The Novel Tuberculosis Vaccine, AERAS-402, Induces Robust and Polyfunctional CD4+and CD8+T Cells in Adults
Bernd AbelMichèle TamerisNazma MansoorSebastian GelderbloemJane HughesDeborah AbrahamsLebohang MakhetheMzwandile ErasmusMarwou de KockLinda van der MerweAnthony HawkridgeAshley VeldsmanMark HatherillGiulia SchirruMaria Grazia PauJenny HendriksGerrit Jan WeverlingJaap GoudsmitDonata SizemoreJ. Bruce McClainMargaret Ann GoetzJacqueline GearhartHassan MahomedGregory HusseyJerald SadoffWillem A. Hanekom
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AERAS-402 is a novel tuberculosis vaccine designed to boost immunity primed by bacillus Calmette-Guérin (BCG), the only licensed vaccine.We investigated the safety and immunogenicity of AERAS-402 in healthy Mycobacterium tuberculosis-uninfected BCG-vaccinated adults from a tuberculosis-endemic region of South Africa.Escalating doses of AERAS-402 vaccine were administered intramuscularly to each of three groups of healthy South African BCG-vaccinated adults, and a fourth group received two injections of the maximal dose. Participants were monitored for 6 months, with all adverse effects documented. Vaccine-induced CD4(+) and CD8(+) T-cell immunity was characterized by an intracellular cytokine staining assay of whole blood and peripheral blood mononuclear cells.AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine induced a robust CD4(+) T-cell response dominated by cells coexpressing IFN-gamma, tumor necrosis factor-alpha, and IL-2 ("polyfunctional" cells). AERAS-402 also induced a potent CD8(+) T-cell response, characterized by cells expressing IFN-gamma and/or tumor necrosis factor-alpha, which persisted for the duration of the study.Vaccination with AERAS-402 is safe and immunogenic in healthy adults. The immunity induced by the vaccine appears promising: polyfunctional T cells are thought to be important for protection against intracellular pathogens such as Mycobacterium tuberculosis, and evidence is accumulating that CD8(+) T cells are also important. AERAS-402 induced a robust and durable CD8(+) T-cell response, which appears extremely promising. Clinical trial registered with www.sanctr.gov.za (NHREC no. 1381).Keywords:
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The emergence of drug-resistant Mycobacterium tuberculosis strains and the widespread occurrence of AIDS demand newer and more efficient control of tuberculosis. The protective efficacy of the current Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine is highly variable. Therefore, development of an effective new vaccine has gained momentum in recent years. Recently, several M. tuberculosis mutants were tested as potential vaccine candidates in the mouse model of tuberculosis. However, only some of these mutants were able to generate protection equivalent to that of BCG in mice. This study reports the vaccine potential of an attenuated 5'-adenosine phosphosulfate reductase mutant (DeltacysH) of M. tuberculosis. Immunization of mice with either BCG or DeltacysH followed by infection with the virulent M. tuberculosis Erdman strain demonstrated that DeltacysH can generate protection equivalent to that of the BCG vaccine.
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BCG strains differ in their ability to elicit immune reactions in mice manifesting as increases in foot pad thickness following challenges with BCG ultrasonicate antigen at different times after vaccination. When we know more about the relevance to protection of these three reactions, such timed skin testing may prove of value for determining the efficacy of BCG in man.
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Abstract Mycobacterium tuberculosis (M. tuberculosis) HN878 causes death and extensive lung pathology in infected C57BL/6 mice. A clinically relevant isolate of M. tuberculosis increases the possibilities of assessing the efficacy of experimental TB vaccines against human TB strains in a relatively inexpensive and immunologically intact small animal model. This model will also allow for the measurement of survival in mice and hence the determination of long-lived effects of M. tuberculosis vaccines. In this study, we show that the ID93/GLA-SE tuberculosis vaccine candidate elicits protection against M. tuberculosis HN878 by reducing the bacterial burden in the lung and spleen, and prevents the extensive lung pathology that is induced by M. tuberculosis HN878 in C57BL/6 mice. Future studies utilizing this model will allow the use of specific knock-out mice on the C57BL/6 mouse background to critically examine key immunological factors that are responsible for long-lived, vaccine-induced immunity and prevention of pulmonary immunopathology induced by a virulent clinical isolate of M. tuberculosis.
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Purpose: To evaluate Myt272 protein antigenicity and immunogenicity by trial vaccination in mice and its in silico analysis as a potential peptide vaccine for tuberculosis.Methods: Myt272 gene, which has 100 % identity with Mycobacterium tuberculosis H37Rv unknown function gene Rv3424c, was ligated by genomic shotgun approach into the expression vector pQE32, and transformed into Escherichia coli SG13009. Expression during cell growth was induced by isopropyl-â-D-thiogalactopyranoside. The recombinant protein was isolated from the harvested cell lysate and injected in mice for immunogenicity experiment up to 42 days. ELISA tests with anti-Hisantibodies were performed on the collected individual blood samples’ sera. Color development in a microplate reader was measured at 450 nm.Results: The protein was predicted to have a mass of approximately 13 kDa and was present in the soluble fraction of the cell lysate. The immunogenicity test on Myt272 protein revealed very statistically significant high levels of antibodies detected by ELISA in the sera of immunized group of mice compared to negative controls.Conclusion: A 10.1 kD unnamed function (IDALA) protein from Rv3424 gene could be the potential peptide vaccine for tuberculosis tested by mice immunogenicity experiment.Keywords: Tuberculosis H37Rv, Myt272 clone, IDALA, Immunogenicity tests, In silico study.
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