New TB Vaccines: Necessity, Possibility and Risk Tanapat Palaga, PhD Department of Microbiology Faculty of Science Chulalongkorn University NVI: 11/07/12.

New TB Vaccines: Necessity, Possibility and Risk

Tanapat Palaga, PhD

Department of Microbiology

Faculty of Science

Chulalongkorn University

NVI: 11/07/12

TB Vaccines

• The Stop TB Partnership (WHO) announced the goal of eliminating tuberculosis by the year 2050 (one new TB case per million) (Geneva, WHO Press, 2006)

• Tuberculosis research makes remarkable progress in recent years

• Lacks of understanding of what constitutes a protective immunity in TB are major obstacles

Current Vaccine: BCG

• The one and only available TB vaccine since 1921• Most widely administered vaccines worldwide• Effective in protection against severe forms of

childhood TB• Fails to protect against adult pulmonary TB• Has not reduced global burden of TB • Can cause disseminated disease called BCGosis in

HIV+ newborns

Estimated TB Incidence in 2010

WHO Report 2010

Necessity of New TB Vaccines

• Nearly 9 million new cases and 1.7 million deaths per year

• Vaccine that prevent pulmonary TB in all age groups is in need to significantly reduce disease incidence in the future

• (Ideal) vaccine that can prevent or terminate infection is a long-term goal

From Empirical to Rational Vaccine Design

• BCG was developed by empirical approach• Modern molecular techniques and new tools

for discoveries in immunology bring novel insights in disease progression and immune response by the host

• Equipped with new knowledge, more and more rational vaccine designs for TB are under development

New TB Vaccines: Live Vaccine

• Replacement of the conventional BCG vaccine (prime vaccine/booster vaccines)

(1) live recombinant BCG (rBCG)

(2) live attenuated M. tuberculosis

Should be:

-safer

-more immunogenic

-inducing long lasting protection and inducing protection against highly virulent strains (drug resistant or Beijing strains)

New TB Vaccine: Subunit Vaccines

• Improving BCG vaccine or new live vaccines (booster vaccine): subunit protein/adjuvants

(1) recombinant proteins/adjuvants

(2) non-replicating viral vectors

(3) DNA vaccines

Preclinical TB Vaccine Development

MicrobiologistMolecular Biologist

MicrobiologistImmunologistVeterinarians

Microbiologist/BiotechnologistImmunologistVeterinariansPharmacologistWalker et al., 2010 (Vaccine)

Pathogenesis and Animal Models

• Tuberculosis does not have good animal models • Mice are used mostly because of abundant genetic

information and readily available immunological tools

• Pathogenesis and disease progression are different from human

• Data obtained from mice have to be carefully translated into pathogenesis in human

TB Vaccine Trials in Animal Models

Okada and Kita, 2010 (Human Vaccines)

Granulomas in Mice and HumanVia et al., Infect Immunity (2008)

-Granulomas are poorly organized and exclusively cellular-Granulomas lack necrosis, fibrosis or hypoxia-Bacteria count remains high throughout the entire course of disease-Mice die of progressive infection (no latent infection is observed)

Non-human Primates Model of Human Tuberculosis

• Histopathology in the lungs• Progression to disease: rapid onset, active-

chronic and latent• Immunologic correlates of infection or disease• Co-infection model with HIV/SIV • Availability of immunologic and other

reagents (cross react with human)

Disease Progression in Non-Human Primates

• Low dose (25 CFU) infection of cynomolgus macaques (Macaca fascicularis) using bronchoscopic instillation into lung

• All animals were tested positive in Tuberculin skin test (successfully infected)

• Out of 17 animals: rapid progressor (1) active chronic/active resolved (9) Latent (7)

• Latently infected animals survived without clinical symptoms for more than 3 years

Capuano et al., Infection Immunity (2003)

Problems with NHP as TB Model

• Containment of bioharzards • Cost• Concerns about animal rights activists• Natural infection in primate colonies and

difficulties in containing the infection

Clinical Developments of Live TB Vaccines

1. Phase I: safety and immunogenicity evaluation in small study group (10 participants)

2. Phase II: optimization of dose and admin. routes in target population with larger study group (100 participants)

3. Phase III: efficacy and safety in large study group in high endemic areas

New TB Vaccine Candidates

• Currently, there are 12 vaccine candidates entered clinical trials

• At least 16 candidates are in advanced pre-clinical pipeline

• More than 20 next generation vaccines are in the discovery pipeline

DiscoveryPre

clinicalClinical

Obstacles in Developing New TB Vaccines

• Lack of knowledge on what constitutes a protective host immune response

• Lack of good animal models• Lack of surrogate endpoint markers

(biomarkers)• Lack of funding (everywhere and especially in

Thailand)

Life Cycle of M. tuberculosis and Targeting Vaccines

Kaufmann , Lancet (2011)

Raviglione et al., Lancet, 2012

Development Pipeline for New TB Vaccines (as of 2011)

BCG or M. tuberculosis

• BCG has a long safety record in human • Genetically modified BCG is considered GMOs

and need to undergo Environment Risk Assessment in countries where regulatory measures are in place (EU)

• Attenuated M. tuberculosis needs to be tested rigorously for safety record

• Rationale attenuation: “Two non-reverting independent mutations”

Evolution of BCG Substrains

Walker et al., 2010 (Vaccine)

Candidate TB Antigens for Vaccine Development

VPM1002: (BCG DureC::hly)

• MPIIB/Vakzine Projekt Management GmbH/TBVI

• Genetically engineered to express listeriolysin from L. monocytegenes as a fusion protein with Ag85B under hsp60 promoter

• Deletion of urease C to keep pH in phagosome to 5.5

• Better protection against

Beijing strains Currently in Clinical Phase 2a

Multi-state Subunit Vaccine for Post-exposure Vaccine

Early antigen (Ag85B and ESAT-6) Latency-associated protein (Rv2660c)

-Better containment of late-stage infection-Control reactivation and lower bacterial load

DNA Vaccine

Okada et al., Human Vaccine (2011)

Kita et al., Human Vaccines (2011)

Research in New TB Vaccines in Thailand

• Almost none exists• Some grant application attempt was made to

government funding agency last year but was not funded

• Recombinant BCG vaccine/DNA vaccine/Subunit vaccine

• Discovery step (pre-clinical vaccine development)

DNA Vaccine to Enhance Immunogenicity against Ag85B

Priming via subcutaneousand boost with nasal route

s.c. s.c. i.n.

0 2 4 6 weeks

s.c.

Meerak and Palaga, 2012

Enhanced Immune Responses in Mice

Partially funded by Bill and Melinda Gates Foundation (Grand Challenge Exploration)

Meerak and Palaga, 2012

TB Vaccine: A Risky Business for Researchers

• Health risk to researchers if not provided with safe and standardized infrastructure

• Career risk for researchers because vaccine development needs time and research in TB generate publication at slower pace

• Funding risk because large funding is needed and not much promise (globally and locally) can be made

Next Generation of Vaccine Candidates

• Most current vaccine candidates are administered pre-exposed to prevent active TB

• The goal is not to achieve sterile clearance • Vaccines that can result in sterile eradication

and therapeutic vaccines (post exposure) are the next generation candidates (with the rise in TB/HIV co-infection)

New Antigens; Therapeutic Vaccines; Environment of Host

Challenges for Initiating New TB Vaccine (Globally and Locally)

• Preclinical evaluation of vaccine candidates (mice, guinea pigs, NHP): Facility for animal studies

• Predictive parameters (biomarkers) for vaccine efficacy

• Financing of preclinical and clinical development• (Re)awakening of TB vaccine research • Human resources: training and incentives (local)

Tuberculosis Vaccine Initiative

Funding, political and multinational support with increase public awareness of the needs for new TB vaccine