- Intravesical Ty21a Vaccine Promotes Dendritic Cells and T Cell-Mediated Tumor Regression in the MB49 Bladder Cancer Model. [Journal Article]
- CICancer Immunol Res 2019; 7(4):621-629
- Preclinical data show that intravesical instillation of Ty21a/Vivotif, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus Calmette-Guérin (BCG) immuno…
Preclinical data show that intravesical instillation of Ty21a/Vivotif, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus Calmette-Guérin (BCG) immunotherapy for non-muscle-invasive bladder cancer (NMIBC). Here, we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor regression toward the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor-bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 106 to 108 colony-forming units. By IHC and morphology, both BCG and Ty21a instillations were associated with bladder inflammation, which was decreased with the use of low, but effective doses of Ty21a. Flow-cytometry analysis showed a significant infiltration of T cells, natural killer (NK) cells, and myeloid cells, compared with controls, after a single dose of Ty21a, whereas this was only observed after multiple doses of BCG. The induced myeloid cells were predominantly neutrophils and Ly6C+CD103+ dendritic cells (DC), the latter being significantly more numerous after instillation of Ty21a than BCG. Ex vivo infection of human leukocytes with Ty21a, but not BCG, similarly significantly increased DC frequency. CD4+ and CD8+ T cells, but not NK cells nor neutrophils, were required for effective bladder tumor regression upon Ty21a treatment. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms behind intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients.
- Expanded table: Some vaccines for travelers. [Review]
- MLMed Lett Drugs Ther 2018 Nov 19; 60(1560):e192-e194
- Vaccines for travelers. [Review]
- MLMed Lett Drugs Ther 2018 Nov 19; 60(1560):185-192
- Retinoic acid elicits a coordinated expression of gut homing markers on T lymphocytes of Zambian men receiving oral Vivotif, but not Rotarix, Dukoral or OPVERO vaccines. [Journal Article]
- VVaccine 2018 06 27; 36(28):4134-4141
- All-trans retinoic acid (ATRA) up-regulates, in laboratory animals, the expression of the gut homing markers α4β7 integrin and CCR9 on lymphocytes, increasing their gut tropism. Here, we show that, i…
All-trans retinoic acid (ATRA) up-regulates, in laboratory animals, the expression of the gut homing markers α4β7 integrin and CCR9 on lymphocytes, increasing their gut tropism. Here, we show that, in healthy adult volunteers, ATRA induced an increase of these gut homing markers on T cells in vivo in a time dependent manner. The coordinated increase of α4β7 and CCR9 by ATRA was seen in 57% (12/21) of volunteers and only when given together with an oral Vivotif vaccine. When this coordinated response to ATRA and Vivotif vaccine was present, it was strongly correlated with the gut immunoglobulin A (IgA) specific response to vaccine LPS (ρ = 0.82; P = 0.02). Using RNA-Seq analysis of whole blood transcription, patients receiving ATRA and Vivotif in conjunction showed transcriptomic changes in immune-related pathways, particularly including interferon α/β signaling pathway, membrane-ECM interactions and immune hubs. These results suggest that exogenous ATRA can be used to manipulate responses to a subclass of oral vaccines, so far limited to a live attenuated Vivotif vaccine.
- Overview of the impact of Typhoid and Paratyphoid fever. Utility of Ty21a vaccine (Vivotif®). [Review]
- JPJ Prev Med Hyg 2017; 58(1):E1-E8
- Cases of diarrhoeal disease number from 1.7 to 5 billion per year worldwide. One of the main causes of diarrhoeal disease is typhoid fever, which is a potentially life-threatening multi-systemic illn…
Cases of diarrhoeal disease number from 1.7 to 5 billion per year worldwide. One of the main causes of diarrhoeal disease is typhoid fever, which is a potentially life-threatening multi-systemic illness. According to the most recent estimates, a total of 26.9 million typhoid fever episodes occurred in 2010. The geographical distribution of the disease differs widely; in developed countries, the incidence rate per 100,000 per year varies from < 0.1 to 0.3, and the disease mainly affects people who travel to endemic areas located in low- and middle-income countries. Low- and middle-income countries are mainly affected owing to the lack of clean water and proper sanitation. In the fight against this plague, prevention is fundamental, and vaccination against typhoid is an effective measure. Vivotif® is an oral live attenuated vaccine which contains a mutated strain of Salmonella (Ty21a) and reproduces the natural infection. The vaccine was first licensed in Europe in 1983 and in the US in 1989, and over the years it has proved efficacious and safe. It is indicated for adults and children from 5 years of age upwards. Specifically, in the most developed countries, vaccination is suggested for highrisk population groups and particularly for international travellers to destinations where the risk of contracting typhoid fever is high. It must also be borne in mind that international travel is increasing. Indeed, international tourist arrivals totalled 1,184 million in 2015 and, on the basis of current trends, international travel is expected to grow by 3-4% in 2017. Vivotif® appears to be a powerful means of disease prevention, the importance of which is highlighted by the spread of antibiotic-resistant strains of Salmonella typhy (S. typhi).
- A case report of anaphylaxis to Typhoid Vaccine Live Oral Ty21a (Vivotif). [Case Reports]
- JTJ Travel Med 2017 Sep 01; 24(5)
- Typhoid Vaccine Live Oral Ty21a (Vivotif) is typically well tolerated, and adverse events are infrequent and mild. To the best of the authors' knowledge, only one prior anaphylactic reaction has prev…
Typhoid Vaccine Live Oral Ty21a (Vivotif) is typically well tolerated, and adverse events are infrequent and mild. To the best of the authors' knowledge, only one prior anaphylactic reaction has previously been reported. We present a case of anaphylaxis related to Vivotif, in which a 66-year-old male with no medical comorbidities developed anaphylaxis following the third of a four-dose course (in the absence of concomitant vaccination administration), which consisted of tongue swelling, difficulty breathing, abdominal discomfort and rash. He was managed with epinephrine, corticosteroids and antihistamines.
- Vaccination of active component US military personnel against Salmonella Typhi. [Journal Article]
- VVaccine 2017 03 27; 35(14):1742-1748
- Vaccination against Salmonella Typhi is one of the leading public health interventions reducing the risk of typhoid fever. There are two available licensed vaccines, Vivotif, oral live-attenuated, an…
Vaccination against Salmonella Typhi is one of the leading public health interventions reducing the risk of typhoid fever. There are two available licensed vaccines, Vivotif, oral live-attenuated, and Typhim Vi, intramuscular Vi capsular polysaccharide. The US military is a high risk travel population commonly vaccinated for S. Typhi. We describe the use of S. Typhi vaccination in this population and the acute reactogenicity profile of these vaccines.
- Preclinical efficacy and safety of the Ty21a vaccine strain for intravesical immunotherapy of non-muscle-invasive bladder cancer. [Journal Article]
- OOncoimmunology 2017; 6(1):e1265720
- Intravesical Bacillus-Calmette-Guérin (BCG) immunotherapy can reduce recurrence/progression of non-muscle-invasive bladder cancer (NMIBC), although significant adverse events and treatment failure ar…
Intravesical Bacillus-Calmette-Guérin (BCG) immunotherapy can reduce recurrence/progression of non-muscle-invasive bladder cancer (NMIBC), although significant adverse events and treatment failure argue for alternative options. Here, we examined whether another attenuated live vaccine, Vivotif/Ty21a, used since more than 30 y against typhoid fever, may be safely used intravesically to improve bladder-tumor treatment. Mice-bearing MB49 orthotopic bladder-tumors treated with intravesical Ty21a or BCG were compared for survival and bacteria recovery. Both Ty21a and BCG enhanced mice survival when treating just after tumor implantation for 4 weeks (p = 0.008 and 0.04, respectively), but only Ty21a was effective when treating once mice with larger already established bladder-tumors (p = 0.0003). In contrast to BCG, no Ty21a bacteria survived in mouse bladder, human urothelial cell-lines or human peripheral blood mononuclear cells. However, Ty21a was as potent as BCG to induce tumor-cell death in vitro. In a human, 3D-bladder-tissue ex-vivo assay, Ty21a bacteria, still not surviving, induced a panel of cytokines associated with effective BCG-treatment in patient's urine. Overall, our pre-clinical data demonstrate that intravesical Ty21a is more effective than BCG for bladder-tumor treatment. Absence of surviving Ty21a bacteria and the excellent safety-record of the typhoid vaccine support its testing in NMIBC patients.
- Evaluating and optimizing oral formulations of live bacterial vaccines using a gastro-small intestine model. [Journal Article]
- EJEur J Pharm Biopharm 2016; 102:115-22
- Gastrointestinal (GI) models that mimic physiological conditions in vitro are important tools for developing and optimizing biopharmaceutical formulations. Oral administration of live attenuated bact…
Gastrointestinal (GI) models that mimic physiological conditions in vitro are important tools for developing and optimizing biopharmaceutical formulations. Oral administration of live attenuated bacterial vaccines (LBV) can safely and effectively promote mucosal immunity but new formulations are required that provide controlled release of optimal numbers of viable bacterial cells, which must survive gastrointestinal transit overcoming various antimicrobial barriers. Here, we use a gastro-small intestine gut model of human GI conditions to study the survival and release kinetics of two oral LBV formulations: the licensed typhoid fever vaccine Vivotif comprising enteric coated capsules; and an experimental formulation of the model vaccine Salmonella Typhimurium SL3261 dried directly onto cast enteric polymer films and laminated to form a polymer film laminate (PFL). Neither formulation released significant numbers of viable cells when tested in the complete gastro-small intestine model. The poor performance in delivering viable cells could be attributed to a combination of acid and bile toxicity plus incomplete release of cells for Vivotif capsules, and to bile toxicity alone for PFL. To achieve effective protection from intestinal bile in addition to effective acid resistance, bile adsorbent resins were incorporated into the PFL to produce a new formulation, termed BR-PFL. Efficient and complete release of 4.4×10(7) live cells per dose was achieved from BR-PFL at distal intestinal pH, with release kinetics controlled by the composition of the enteric polymer film, and no loss in viability observed in any stage of the GI model. Use of this in vitro GI model thereby allowed rational design of an oral LBV formulation to maximize viable cell release.
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- Review: UK medicines likely to be affected by the proposed European Medicines Agency's guidelines on phthalates. [Review]
- BPBMC Pharmacol Toxicol 2015 Jun 13; 16:17
- CONCLUSIONS: These findings indicate that very few UK licensed medicines will be affected by the proposed EMA guidelines. For those medicines identified as exceeding recommendations, these findings highlight the need to instigate a risk-benefit review.