TB Vaccine Development Update

16th Annual Conference of the UnionNorth America Region

New Tools Session24 February 2012Lew Barker, MD, MPHAeras. Rockville, MD

WHO Global Tuberculosis Control 2011 Report

“Major progress in TB care and control has been achieved since the introduction of the DOTS strategy in the mid-1990s and the launch of its successor, the Stop TB Strategy, in 2006. However, progress is constrained by old technologies. To achieve the Stop TB Partnership’s target of eliminating TB by 2050, a transformation in TB prevention, diagnosis and treatment is required.”

Outline of Presentation

• Introduction: Need for New TB Vaccines

• New TB Vaccines: Challenges and Public Health Impact

• Clinical Development Progress

• Conclusions

The Need for a New TB Vaccine

• BCG introduced over 90 years ago, not improved upon since then

• Reduces risk of severe pediatric (meningeal and miliary) TB disease, but:

– Unreliable protection when given to newborns against adult pulmonary TB and TB transmission, which accounts for most TB worldwide

– Wide use, but no apparent impact on the global TB epidemic

– Not known to protect against latent TB– Not recommended by WHO for use in

infants infected with HIV– Many genotypes and phenotypes = BCGs

The Potential of New TB Vaccines

New, more effective TB vaccines could:

• Be safer and more effective in preventing TB in children, adolescents and adults, including people with HIV (for whom BCG is unsafe)

• Protect against all forms of TB – including MDR and XDR

• Reduce the cost and burden of TB on patients, health care systems and national economies

• Contribute significantly to global efforts to control TB

Impact of Immunization on Vaccine Preventable Disease

From: “Understanding Vaccines” USDHHS NIH/NIAID Science Education)

Smallpox

Challenges in TB Vaccine Clinical Development

– Many potential antigens; no correlates of protection or validated animal model and complex cell-mediated immunity

– TB case definition/diagnosis, especially for infants, difficult– Very large sample sizes required for Phase III efficacy studies– Limited numbers of field sites with high TB incidence for efficacy

studies– Large-scale trials are extremely complex and expensive – Lack of regulatory capacity for approving vaccines in developing

countries

SK Parida and SHE Kaufmann

9

Am J Resp Crit Care Med 2010; 182:1073-1079

Better TB Vaccines: Reasons to be Optimistic

• Most people (80-90%) do not get disease when infected w Mtb

• Evidence of limited BCG vaccine efficacy

• HIV/AIDS patients w low CD4 T cells more susceptible to Mtb infection [ role of antibodies controversial ]

• New TB vaccine candidates protect in TB animal models

• New TB vaccines boost cellular immune responses in multiple clinical studies

Potential Impact of a 50% Effective Vaccine

TB (all types) Incidence

0

400

800

1200

1600

2000

2010 2015 2020 2025 2030 2035 2040 2045 2050Year

Inci

den

ce p

er m

illio

n

Neonatal pre-exposureNeonate pre-exposure + add effectsPost-exposureMass pre-exposureMass pre-exposure + post-exposure

Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD, Longini IM Jr, Dye C, Halloran ME. Epidemiological benefits of more effective tuberculosis vaccines, drugs and diagnostics. Proc Natl Acad Sci USA. 2009;106(33):13980-5

All age groups

39 & 37%

52%

80%92%

TB Epidemiology: Differences in Disease Populations in Different Countries Can Impact Vaccine Approach

TB Disease India

Primary Infection 62% 19%

Re-infection 20% 9%

Reactivation 18% 72%

* Adapted from Chris Dye, WHO

Meeting the Public Health Need

Active Disease

Latently Infected

Pre-infection

Infants Adolescents Adults HIV+ All Ages

Covered by existing vaccine

No coverage or impact from existing vaccine

Big Picture

• A vaccine or vaccine regimen (prime-boost) that interrupts transmission is key to controlling TB incidence, and can eventually have a big public health impact

• Need to prevent disease after initial infection or reactivation from latency

• Need to focus on adolescents and young adults (and possibly the elderly), and effect of vaccines in communities

Strategy for TB Vaccine Development

Preventive/Prophylactic Vaccines– Improve priming vaccines - Recombinant BCG

(rBCG) or live Mtb vaccine– Develop novel booster vaccines to extend and

enhance immune protection• Deliver in infancy as part of prime-boost

regimen• Deliver in adolescents or adults to boost

BCG received as infants

Immunotherapeutic vaccines– Prevent reactivation of latent TB– Shorten the course of chemotherapy

Global TB Vaccine Pipeline(as of December 2000)

Phase II Phase IIIPhase IIbPhase I

Prime

Boost

Post-infection

Immunotherapy

M. vaccaeNIH

Mw [M. indicus pranii (MIP)]Dept of Biotechnology (India), M/s. Cadila

AERAS-422-§Aeras

AdAg85AMcMaster University

Hybrid-I+CAF01SSI

Hyvac 4/ AERAS-404SSI, Sanofi-Pasteur, Aeras, Intercell\

SSI H56-IC31SSI, Aeras, Intercell, TBVI

M72+AS01GSK, Aeras

RUTIArchivel Farma

VPM 1002Max Planck, Vakzine Projekt Mgmt, TBVI

Hybrid-1+IC31SSI, TBVI, EDCTP, Intercell

MVA85A/AERAS-485Oxford-Emergent Tuberculosis Consortium (OETC), Aeras

AERAS-402/ Crucell Ad35Crucell, Aeras

Mw [M. indicus pranii (MIP)]Dept of Biotechnology (India), M/s. Cadila

Phase II Phase IIIPhase IIbPhase I

Source: Tuberculosis Vaccine Candidates – 2010; Stop TB Partnership Working Group on New TB Vaccines

With updates from sponsors

Prime

Boost

Post-infection

Immunotherapy

TB Vaccine TypesViral-vectored: MVA85A, AERAS-402, AdAg85AProtein/adjuvant: M72, Hybrid-1, Hyvac 4, H56rBCG: VPM 1002, AERAS-422Killed WC or Extract: Mw, RUTI

Currently 12 novel TB Vaccines are in Clinical Trials

Candidates in Phase IIb:AERAS-485 / MVA85A

• Recombinant Modified Vaccinia Ankara Expressing Mtb Antigen 85A

• Multiple clinical trials completed and ongoing, including in:– Adults with latent TB infection– HIV+ adults– Infants– Adolescents and children

Safety and immunogenicity demonstrated in all clinical trials to date

• Two Phase IIb proof-of-concept trials underway– Enrollment of 2797 infants in South Africa completed in April 2011– Study in HIV+ adults recently initiated in South Africa in Senegal, designed

to enroll 1400 participants– Results of Phase IIb trial in infants available in early 2013

AERAS-402: Ad35-Vectored TB VaccineITRITR E2B E2A E4

E1 L1-L3 E3L4 L5

ITRITR E2B E2A E4

E1 L1-L3 E3L4 L5

E3 partially deleted

E1 deleted;replaced by

gene expressing Ag85A/Ag85B/TB10.4

fusion protein

• Jointly developed by Crucell NV, Leiden, Netherlands and Aeras

• Vector is replication deficient Adenovirus Serotype 35 (Ad35)

Genomic Structure

Candidates in Phase IIb:AERAS-402 / Crucell Ad35

• Adenovirus 35 (Ad35)-vectored vaccine containing M. tuberculosis antigens 85A, 85B, and TB10.4 

• Multiple trials completed and ongoing, including in:– Adults with latent TB infection – Adults with active TB – HIV+ adults– Infants

• Acceptable safety profile to date and appears to be immunogenic (CD8+ T cell responses preferentially)

• Multicenter Phase IIb proof-of-concept study underway– Currently (Feb 2012) in expanded safety (n=250) and early efficacy phase– Targeted enrollment:4000 infants across multiple trial sites in Africa,

Phase IIb Proof-of-Concept Trials

AERAS-402/Crucell Ad35

1 Phase IIb trial underway

•Infants (Kenya, Mozambique, South Africa, Uganda, Botswana)

Partners - Aeras, Crucell, EDCTP, SATVI/UCT(South Africa),KEMRI/CDC (Kenya), CISM (Mozambique), NIAID/DAIDS:IMPAACT and HVTN (6 sites)

MVA85A

2 Phase IIb trials underway

•Infants (South Africa)

•HIV+ Adults (South Africa, Senegal)

Partners – Aeras, Wellcome, Emergent/OETC, EDCTP, MRC (The Gambia), IIDMM/UCT, SATVI/UCT (South Africa), Laboratoire de Bacteriologie-Virologie du Centre Hospitalier Universitair Aristide Le Dantec (Senegal)

Together, these trials are designed to enroll ~8,000 volunteers

TB Vaccine DevelopmentA Decade of Progress but much more to do!

2000 202 2009 2011

2000 2002 2009 2011

No new preventive TB vaccines in clinical trials

1st preventivevaccine enters clinical trials (MVA85A)

1st Phase IIb proof-of-concept of preventive vaccine initiated

15 vaccines have entered clinical trials, 12 currently in clinical trials

•15 novel TB vaccine candidates have been in clinical trials in the last decade but no “winner” yet

•Robust pipeline of 2nd generation candidates, novel vaccine constructs and new delivery platforms continue to be explored

• New TB vaccines could have a significant impact on the global TB epidemic

• Considerable progress is being made in the field of TB vaccine development, with two preventive vaccine candidates now in Phase IIb trials

• Manufacturing capacity being developed and manufacturing agreements are being explored with particular emphasis on emerging country manufacturers

• Regulatory pathways and market and economic impact research being conducted now to lay the groundwork to accelerate adoption and uptake of new TB vaccines

• Scientific, infrastructure and financial challenges remain; solutions will require global partnership and commitment

• With sufficient resources and positive results for current clinical trials, it is possible for a new TB vaccine to be available by the end of this decade

Summary TB Vaccines Development

Aeras gratefully acknowledges the support of the following major donors and contributors

Netherlands Ministry of Foreign Affairs

US Food and Drug Administration

Thank You!

For more information:

www.aeras.org

lbarker@aeras.org