recent advances in antitubercular vaccines
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RECENT ADVANCES IN ANTITUBERCULAR
VACCINES
DR. PRIYANKA KUMAWATPharmacology deptt.
PGIMS, Rohtak
INTRODUCTION
• Tuberculosis is caused by mycobacterium tuberculous bacilli.
• Currently >9 million new cases per annum and 2 million deaths throughout the world
• One third of the world (2 billion people) population are latently infected with Mycobacterium tuberculosis , and are at risk of reactivation of disease
• At least 1/3 of the people living with HIV are also infected with TB and have a greater risk of developing TB disease (5-10 % annually)
IMMUNITY
• Mycobacterium tuberculosis is able to persist inside the host cell by-inhibition of
- phagosome maturation
- autophagy
- apoptosis• CD4+ Th1 cells (IFN-γ, TNF-α) activate macrophage to kill
Mycobacterium• CD8+ T-cells, lyse and kill infected cell and Mycobacterium
BCG
• An attenuated strain of Mycobacterium bovis (M. bovis), is currently the only available vaccine against TB.
• Part of expanded immunization programme since 1974 covers >80% infants.
• When administered at birth,BCG confers consistent and reliable protection against disseminated disease, particularly TB meningitis, in the first 10 years of life.
• Efficacy is 50% for pulmonary TB while efficacy of 50-80% for prevention of miliary and meningeal form of the disease.
NEED FOR NEWER VACCINES
• New TB vaccines are urgently needed to achieve the goal of substantially reducing the incidence of TB by 2050
Drawbacks of BCG• BCG is the only available vaccine,not improved till date.• Poor/variable efficacy of BCG against adult pulmonary TB.• BCG is not known to protect against latent TB. • Disconcerting safety of BCG in immunocompromised individual. • NTM and helminth infection can also affect the immune response
induced by BCG (polarization towards Th2 response, T-cell exhaustion).
• According to the Global Plan to Stop TB (2006-2015), there is an urgent need for modern,safe & effective vaccine that prevent all forms of TB,in all age groups and people with HIV….
• Effective TB vaccines and vaccination strategies will make a crucial contribution to achiev the goal to reduce the global incidence of TB disease to less than one case per million population by 2050
STOP TB STRATEGY
ATTRIBUTES OF AN IDEAL TB VACCINE
Safety
Efficacy (in at risk)
Effectiveness (for all forms Of TB)
Logistically practical(timing & noninterference with immunization)
Formulation (manufacture,storage, administration)
Attributes
TYPES OF NEW VACCINES
• PROPHYLACTIC VACCINES
Given in healthy/apparently healthy person to prevent infection,primary disease,latent infection & reactivation
Two types-
-Pre exposure
-Post exposure
• THERAPEUTIC VACCINES
Vaccine given along with
Chemotherapy to shorten the duration and increase the response of it.
eg. RUTI
M.vaccae
NEW DEVELOPMENT IN VACCINES
• • Pre-exposure TB vaccines: Intended for use in newborns or young infants to replace or amplify BCG early in life and before exposure to TB, these vaccines and intended to prevent TB in people who have not been infected with M.tb. (MVA85A, Aeras 402. Aeras 404/ Hyvac 4, M72, rBCG30, VPM1002,Aeras rBCG
• • Post-exposure TB vaccines: Given post-infancy, typically to school children, adolescents or adults, who have either been vaccinated or latently infected with the TB bacteria or both, these vaccines reduce progression to active disease. (H56, ID93)
• • Therapeutic vaccines: These vaccines are given to individuals with active TB in conjunction with TB drug therapy with the aim of shortening the duration of the drug therapy. (RUTI, M.vaccae).
Prophylactic vaccines
BCG Replacing vaccines
By overexpressing live attenuatedImmunodominant M.tbChanges in BCGEg. Eg.MTBVAC01rBCG30(AERAS422)VPM1002rBCGΔure-cHly
BCG booster (subunit vaccine) Viral vectored using protein Pox virus adjuvant Adeno virus systemEg.MVA85A Eg.M72 AERAS402 HYBRID1 HyVac4
-
Subunit vaccines
• They enhance effectiveness of BCG by delivery of immunodominant mycobacterial Ag to immune system
• Heterologous prime-boost strategies, with BCG or rBCG as the prime-
✪ Viral vectored -MVA85A(vaccinia virus) ,
AERAS-402(Adenovirus) , AdAg85A
✪ fusion proteins of immunodominant antigens-
Hybrid-1(Ag 85B & ESAT-6,adjuvant IC-31, CAF01),
HyVac4(Ag 85B & TB10.4, adjuvant IC-31),
M72(Ag Rv1196 & Rv0125,adj AS01 or AS02)• NTM can not block the protective effect of subunit vaccine
MVA85A
Modified vaccinia Ankara (MVA) • Poxvirus • No replication in
mammalian tissues • Good T-cell boosting
vector • Excellent safety record
M.tb antigen 85A • Mycolyl transferase • Major target antigen • Protective in small
animals In all environmental mycobacteria
• Doesn’t interfere with new diagnostic tests
Safety data of MVA85A
Over 2000 subjects vaccinated, including
– 47 latently infected
– 108 HIV infected
– 24 children
– 1649 infants • 2 doses of MVA85A(108CFU), 6-9 months apart in phase IIb trial• Well tolerated
• Mild local reactions common (>90%) • Mild systemic side effects common • No signs of immunopathology • No effect on HIV RNA load • No effect on CD4 count
AERAS-402/Ad35
• Non replicating adenovirus(Ad)type 35 expressing a fusion protein of mycobacterial Ag 85A,85B & TB10.4.
• Adeno vectored vaccines consistently induce high levels of CD8+ T cell responses,CD4 cells & IFN-γ.
• Intranasal & intramuscular mode of delivery• Single dose of 1 ml containing 3 ×108 viral particles
(VP)given in trial• AERAS-402 Displayed an Acceptable Safety Profile in
Healthy Mtb-uninfected Adults
Protein-adjuvant vaccines
• Protein base-produce high levels of purity in bulk• Adjuvants used – - As Ag delivery system eg. Aluminium based compounds -Immunopotentiating agents eg. TLR ligands,saponins, cytokines and bacterial toxins in order to induce a potent and durable immune response.
M72
• Fusion of two proteins, Mtb32 and Mtb39(induce production of IFN-γ)
• Formulated in the adjuvant AS02A- oil-in-water emulsion and the immunostimulants 3-deacylated monophosphoryl lipid A (MPL) and QS-21, a detergent purified from the bark of Quillaja saponaria
• Well tolerated in a Phase I trial of healthy adult subjects and induced antigen-specific IFN-γ and IL-2 production and CD4+ T cells
• Phase IIa trials in TST-positive healthy adults in a TB-endemic area (South Africa) and of different formulations in the Philippines have also been completed
Hybrid 1
• Fusion protein of antigens 85B and ESAT-6• Ag85B,ESAT-6 adjuvanted with IC31® promotes strong and long-
lived Mycobacterium tuberculosis specific T cell responses in volunteers with previous BCG vaccination or tuberculosis infection. The T-cell responses were maintained for 2 years
• Hybrid 1 formulated with a novel liposomal adjuvant, cationic adjuvant formulation (CAF01), is now in an open-label Phase I clinical trial in The Netherlands
• Significant protective efficacy (>10, 000-fold versus BCG alone) against TB infection in the lungs of mice.
BCG replacing vaccines
• Approach to improve the current BCG vaccine-
✪ Recombinant (r)BCG strains-
AERAS-422(rBCG30),
VPM1002rBCGΔUreC:Hly
✪ Live mycobacterial vaccines-
MTBVAC01• Build upon the efficacy conferred by BCG against systemic
disease• Overexpress immunodominent Ag by modification to the
existing vaccine
AERAS-422
• Genetically modified BCG such that it overexpresses major secretory proteins, early targets for the host immune response against M.tb (antigen 85A,85B,Rv3407).
• Antigen 85B-specific T-cell proliferation and IFN-γ responses were enhanced and antigen specific CD4+ and CD8+ effector T-cell expansion was demonstrated
• In a Phase I RCT, rBCG30 was well tolerated and had a comparable safety profile to BCG.
• Dose tried in phase I -0.1ml intradermal containing105-106 CFU
VPM1002 rBCGΔUre-C:Hly
• Expresses listeriolysin (Hly) derived from Listeria monocytogenes and enables Bacteria to escape from the endosome.
• Made urease-C-deficient to provide the optimal pH for Hly activity .
• Phase IIa comparing the safety and immunogenicity of VPM1002 and BCG in neonates is ongoing
Advantages over BCG-• Enhance CD8+T-cell production • Superior mixed TH1/TH17 • Accelerate recruitment of antigen-specific
T cells to the lung compared to BCG• No negative effect on immune
compromised species (e.g.) SCID
Therapeutic vaccines in clinical trials
Mycobacterium vaccae: • Inactivated whole cell vaccine• Single dose given with standard chemotherapy was well
tolerated• IN HIV-infected patients 1 dose was not very effective,5 doses in
BCG-vaccinated, in Trial demonstrated significant protection against the secondary end point of definite (culture positive) TB.
RUTI: • Detoxified liposomal cellular fragments of M. tuberculosis bacilli.• Vaccination provide both prophylaxis & immunotherapy for TB, it
decreases the possibility of reactivation of TB.• Rationale of this therapy is first to take advantage of the bactericidal
properties of chemotherapy so as to avoid Koch phenomenon. After chemotherapy, RUTI can be inoculated to reduce the probability of regrowth of the remaining latent bacilli.
• Local accumulation of specific CD8 T cells and a strong humoral response are characteristic features of RUTI
• Phase I RCT in BCG-naive healthy person, RUTI proved to be safe & immunogenic.
• Vaccination-S.C 2 doses 3 wk apart,as iv
Type Vaccine Vaccine characteristics Phase of development
BCG replacing vaccine
AERAS 422(rBCG30) Recombinant BCG overexpressing antigen 85B Phase I
AERAS 403 Recombinant BCG with endosome escape Aeras Preclinical developmentand overexpressing antigen 85A, antigen Band TB10.4
Phase I
rBCGDUreC:Hly BCG with endosome escape Phase IIa
Protein adj. vaccine
Mtb72F/M72 Fusion protein of 2 antigens from M.tb (32 and 39kDa antigens); used withAS01/AS02 adjuvant
Phase IIa
Hybrid1 Fusion protein of antigen 85B and ESAT6 Phase I
HyVac4 Fusion protein of antigen 85B and TB10.4 Phase I
Viral vectored vaccine
Aeras 402 Recombinant adenovirus (AdHu35) expressingantigen 85A, antigen 85B and TB10.4
Phase IIb
MVA85A Recombinant MVA expressing antigen 85A Phase IIb
Therapeutic vaccine
RUTI Detoxified Mycobacterium tuberculosis in liposomes
Phase IIa
M. vaccae Inactivated M. vaccae Phase III
Future Strategies
Newer routes of vaccination
• Intranasal-i.n. delivery of live or killed BCG vaccine protein subunit vaccines,lipoglycan-protein conjugate vaccine,plasmid DNA ,messenger RNA recombinant bacterial vector or viral vector vaccines expressing M. tuberculosis proteins induce a stronger immune response or imparts improved protection against M. tuberculosis challenge than subcutaneous (s.c.) or other parenteral routes of vaccination
• Oral-Oral delivery of BCG, gives equivalent protection against tuberculosis but with reduced pathology compared to parenteral BCG Danish vaccination
• Inhalation-by air-jet nebulizers(sheer force generated by the nebulizer
may decrease vaccine potency)eg:BCG,all the discussed vacines
before.• Aerosole- many vaccines among all discussed are given via this
route eg:MVA85A
TRANSGENIC ORAL VACCINE
• Transgenic plants are noval way to produce and deliver oral vaccines.
• The plant made Antigen ESAT-6 fused to the B subunit of E-coli(LTB)induce antigenic specific response from CD4 cells and increased IFN-g production indicating a Th-1 response
• This is the first report of an orally delivered subunit,TB vaccine priming an Ag-specific,Th1 response.
B-cell as target vaccine
• Target M.tb to macrophage for destruction• Exert cheamotactic function and attract additional immune cells like
neutrophills,monocytes,NK-cells.• Targeting M.tb to fc receptor,antibodies might promote activation & Ag
processing/presentation by dendritic cells & promote microbial activity.
CHALLENGES IN DEVELOPMENT OF TB VACCINES
• Lack of proper & reliable animal models• Lack of surrogate markers to assess vaccine efficacy• Lack of additional funding for clinical trials• Lack of sufficient clinical trial sites• Mycobacterium evokes cellular immune response but
majority vaccine against disease which evokes
humoral immune response.
CONCLUSION
• Good steady progress has been made with TB vaccine development with certain candidates having reached the phase IIb and III stage.
• Hope that new vaccines can contribute to the ambitious goal of reducing the yearly incidence of TB by 2050.
• TB vaccine is predicted to result in considerable cost savings, as well as a reduction in TB morbidity and TB-related mortality, when added to existing control strategies
• RUTI could represent a viable option to reduce the time required to treat M tuberculosis infection to a minimum that is both effective and practical
• For a vaccine with waning efficacy, a prime-boost strategy is more cost-effective in the long term.
References
• PLoS Pathog. 2012;8(5):e1002607. doi: 10.1371/journal.ppat.1002607. Epub 2012 May 10. Review
• Philos Trans R Soc Lond B Biol Sci. 2011 October 12; 366(1579): 2782–2789.doi: 10.1098/rstb.2011.0097
• YALE JOURNAL OF BiOLOGY AND MEDiCiNE 83 (2010), pp.209-215.Copyright © 2010.
• SWISS Med Wkly 2009;139(11–12):156–160·www.smw.ch• PLoS ONE 6(5): e20404. doi:10.1371/journal.pone.0020404• Arch Bronconeumol. 2006;42(1):25-32• Am J Respir Crit Care Med Vol 181. pp 1407–1417, 2010• Lancet 2010; 375: 2110–19
THANK YOU
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