressing the mycobacterial antigen TB10.4 (BCG/Ad-TB10.4), we demonstrate, parenteral boost of BCG immunised mice to induce specific CD8(+) IFN-γ producing T cells via synergistic priming of new epitopes. This induces significant improvement in pulmonary protection against Mycobacterium bovis over that provided by BCG when assessed in a standard 4week challenge model. However, in a stringent, year-long survival study, BCG/Ad-TB10.4 did not improve outcome over BCG, which we suggest may be due to the lack of additional memory cells (IL-2(+)) induced by boosting. These data indicate BCG-prime/parenteral-Ad-TB10.4-boost to be a promising candidate, but also highlight the need for further understanding of the mechanisms of T cell priming and associated memory using Ad delivery systems. That we were able to generate significant improvement in pulmonary protection above BCG with parenteral, rather than mucosal administration of boost vaccine is critical; suggesting that the generation of effective mucosal immunity is possible, without the risks and challenges of mucosal administration, but that further work to specifically enhance sustained protective immunity is required.

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Section: Introductionmentioning

confidence: 97%

Parenteral adenoviral boost enhances BCG induced protection, but not long term survival in a murine model of bovine TB

Kaveh¹,

García-Pelayo²,

Webb³

et al. 2016

Vaccine

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“…Recombinant adenovirus vectors elicit potent humoral and cellular immunity, mediated by CD8 + T cells in particular, against their transgene products. Adenovirus vectors are considered as candidate vaccine vectors against diverse pathogens, including HIV [Buchbinder et al, 2008], rabies virus [Xiang et al, 2002], Plasmodium falciparum [Shott et al, 2008], Trypanosoma cruzi [de Alencar et al, 2009], and Mycobacterium tuberculosis [Mu et al, 2009].…”

Section: Introductionmentioning

confidence: 99%

Seroprevalence of neutralizing antibodies to human adenoviruses type‐5 and type‐26 and chimpanzee adenovirus type‐68 in healthy Chinese adults

Zhang

Huang

Zhou

et al. 2013

Journal of Medical Virology

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Replication-defective adenoviruses have been utilized as candidate vaccine vectors. However, clinical application of the best-studied human adenovirus type-5 (AdHu5) is limited by the high prevalence of preexisting neutralizing antibodies resulting from natural infection. Therefore, rare adenovirus serotypes, such as human adenovirus type-26 (AdHu26) and chimpanzee adenovirus type-68 (AdC68), have been employed as substitutes for AdHu5. However, few studies have described the epidemiology of pre-existing immunity to these adenoviruses in China. Thus, 1,154 participants from six regions in China were examined to assess the presence of neutralizing antibodies against AdHu5, AdHu26, and AdC68. The seroprevalence rates of neutralizing antibodies were as follows: AdHu5, 73.1% (844/1,154) (95% confidence interval: 70.5-75.6%); AdHu26, 35.3% (407/1,154) (95% confidence interval: 32.6-38.1%); and AdC68, 12.7% (147/1,154) (95% confidence interval: 10.9-14.8%), respectively. The most frequently detected and highest titer antibodies were specific for AdHu5. The results indicate that AdHu26 and AdC68 serve as more suitable vaccine vectors than AdHu5.

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“…tuberculosis Ag85A or the fusion between Ag85A and TB10.4. Following vaccination and subsequent challenge with H37Rv, bacterial burden in the lungs of the antigen fusion strain was significantly reduced compared to the monovalent adenovirus-Ag85A and about 10 fold reduced compared to BCG alone [52]. Similarly, purified recombinant M .…”

Section: Discussionmentioning

confidence: 99%

Overexpression of a Mycobacterium ulcerans Ag85B-EsxH Fusion Protein in Recombinant BCG Improves Experimental Buruli Ulcer Vaccine Efficacy

Hart

Lee

2016

PLoS Negl Trop Dis

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Buruli ulcer (BU) vaccine design faces similar challenges to those observed during development of prophylactic tuberculosis treatments. Multiple BU vaccine candidates, based upon Mycobacterium bovis BCG, altered Mycobacterium ulcerans (MU) cells, recombinant MU DNA, or MU protein prime-boosts, have shown promise by conferring transient protection to mice against the pathology of MU challenge. Recently, we have shown that a recombinant BCG vaccine expressing MU-Ag85A (BCG MU-Ag85A) displayed the highest level of protection to date, by significantly extending the survival time of MU challenged mice compared to BCG vaccination alone. Here we describe the generation, immunogenicity testing, and evaluation of protection conferred by a recombinant BCG strain which overexpresses a fusion of two alternative MU antigens, Ag85B and the MU ortholog of tuberculosis TB10.4, EsxH. Vaccination with BCG MU-Ag85B-EsxH induces proliferation of Ag85 specific CD4+ T cells in greater numbers than BCG or BCG MU-Ag85A and produces IFNγ+ splenocytes responsive to whole MU and recombinant antigens. In addition, anti-Ag85A and Ag85B IgG humoral responses are significantly enhanced after administration of the fusion vaccine compared to BCG or BCG MU-Ag85A. Finally, mice challenged with MU following a single subcutaneous vaccination with BCG MU-Ag85B-EsxH display significantly less bacterial burden at 6 and 12 weeks post-infection, reduced histopathological tissue damage, and significantly longer survival times compared to vaccination with either BCG or BCG MU-Ag85A. These results further support the potential of BCG as a foundation for BU vaccine design, whereby discovery and recombinant expression of novel immunogenic antigens could lead to greater anti-MU efficacy using this highly safe and ubiquitous vaccine.

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Immunization With a Bivalent Adenovirus-vectored Tuberculosis Vaccine Provides Markedly Improved Protection Over Its Monovalent Counterpart Against Pulmonary Tuberculosis

Cited by 34 publications

References 34 publications

Parenteral adenoviral boost enhances BCG induced protection, but not long term survival in a murine model of bovine TB

Parenteral adenoviral boost enhances BCG induced protection, but not long term survival in a murine model of bovine TB

Seroprevalence of neutralizing antibodies to human adenoviruses type‐5 and type‐26 and chimpanzee adenovirus type‐68 in healthy Chinese adults

Overexpression of a Mycobacterium ulcerans Ag85B-EsxH Fusion Protein in Recombinant BCG Improves Experimental Buruli Ulcer Vaccine Efficacy

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