Update on Tuberculosis Vaccines_Prof. R. Dixit_19th Feb 2016 - Copy


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Update on Tuberculosis Vaccines


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Update On Tuberculosis Vaccines :

Update On Tuberculosis Vaccines Prof. R. K. Dixit Pharmacology and Therapeutics King George’s Medical University Lucknow, Uttar Pradesh dixitkumarrakesh@gmail.com


Objectives A brief revision of some basic facts about tuberculosis (Epidemiological, Pathological, Preventive and Treatment) Limitations of presently available treatment (MDR and XDR) Need for Vaccine against tuberculosis BCG the great……….. Efficacy, Contribution towards tuberculosis control and Limitations Of BCG Newer vaccines against tuberculosis Brief description of newer vaccines Ground reality regarding newer vaccines Waiting for the Black Swan in Tuberculosis Vaccine Development ? Summary and take home messages

Tuberculosis – Facts...:

Tuberculosis – Facts... TB, AIDS and Malaria are the “ BIG THREE” killer infectious diseases. Mycobacterium tuberculosis is the world’s most successful pathogen. Worldwide in distribution Leading cause for mortality and morbidity- (7 th leading cause of death) 1/3 of the world's population is likely to receive infection 1.45 million people die every year due to TB- (3800 deaths per day) 8.8 million new cases of TB in one year Global incidence rate of 128/100 000 (worse in African and Asian Countries including India) WHO declared TB a GLOBAL EMERGENCY IN 1993, but cases still increasing Most cases in Asia (59%) and Africa (26%) > 80% can be cured Prevention can be effective One-third of TB cases missed Global tuberculosis control: WHO report 2013

Tuberculosis Facts Contd…:

No new drugs to the first-line regimen for TB for >30 yrs. Two new drugs BEDAQUILINE and DELAMANID approved for the treatment of MDRTb . Waiting still for Indian entry. Both dugs induce arrhythmia, and are recommended only in patients whom other failed Treatment for drug-resistant TB is much longer, complex and more expensive - with much lower success rates The neediest population do not have access to treatment Multi-drug resistant (MDR) TB 3.7% among new cases 20% among previously treated 9% of MDR is XDRTB Because of these deadly statistics, the World Health Organization (WHO), Centres for Disease Control (CDC), and Bill and Melinda Gates foundation, have committed to eradicate M. tuberculosis by the year 2050. (Global Plan to Stop TB). TB vaccines will be an essential component of any strategy to control TB by 2050 Tuberculosis Facts Contd…

TB incidence rates :

TB incidence rates WHO report 2013

Prioritized list of countries by WHO with highest TB rate per 100,000 population:

Prioritized list of countries by WHO with highest TB rate per 100,000 population By WHO Dept. of Immunizations, Vaccines and Biologicals, the WHO Global Tuberculosis Programme and UNICEF Supply and Programme Divisions 22 July 2015

HIV/AIDS and TB: A Deadly Combination:

HIV/AIDS and TB: A Deadly Combination HIV suppresses the human immune system TB enjoys the suppressed immune system Each makes the other worse synergistically The number of new cases of TB has more than doubled in countries with high HIV prevalence in the past 15 years About 13% co-infected with HIV TB remains the largest attributable cause of death in HIV-infected individuals and is responsible for 32% of the deaths in HIV One in four HIV deaths is linked to TB + Estimated number of cases Estimated number of deaths All forms of TB 8.8 Mio (8.5–9.2 Mio) 1.45 Mio (1.2–1.5 Mio) HIV-associated TB 1.1 Mio (13%) * (1.0–1.3 Mio) 0.35 Mio (0.32–0.39 Mio) WHO report 2011

Controlling tuberculosis:

Controlling tuberculosis Early diagnosis Prompt treatment Use of observed / supervised treatment if necessary Help of tuberculosis Vaccines

Bacille Calmette-Guerin The Great:

Bacille Calmette -Guerin The Great Live attenuated strain of Mycobacterium bovis Developed in 1921 by French microbiologist, Albert Calmette , and the veterinary surgeon, Camille Guerin , Remains the only vaccine used against tuberculosis at present One of the most widely administered vaccines in the world; Given principally in routine newborn immunization (guidelines of the WHO) Supplied as a lyophilized freeze dried preparation , multi-dose, dark colored ampoules ( 1 mg of vaccine, contains 20 doses, each of 0 . 05 mg of the preparation ) with normal saline as diluent Can be stored for 12 months at 2-8 o C but Light sensitive Should be used 4-6 hours after reconstitution Left shoulder; intradermal; 26 gauze needle, dose 0.05 mg in the volume of 0.1 ml May be given with all vaccines on same day or at any interval with the exception of measles & MMR vaccines where a gap of 4 weeks. Avoided in Immunocompromised children; ( may be in children born to HIV positive mothers) At birth or as soon as possible or at 6 weeks with other vaccines Catch-up vaccination: till 5 years of age

Classical BCG reaction :

Classical BCG reaction


EFFICACY  —  (0 to 80%) and depends on Underlying immune status of the recipient, Extent of background exposure prior to vaccination, and Potency of the BCG strain used in the vaccine BCG vaccination reduces the risk of active TB by about 50 percent Diminished risk of tuberculous meningitis and disseminated disease in children (75 to 86%) Durability of protection  — approximately 5 to 15 years PRECAUTIONS: Persons with immunodeficiency Prematurely born child body mass less than 2000 g; Intrauterine infection; Purulent-septic illnesses; Hemolytic disease of newly-borns Severe puerperal traumas with neurologic symptoms Generalized skin wounds; Pregnancy SIDE EFFECTS Local Skin ulceration Regional lymphadenitis Subcutaneous abscess Generalized Anaphylaxis Generalized BCG infection


The WHO does not recommend use of BCG vaccine in following countries Average annual rate of smear-positive pulmonary TB < 5 per 100,000 Average annual rate of tuberculous meningitis in children under five years < 1 per 10 million Average annual risk of TB infection < 0.1 percent




VACCINE VIAL MONITOR 3 = bad: Don’t Utilize 4 = bad: Don’t Utilize The central square is equal to, or darker than the surrounding circle X X 1 = good: Utilize 2 = good: Utilize The central square is lighter than the surrounding circle

Existing TB Vaccine (BCG) introduced in 1921 Effective/Ineffective?....:

Existing TB Vaccine (BCG) introduced in 1921 Effective/ Ineffective?.... BCG -unreliable protection against pulmonary TB BCG -not know to protect against latent TB BCG -not recommended in infants infected with HIV BCG-no apparent impact on the growing global TB epidemic Inadequate protection against pulmonary TB in adults Only Prevents disease, not infection BCG vaccination reduces the risk of active TB by about 50 percent, Vaccination of newborns and infants appears to confer protection in about 80 percent of cases, The greatest benefit of BCG appears to be diminished risk of tuberculous meningitis and disseminated disease in children (75 to 86 percent efficacy) BCG does reduce risk of severe pediatric TB disease, so it should be used until a better TB vaccine is available

Reasons for observed variations in efficacy:

Reasons for observed variations in efficacy Differences in potency of various strains of BCG- At least 11 different types of BCG vaccines currently available Genetic diversity Role of SNPs to confer immune system, mutations in the IFN-γ receptors leads to an increased risk of developing disseminated disease from BCG vaccination rather than protection Prior exposure to non-tuberculosis mycobacteria Pre-vaccination exposure to the pathogen- A child could be exposed to both M. tuberculosis or to environmental nontuberculous mycobacteria (NTM) – both of which could alter how that child responds to a vaccine. Inaccurate diagnostic methods-


Special Points regarding BCG:- Children not immunised due to contraindications are vaccinated after recovery with BCG-M during 1-6 months . I f a baby has reached a 2-months age and more, the Mantoux test should be done before inoculation. Children with negative tuberculine reaction are vaccinated. The interval between Mantoux test and vaccination must be not less than 3 days and not more than 2 weeks. Only healthy persons with negative Mantoux test are revaccinated. Revaccination: Benefit? Contra-indicated in individuals with symptomatic HIV infection Globally, about 1 million cases of paediatric tuberculosis are estimated to occur every year accounting for 10–15% of all tuberculosis (TB). The burden of childhood TB in India is estimated to be 10% of the total adult incidence. Prevention of childhood tuberculosis is thus an important priority. However, in comparison to other vaccines, efficacy of BCG is limited.

BCG-M vaccine :

BCG-M vaccine M anufactured in a half dose (0 . 5 mg in an amp o ul e , which contains 20 doses, each of 0 . 025 mg of the preparation), M eant for vaccinating prematurely newly borns and children who were not immunised at birth in connection with contraindications .

Need for Better TB Vaccines :

Need for Better TB Vaccines To Eliminate TB as a public health threat , in line with global targets (<1 case/million), To Safely and effectively preventing TB in Children, Adolescents and Adults, People with HIV (for whom BCG is unsafe) To Protect against all forms of TB – including MDR and XDR


New vaccine candidates A wide range of potential vaccine candidates subjected to tests for protective efficacy. Newer TB vaccine candidates include Live attenuated vaccines Subunit vaccines and DNA vaccines Prime, Boost or Immunotherapeutic vaccines or Therapeutic Vaccination


Live attenuated vaccines- Delete genes encoding for potential virulence factors in M. tb, Producing the generation of attenuated mutants. In addition to attenuated strains of M. tb, the natural attenuated Mycobacteria, such as M. vaccae and M. microti are being studied as possible vaccine candidates. Another approach has been the improvement of the BCG immunogenicity by the addition of genes encoding cytokines, such as IFN or Mycobacterial proteins, such as the antigen 85 complex (Ag85).


Subunit vaccines- Currently the most widely studied . Focused in particular on proteins present in filtrates prepared from in-vitro cultures of M. tb, Limiting factor is the need of adjuvant for vaccine delivery. The most extensively studied antigens are members of the Ag85 complex, a family of mycolyl transferases enzymes involved in cell wall biosynthesis and present in culture filtrates. The Ag85 induces strong activation of T-cells. Other antigens being studied are: Early secreted antigenic target (ESAT-6), induce T-cell and antibody réponses. Heat-shock proteins (HSP) such as HSP-65 and HSP-70 , found to induce a prominent immune response at both, the antibody and the T cell levels. PstS-1 a glycoprotein exposed on the surface of the Bacillus and reported to be a powerful B and T-cell antigen.


DNA vaccines- Naked DNA has the potential of eliciting both cellular and humoral immunity against encoded antigens. Although the results are promising, various concerns about the safety of DNA vaccination have been raised mainly regarding the possibility of DNA integration into the host genome affecting oncogenes. (BIOETHICS)

Vaccines – where they MAY act?:

Vaccines – where they MAY act? Pre-exposure vaccination Post-exposure vaccination Therapeutic vaccination Kaufmann (2011) Lancet Infect Dis 11: 633


At present there are Fifteen Vaccines under trial S ix vaccines in phase I clinical trials, AdAg85A, MTBVAC, ID93+GLASE, Crucell Ad35/MVA85A, DAR 901 and TB/FLU04L S ix vaccines in phase II clinical trials, VPM 1002, H1 H56 H4+IC3 Crucell Ad35 AERAS402 Two vaccines in phase IIb MVA85A and M72+AS01E O ne vaccine in phase III clinical trials. M. vaccae (MV) Innovative systemic biology, genomics and bioinformatics, animal modelling, and contemporary immunologic and molecular tools contributing towards TB vaccine research Bill & Melinda Gates Foundation (BMGF), the largest funder of TB vaccine R&D globally.


Phase I AdAg85A A recombinant replication deficient adenovirus serotype 5 vaccine vector Developed by McMaster University (Canada) in with CanSinoo. Safe, immunogenic protection in murine, bovine and guinea pig models. Reduced pathology compared with BCG in lungs & lymph nodes. The pathological and bacteriological results showed antigen specific interferon γ ( IFN γ) and humoral responses as prognostic biomarkers of vaccination. Intranasal BCG boosted with AdAg85A is able to significantly enhance the long term survival of BCG primed guinea pigs. MTBVAC A live attenuated Mtb strain with deleted pho P and fad D26 genes Developed by TBVI, Netherlands, University of Zaragoza, and Biofabri, Spain. Exhibits safety and bio-distribution profiles similar to BCG and confers superior protection in preclinical studies. Highly attenuated MTBVAC constructed with inactivation of an additional gene generated in exported repeated protein (Erp). A potential Tb vaccine candidate for use in a high risk immunosuppressant population . DAR 901 A heat-inactivated Mycobacterium obuense strain of Mtb Developed by Darmouth University in collaboration with Aeras.


I D93+GLASE Consists of the four antigen Mtb recombinant protein (Rv2608, Rv3619, Rv3620 and Rv1813) in a novel glucopyranosyl lipid adjuvant stable emulsion (GLASE; TLR4 agonist) Developed by the Infectious Disease Research Institute, USA, in collaboration with Aeras. Induce a poly-functional T helper type 1 (TH1) immune response characterized by CD4+ T cells producing IFN γ, tumour necrosis factor (TNF) and interleukin 2 (IL2) when combined with ID93. The addition of another TLR agonist to ID93+GLASE enhances the magnitude of poly functional TH1 of the antigen specific CD4+cell response characterized by IFN γ and TNF for the control of Tb Cruel Ad35/MVA85A Crucell Ad35/AERAS 402, An adenovirus vectored vaccine expressing three Mtb antigens Ag85A, Ag85B and TB10.4, Developed by Crucell, Netherlands, Aeras and Oxford, United Kingdom. Provided CD4+ and CD8+ Tcell response in mice with an emphasized role of IFN γ I nduced a potent CD8+ Tcell response, characterized by cells expressing IFNγ and TNF α TB/FLU04L TB/FLU04L is a recombinant influenza vaccine candidate Developed by Research Institute for Biological Safety Problems and the Research Institute on Influenza, Russia Influenza virus strain A/Puetro Rico/8/34 H1N1 and MTb antigens Ag85A and early secretory antigenic target 6 (ESAT6).


Phase II VPM 1002 A recombinant BCG strain having a gene of Listeria monocytogenes coding for the protein listeriolysisn ( Hly ) integrated into the genome with inactivated urease C gene (to improve immunogenicity) and contains a hygromycin resistance marker Developed at the Max Plank Institute of Infection Biology in collaboration with Vakzine Projekt Management, Germany. Safe and well tolerated and induced multifunctional CD4+ and CD8+ Tcell immunogenicity A phase II study to evaluate safety and immunogenicity of VPM 1002 in comparison with BCG in newborn infants in South Africa was found to be as safe and well tolerated as that with BCG Safety and immunogenicity of VPM1002 in comparison with BCG in HIV exposed and unexposed newborn infants in South Africa will be started soon H1:IC31 A protein subunit adjuvant vaccine developed by the Statens Serum Institute (SSI) in Copenhagen, Denmark in collaboration with TBVI, Netherlands, Phase I studies did not cause any local or systemic adverse effects and elicited strong antigen specific Tcell response (IFN γ responses) Safe and induced a specific and durable TH1 immune response.


RUTI RUTI is a nonlive vaccine based on fragmented, detoxified Mtb bacteria encapsulated in liposome Developed by Archivel Pharma, Spain Designed to shorten the treatment of latent Tb infection (LTBI) with isoniazid and found effective in animals Increased I FN γ production and dose dependent elevated the Tcell response in healthy volunteers Induced stronger activation of IFNγ, CD4+ cells and CD8+ cells against tuberculin purified protein derivative, ESAT6 and Ag85B H56:IC31 A protein subunit adjuvanted vaccine, contains antigens 85B and ESAT6 as well as AgRv2660c in adjuvant IC31, Developed by SSI in Copenhagen, Denmark in collaboration with Aeras and Intercell. H56+IC31 boosting was found to be able to control late stage infection with Mtb and contains latent Tb. H4:IC31 A protein subunit adjuvant vaccine, Contains antigens Ag85B and TB10.4 Developed by SSI in collaboration with Sanofi Pasteur, France, Aeras and Intercell. Effectively boosted and prolonged immunity induced by BCG, Increased protection against Mtb owing to immune response dominated by IFNγ, TNFα, IL2 or TNFα, IL2, CD4+ cell . Crucell Ad35/AERAS402 An adeno virus vectored vaccine expressing three antigens: Ag85A, Ag85B and TB10.4 of Mtb.


MVA85A A viral vector, is a modified recombinant strain of Vaccinia virus Ankara expressing the Mtb antigen 85A Well tolerated and immunogenic effect in ADULTS WITH HIV INFECTION . In a study on nonhuman primates, MVA85A showed a high immunogenic effect when delivered by the AEROSOL ROUTE, and suggested evaluation of this route of immunization in humans in clinical trials Phase IIb studies in 2797 infants showed MVA85A was well tolerated and immunogenic but showed poor protection against Tb infection MVA85A showed poly-functional CD4+ T cells expressing IFN γ, IL2, TNF α, IL17 M72+AS01E A protein subunit containing a fusion protein of the Mtb antigens 32A and 39A in adjuvant. AS01E Developed by GSK, United Kingdom in collaboration with Aeras Phase II studies of M72 and the liposome based AS01 adjuvant system were clinically safe and induced M72specific CD4+ Tcell and humoral responses. Highly immunogenic in Mtb infected and uninfected adults. The phase II trials on safety and immunogenicity of M72/AS01 in adults with Tb infection and HIV are ongoing


Phase III M. Vaccae MV A whole heat-killed IMMUNOTHERAPEUTIC AGENT in Tb Developed by Anhui Zhifei Longcom, China. A phase III trial to study efficacy and safety in China is ongoing. Well tolerated and no serious adverse effects were reported. Safe and immunogenic in adults who were HIV positive and induced CD4+ Tcell expressing IFNγ and IL10 responses Heat-killed MV added to chemotherapy of patients with never treated Tb showed improved sputum conversion and Xray apparences

Characteristics of successful vaccines:

Characteristics of successful vaccines Rappuoli & Aderem (2011) Nature 473: 463 CMV

TB genome. Where to look?:

TB genome. Where to look?


Role of REVERSE VACCINOLOGY G enome sequence provides a catalogue of protein antigens B ased on in- silico prediction of vaccine antigen candidates using the genetic sequence rather than the pathogen itself. All genes of a pathogen can be tested without any bias in a high-throughput system to screen for protective immunity. Unfortunately, good correlates of protection are rare and inability to identify non-protein antigens such as polysaccharides and CD1-restricted glycolipids.

Vaccine approval process :

Vaccine approval process The FDA approval process involves an Exploratory stage, Pre-clinical stage ( Animal (mouse, guinea pig, and non-human primates) screening toxicity and efficacy) Investigational New Drug (IND) application, Three phase clinical trial in human subjects. Biologics License Application (BLA). The BLA will include not only safety and efficacy information but also guidelines for the mass manufacture and distribution of the vaccine as well. Process of vaccine approval often takes 10-15 years . The enormous cost

Ethical considerations :

Ethical considerations To consider the health and safety of the control groups as well as those receiving the novel vaccine. (Ethically cannot withhold access to that vaccine simply because need of a placebo control group for research study). Because of these significant ethical complications, much of the recent research into TB vaccines has been for the development of adjuvant to boost BCG rather than to develop completely new vaccines.


Conclusion and Take Home Messages The Tb vaccine developmental pipeline appears to be healthy today, with around 15/16 vaccines in various phases of clinical trials. All these vaccines may be used as P rime, B oost or Immunotherapeutic vaccines. The ambiguous correlations between immunity and Tb, together with lack of information about Tb antigens, are big obstacles Only by providing continuous, protective immunity against recurrent infection can we hope to eradicate this devastating disease from the population. Although BCG protects against TB disease and mortality in some populations, its efficacy is suboptimal and clearly not adequate for disease control.


Key role in protection by CD4+ Th1 (type T helper) cells producing IFN-γ, TNF-α and IL-2 Hence, when developing novel TB vaccines, the type of immunity that is mainly sought is cellular adaptive immunity with CD4+ Th1 cells and CD8+ T cells. The ideal TB vaccine would be a pre-exposure vaccine that is able to elicit sterilizing immunity preferably at the time of initial infection. A new generation of TB vaccines must offer greater protection in HIV Currently, none of the subunit vaccines that are in clinical trials have exhibited greater efficacy than BCG. Newer TB vaccines are mainly considered as a booster rather than a replacement for BCG. Conclusions (Take Home Messages)

Conclusions (Take Home Messages):

Conclusions (Take Home Messages) Designed as booster vaccines are the viral-vectored sub-unit vaccines MVA-85A, MVA-85A-IMX313, AdHu5Ag85A, AERAS-402 and ChAdOx1 85A based on Modified Vaccinia virus Ankara (MVA) or on modified adenoviruses (Ad). Different recombinant proteins (genetically engineered fusions of mycobacterial antigens) are also currently in clinical development. Hybrid1 (a fusion of Ag85B and ESAT-6), Hybrid56 (a fusion of Ag85B, ESAT-6 and Rv2660) or Hybrid4 (a fusion of Ag85B and TB10.4) formulated in the adjuvant IC31 and finally the ID93 fusion of four Mtb antigens linked in tandem (namely Rv3619, Rv1813, Rv3620 and Rv2608) formulated in GLA-SE ( Glucopyranosyl lipid adjuvant-stable emulsion), a synthetic adjuvant based on a TLR4 agonist BCG does reduce risk of severe pediatric TB disease, so it should be used until a better TB vaccine is available. BCG is still Cost-effective “Better to Give”

Thanks “The Tuberculosis Vaccines Pipeline: A New Path to the Same Destination. Vaccines are the tugboats of preventive health”. – William Foege :

Thanks “ The Tuberculosis Vaccines Pipeline: A New Path to the Same Destination. Vaccines are the tugboats of preventive health”. – William Foege


MCQ-1 Which of the following is NOT a tuberculosis vaccine presently undergoing in clinical trials MVA85A MTBVAC Mycobacterium voccoe MVA87A Ans:- D


MCQ-2 Which of the following figure is correct regarding the protective capacity of BCG in different clinical trials 0 to 10% 0 to 20% 0 to 100% 0 to 80% Ans :- D


MCQ-3 Which of the following statement is INCORRECT regarding BCG vaccination BCG vaccination started in 1921 Presently BCG vaccine is the only available vaccine against tuberculosis BCG is injected intradermal in the right upper arm by 26gauge needle Protection by BCG is least against adult tuberculosis Ans :- C


MCQ-4 Which of the following is NOT correct related to tuberculosis vaccine development. Oral method for tuberculosis vaccine administration is under clinical trial First of all the vaccine is tested in the animals like mice and rabbits Aerosol method for tuberculosis vaccine administration is under clinical trials Tuberculosis vaccine development is now likely to improve due to decoding of genome of Mycobacterium tuberculosis Ans :- A


MCQ-5 Which of the following TB vaccines is in Phase III clinical trial? MVA-85A IMX313 M.Vaccae AERAS-402 Ans : C

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