Tuberculosis:

Why Adult Vaccination?

September 4, 2013

Adult Vaccination Workshop

Ann M. Ginsberg, MD, PhD

Chief Medical Officer, Aeras

WHO declared global public health

emergency

Respiratory infection – i.e., airborne

8.7 million new cases and 1.4 million

deaths in 2011; 0.5 million cases,

64,000 deaths in children <15 yrs old

Over 2 billion people (1/3 of the

world’s population) are infected with

M. tuberculosis

TB/HIV co-epidemic – TB is leading

cause of death for people living with

HIV; 13% of TB is in HIV+s

MDR/XDR-TB on the rise. XDR-TB

identified in 84 countries.

Tuberculosis: A Devastating Epidemic

FAMILY

TB primarily strikes down working-age adults

The Economic Impacts of TB

COUNTRIES

TB costs the global economy an estimated $1B

each day

TB is reaching deep into the emerging economies,

with country costs, for example, for China

estimated to be up to $1.182 trillion from 2006-2015

BUSINESS SECTOR

Annual cost to the South African mining sector is

over $880 million

GROWING COST OF DRUG-RESISTANT TB

Cost of treatment for MDR - $12,462 per patient

in highest burden countries and $250K in the

U.S.

Hospitalization for one XDR patient - $483K in

the U.S.

Figure 2. Incidence of TB by age group and gender, Latvia, 2007

TB cases among children constituted 5 – 9% out of all new cases during 1998 – 2007

Riekstina V., Sture I., Leimane V., Leimans J. Effective tuberculosis control in the setting of high level anti-tuberculosis drug

resistance.EpiNorth,2009;10(3):128-135.

TB Incidence by Age

Indoor social networks in a South African township: potential

contribution of location to tuberculosis transmission

HOUSEHOLD CONTACTS TRANSPORT CONTACTS

SCHOOL CONTACTS WORK CONTACTS

R Wood et al, PLoSOne, 2012; 7(6):e39246.

Failure to Innovate Has Worsened the Epidemic

Underinvestment in new drugs,

diagnostics and vaccines has led to

growth of drug-resistant TB

TB evolving, with some strains

becoming virtually untreatable

Novel TB vaccines will aim to prevent

all strains of TB

7

R&D investments in new tools remain the cornerstone to eliminating TB

within the coming decades

THE NEED FOR A

NEW VACCINE

90-year-old BCG vaccine is the most widely

used vaccine in the world

Reduces the risk of severe pediatric TB disease, but: • Unreliable protection against adult pulmonary TB, which accounts for most TB worldwide • Limited impact on the global TB epidemic

• Not known to protect against latent TB infection • Not recommended for use in infants infected with HIV

1920s 2013

Risk of Infection and Disease

Risk of Infection and Disease – Opportunities for

Vaccination

PREVENT

INFECTION

PREVENT

PRO-

GRESSION

TO ACTIVE

TB

DECREASE

RECURRENCE

RATE/SHORTEN

RX

RX

New vaccines are urgently needed to protect against all

forms of TB, in all age groups, and in all global populations

The Potential of New TB Vaccines

The goal is to deliver new TB vaccines that would:

Be safer and more effective in

preventing TB in children,

adolescents and adults, including

people with HIV

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

Play a crucial role in global efforts to

control TB

Strategies for TB Vaccine Development

Preventive Vaccines: Prime-Boost Regimen

• Improve the prime - recombinant BCG

(rBCG) or live Mtb vaccine

• Develop novel booster vaccines to extend

and enhance immune protection

Immunotherapeutic Vaccines: Boost

• Prevent relapse or reinfection

following treatment

• Shorten the course of chemotherapy

AERAS

• Not-for-profit

• Mission:

– Developing and advancing TB vaccines

for the world

• Located in Rockville, Maryland, USA,

Cape Town, SA and Beijing, China

• Fully integrated biotechnology

organization

17

Regulatory Clearance

Preclinical Development

Discovery Process

Development

cGMP Clinical

Manufacture

Clinical Trials

Support

Collaboration Is Key

AERAS

FUNDERS

ACADEMICS/

NON-PROFITS

GOVERNMENTS

MANUFACTURERS

CLINICAL SITES

PHARMA/

BIOTECH

Collaborating, catalyzing, conducting…

The Global Pipeline of TB Vaccine Candidates

19

Ad5 Ag85A McMaster CanSino

VPM 1002 Max Planck, VPM,

TBVISII

H1 + IC31

SSI, TBVI, EDCTP,

Intercell

Phase IIa Phase III Phase IIb Phase I

Immunotherapeutic:

Mycobacterial – whole cell

or extract

ID93 + GLA-SE IDRI, Aeras

H4/ AERAS-404 + IC31

SSI, sanofi-pasteur, Aeras, Intercell

H56/AERAS-456 + IC31

SSI, Aeras, Intercell

MVA85A/AERAS-485

Oxford, Aeras

Crucell Ad35/ AERAS-402

Crucell, Aeras

RUTI

Archivel Farma, S.L

M. Vaccae

Anhui Longcom,

China

M72 + AS01

GSK, Aeras

MTBVAC TBVI, Zaragoza,

Biofabri

rBCG

Viral vector

Protein/adjuvant

Attenuated M.tb

Crucell Ad35/ MVA85A combo Crucell, Oxford,

Aeras

Potential World-wide Health Impact of New TB Vaccines

CONFIDENTIAL - NOT FOR CIRCULATION

DATA ARE ESTIMATES AND SUBJECT TO CHANGE

Potential World-wide Health Impact of New Adult

and Infant TB Vaccines

Immunization of infants, adolescents, adults with a 60% efficacious vaccine:

90% coverage rate for infants;

20% coverage rate for adolescents and adults

22

TB Vaccine Development:

Highlights for 2013-2014

• Phase IIb trial of a new vaccine candidate, M72, to begin enrolment

• Potential to expand to new countries to conduct clinical trials

• New scientific partnerships and collaborations – from research and discovery to clinical trials –focus on

enabling biomarker and correlate discovery

• Implementation of innovative trial designs – immunotherapy; prevention of infection

• New evidence-based tools for advocacy, including modeling cost-effectiveness and public health impact of

new TB vaccines

Major Funders and R&D Partners

Thank you.

Advancing Tuberculosis Vaccines for the World

Thank you.

TB anywhere is TB everywhere/

EXPOSED:

A Film Series on Innovation for TB

EXPOSED: A Film Series on Innovation for TB

Advocacy Tool

Each 5-7 minute chapter of this four-part Aeras film series will focus on the personal story of one

individual who is working on or would benefit from TB vaccine development, including a TB

survivor, a doctor, a clinical trial participant and a researcher. Stories and over 30 interviews

from leading TB experts were filmed in the US, the UK, South Africa, India and Malaysia.

27

Ch 1: A Global Epidemic

The story of Natalie Skipper, an

MDR-TB survivor from

Tennessee, is interspersed

with expert interviews from

around the world to give a

sense of the global TB

epidemic.

Ch 2: Insufficient Tools

This film centers on the story of

Dr. Banavaliker, who is

struggling to treat patients in

India using today’s limited

drugs, diagnostics and

vaccines, along with expert

commentary.

Ch 3: The Innovation

Movement

This chapter details innovation

in the fight against TB and

follows Unathi, a passionate

participant in a clinical trial in

South Africa, to show progress

in TB vaccine development.

Ch. 4: The Last Mile

The final chapter will show

what is needed to deliver a

new TB vaccine for the world

and how it could impact the

lives of millions, and includes

the story of TB vaccine

researcher Helen McShane.

Driving Innovation. March 8, 2013

Our Approach

28 AERASDRIVING INNOVATION

We work with partners to review and prioritize candidates with a goal of advancing at

least two candidates to Phase III efficacy trials. With each advance, we collaborate to

adjust site capacity, regimens, R&D, and regulatory approaches.

TB is complex and may require more than one vaccine

to address geographic variations in the strains, stages of

the disease, and populations. We continually invest in

next-generation candidates, applying lessons learned and fostering novel partnerships and

approaches.

In collaboration with partners, we evolve and standardize processes to focus on the most

promising investigational vaccines. By using scientific approaches including challenge

models, systems biology and innovative vaccine designs we accelerate advancement and

cut costs.

We mobilize resources across public and private entities

to sustain the growing costs of TB vaccine R&D efforts as

we advance toward the finish line. Only by expanding our network of support and forging

new partnerships can we address the immense scientific challenges and global need.

29

Preclinical Research

• Staff expertise in vaccine design, assay development, immunology, animal studies, antigen selection, platform development, patent and regulatory filings

Process Development & Manufacturing

• Fully integrated BSL-2 compliant biopharmaceutical manufacturing facility

Clinical Research

•Network of clinical trial partner sites in North America, Europe, Africa and Asia

•Diagnostic and mycobacteriology lab capacity at sites

•25+ clinical trials conducted with multiple candidates and partners

•Highly trained and skilled clinical research infrastructure in Rockville, Maryland and South Africa

Fully Integrated R&D Capabilities

30

Key Challenges

R&D:

• Incomplete understanding of TB pathogenesis

and human protective immune response

• TB case definition/diagnosis problematic,

especially in infants

• Late stage clinical trials are long, large and

expensive

• No shortcuts for evaluating human efficacy

• Multiple animal models; ? predictive ability

• No validated correlate(s) of protection

Possible Approaches

• More, innovative, basic research – enhanced

investment

• Better pediatric diagnostics; adolescent/adult

studies

• Potential human challenge model (BCG-based):

triage candidates early in development. High risk

populations

• Use Ph IIb/III data to identify/validate animal

model(s) and candidate correlates of disease risk

and protection

Key Challenges in TB Vaccine Development

31

Key Challenges

R&D:

• May need multiple vaccines with different

mechanisms of action and Target Product

Profiles

• Role of non-tuberculous mycobacteria in

different geographic settings not clear

• Different proportions of new infection,

reinfection and reactivation

• Need to address TB in different stages of

its life cycle

Possible Approaches

• Ensure robust pipeline

• E.g., innate vs. adaptive immunity;

CD4+ vs. CD8+ vs. other

• Include multiple settings/populations in

clinical trials

32

Key Challenges

• Delivery/market access

• Need low cost vaccines for most high

burden countries

• Infrastructure doesn’t yet exist for

mass campaigns in adults and

adolescents

• Multiple manufacturers in high

burden regions may be required to

meet # doses needed for mass

campaigns

Possible Approaches

• Appropriate TPPs; Innovative platforms;

Innovative financing mechanisms; Tiered

pricing

• Start laying groundwork many years in

advance; learn from other adolescent/adult

vaccines (e.g., HPV, Mening)

• Start laying groundwork many years in

advance; partner with regional

manufacturers early

33

TB Vaccine Development:

A Decade+ of Progress

• 15 novel TB vaccine candidate have been in clinical trials in the last decade

• Robust pipeline of 2nd generation candidates generated

• New delivery platforms explored

• Capacity and infrastructure development for large-scale trials enhanced in several high burden countries

• Epidemiological cohort studies conducted to provide baseline TB incidence datai n several countries

2000 202 2009 2011

2000 2002 2009 2012

No new

preventive TB

vaccines in

clinical trials

1st preventive

vaccine 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

35

Globally and regionally, we see some consistent patterns, such as very

low rates in children, in which female notifications are similar or a bit

higher then male, followed by an abrupt increase in adolescence with

an increasing male/female gap with age. In the Eastern

Mediterranean, female notifications surpass male notifications in

certain age groups, though it is not known why.

TB Incidence by Age

36

R Wood et al, PLoSOne, 2012; 7(6):e39246.

Indoor social networks in a South African township: potential

contribution of location to tuberculosis transmission

37 Donald P, INT J TUBERC LUNG DIS 8(5):627–629. © 2004 IUATLD

Figure The age- and gender-related incidence of tuberculosis in a hypothetical high

tuberculosis incidence community with a large number of children and a low tuberculosis

community with a relatively small number of children.

TB Incidence by Age