Leal Rodríguez, Cristina

Universitat Autònoma de Barcelona. Facultat de Biociències

Diposit Digital de Documents de la UAB

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Table 2. Strengths and limitations comparison between the described vaccines and the old BCG [6, 7].Comparative vaccine pipeline against Tuberculosis:  VPM1002, H1/IC31®, H56/IC31® and RUTI®Cristina Leal Rodríguez · Marina Luquin Microbiology Degree, Bioscience faculty, Universitat Autònoma de BarcelonaTuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb) that ranks as the second leading cause of death from an infectious disease worldwide. Efforts to develop new diagnostics, drugs and vaccines have intensified during the past decade. A bibliographic analysis of the current status in research and development aiming to briefly describe, evaluate and compare four novel vaccine candidates is attempted in this review.Analysis of four of the state-of-the-art candidate vaccines Stop TB Partnership targets [1, 5]:!• By 2015: Reduce prevalence and death rates by 50%!• By 2050: Reduce the global incidence of active TB cases to <1 case per 1M population per year (=eradication)!Development of new diagnostics, drugs and vaccines are urgently needed as well as better biomarker correlates of immunity.!!!!!!!!!!!!!!!!!!!!!!!!!Table 1. Comparative evaluation of VPM1002, H1, H56, and RUTI® as candidate vaccines in current clinical development [6, 7].!!!!!!!!!!!!!!!!!!!!!!!!!!!DiscussionBoosting vaccines seek to extend prime protection by subsequent boosting vaccination(s).Immunotherapeutic vaccines aspire to shorten treatment by synergizing with chemotherapy if there is active TB or LTBI.Future vaccines are based in 3 different approaches: (1)Prime, (2)Boost, and (3)Immunotherapy.Priming vaccines aim to replace the actual BCG, by either attenuation or by complementing it with new Ags.Ideal vaccineReferences:![1] WHO, “Global Tuberculosis Report 2013”, 2013.![2] B. Beresford and J.C. Sadoff, “Update on research and development pipeline: tuberculosis vaccines.,” Clin. Infect Dis., vol. 50 Suppl. 3, no. Suppl.. 3, pp. S178-S183, May 2010.![3] C. a Thaiss and S. H. E. Kaufmann, “Toward novel vaccines against tuberculosis: current hopes and obstacles.,” Yale J. Biol. Med., vol. 83, no. 4, pp. 209–15, Dec. 2010.![4] A. Zumla, M. Raviglione, R. Hafner, and C. F. von Reyn, “Tuberculosis.,” N. Engl. J. Med., vol. 368, no. 8, pp. 745–55, Feb. 2013.![5] T. H. M. Ottenhoff and S. H. E. Kaufmann, “Vaccines against tuberculosis: Where are we and where do we need to go?,” PLoS Pathog., vol. 8, no. 5, p. e1002607, Jan. 2012.![6] S. H. E. Kaufmann, G. Hussey, and P.-H. Lambert, “New vaccines for tuberculosis.,” Lancet, vol. 375, no. 9731, pp. 2110–9, Jun. 2010.![7] D. Marinova, J. Gonzalo-Asensio, N. Aguilo, and C. Martin, “Recent developments in tuberculosis vaccines.,” Expert Rev. Vaccines, vol. 12, no. 12, pp. 1431–48, Dec. 2013.Mul$func$onal!(pre&!and!post&exposure)!Polyantigenic!•  Early-secreted Ags!•  Latency Ags!Immune response!•  Long-lasting!•  Humoral!•  Cellular!Safe!•  Infants!•  Adults!•  HIV+!•  LTBI!Product name Strengths LimitationsBCGProtection against miliary !TB and meningeal TB;!Cheaply producedNot effective against pulmonary TB and!most forms of extrapulmonary TB;!Durability protection unclear;!Cannot be boosted with !repeated vaccination;!Contraindicated for use in!immunocompromised individuals;!Can cause BCGitis (local infection)!and BCGosis (systemic disease)VPM1002Superior protection than !BCG (even against high !virulence isolates);!Induction of CD8+ T cell !response;!Activation of Th17 cells !subset;!Humoral responseHly inclusion toxin gene may!cause additional regulatory scrutiny!for safety;!Hygromycin resistance marker !included in the constructH1/IC31Superior protection !than BCG;!Long lasting CD4+ !Th1 response (>2.5 years)No humoral response triggered;!Local vaccine-related reactions !in high dose adjuvanted vaccine;!Presumptive interference with!QuantiFERONH56/IC31Superior protection than !BCG and H1;!Improved prevention of reactivation !and improved long-term !containment of LTBI;!Strong multifunctional CD4+ !T cell response;!Effective vaccination !also after exposureNo detectable CD8+ T cells response;!No humoral response triggeredRUTIInduction of CD8+ T cell !response;!Humoral response;!Could also be used as a booster !and soon after recent infectionsDoes not decrease bacterial load directly;!As potent as BCG;!Dose dependent local adverse !reactions (mild)Name Type Route of!administration Strategy Immune response triggered Target population Safety profile Development stage SponsorsVPM1002Live recombinant!BCG (rBCG) !with an!endosome escape!mechanism !through!lysteriolysin !expression and urease !C deletionIntradermal injectionPrime!(Pre-exposure);!BCG replacementStimulation of antigen-specific!CD4 and improved CD8 T !cell responses;!Th17 cells activation;!Humoral response induction;!Polyantigenic__No safety concerns;!safe and well!tolerated (Absence of!severe adverse effects)Phase I completed;!ongoing Phase IIaVakzine Projekt!Management!(VPM),!Tuberculosis!Vaccine Initative!(TBVI),!Max Planck!Institute,!Statens Serum!Institute (SSI)!H1/ IC31Protein-adjuvant!fusion of!Ag85B-ESAT-6 in!IC31Intramuscular!injection (deltoid!muscle / arm)Prime-boost!(Pre-exposure)!Stimulation of strong and!long-lasting  Th1 cellular!response;!Pauciantigenic;!No humoral response!stimulationAdolescents;!adultsNo safety concerns;!local adverse events in!high dose adjuvanted!vaccinePhase I completed;!ongoing Phase IIaStatens Serum!Institute (SSI),!Tuberculosis!Vaccine Initiative!(TBVI),!European and!Developing Countries!Clinical Trial!Partnership (EDCTP),!IntercellH56/ IC31Protein-adjuvant fusion!of!Ag85B-ESAT-6-Rv2660c!in IC31Intramuscular!injectionPrime-boost;!Immunotherapy!(pre- and post-exposure)!Stimulation of strong!multifunctional CD4 T cell!responses;!Limitation of reactivation of!LTBI;!PauciantigenicAdolescents;!adults __Phase I completed;!ongoing Phase I/IIa!Statens Serum!Institute (SSI),!Aeras,!Intercell!RUTINon-live detoxified!M. tuberculosis in!liposomesSubcutaneousImmunotherapy*;!Boost (post- and!pre-exposure)!!*Adjunct to LTBI!INH prophylaxis!Mixed Th1, Th2, Th3!response towards latency!antigens;!Humoral response induction;!Polyantigenic!HIV+;!adults;!LTBI diagnosedNo hypersensitivity!observedPhase I completed;!ongoing Phase IIa Archivel Farma, S.L.Figure 1. Global estimated TB incidence rates, 2012. Source taken from Stop TB Partnership[1].!• 1/3 of the world’s population are infected.!• Leading killer of people with HIV.!• Treatment:!• Too long!• Ineffective against resistant strains (MDR, XDR, TDR)!• Difficult early diagnosis.!• Inconsistence efficacy of the only vaccine available, BCG (see discussion) [1, 2, 3, 4].Where are we? In 2012:!8.6M new cases!1.3M deathsWhere do we need to go?

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Comparative vaccine pipeline against tuberculosis : VPM1002, H1/IC31© , H56/IC31© and RUTI©

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