TB vaccines: what is on the horizon? Tom Evans, MD Chief Scientific Officer, Aeras IAC, Washington, D.C., July 27, 2012.

TB vaccines: what is on the horizon?

Tom Evans, MDChief Scientific Officer, Aeras

IAC, Washington, D.C., July 27, 2012

Global Plan will not eliminate TB by 2050

1

10

100

1000

10000

2000 2010 2020 2030 2040 2050

Year

TB

inc

ide

nc

e/m

illio

n/y

r

Elimination -16%/yr

Global Plan -6%/yr

Current trajectory -1%/yr

Projected incidence in 2050 >100x elimination

threshold

Chris Dye, WHO; London 2009

Predicted Impact of a 60% Efficacious TB Vaccine

Abu-Raddad LJ, Sabatelli L, Achterberg JT, Sugimoto JD, Longini IM Jr, Dye C, Halloran ME Proc Natl Acad Sci USA. 2009

39%52%37%80%92%

Key Challenges

– Lack of validated animal models or clear correlates of protection of immunity

Covered by existing vaccine

No coverage or impact from existing vaccine

Active Disease

Latent

Pre-infection

Infants Adolescents Adults HIV+ All Ages

BCG

– Large and expensive trials needed to prove efficacy

– Diversity of BCG, populations, and environmental factors may require more than one vaccine

Better TB Vaccines: Reasons to be Optimistic

‒ Most people (80-90%) do not get disease when infected‒ Evidence of BCG vaccine efficacy in children‒ New TB vaccine candidates protect in animal models‒ There are clinical clues to guide immunologic hypotheses

• Low CD4+ T cells are more susceptible to M.tb infection• Anti-TNF treatment is associated with reactivation

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

Strategies for TB Vaccine Development

‒ Pre-infection: to prevent infection• Improved priming vaccines• Novel booster vaccines Block Initial

Infection

Prevent Early Disease

Prevent LatentInfection

Prevent Reactivation

Disease

‒ Post-infection: to prevent disease • Develop novel booster vaccines to

extend and enhance immune protection

‒ Immunotherapeutic: treatment • Shorten the course of chemotherapy

for active TB• Improve efficacy of MDR/XDR/TDR-

TB treatment

Why conduct TB vaccine studies in HIV+ patients?

PROS‒ 1/3 of all deaths from HIV in Africa‒ Incidence ~ 2% annually despite ART and INH preventative Rx‒ Population with high mortality‒ Able to access through the medical system ‒ Easier “downstream” population to vaccinate

CONS‒ Immune response may be modified, with possible negative results‒ Use of preventative INH as recommended by WHO is not uniformly

followed‒ May be a greater rate of re-infection as opposed to reactivation‒ Continually changing treatment and prevention landscape for trials lasting

3-4 years‒ Possible issues of safety, especially with live vaccines

Reality of TB vaccine trials in HIV+Samandari et al., 2011, Botswana

‒ The increased incidence is made almost entirely from those that are skin test +‒ There is a lag between INH preventative therapy and this increased incidence‒ If given preventative therapy, on ART and CD4>200, incidence is not highly

differentiated from the general population

Should trials be first done in the general population, and only then bridged back to the HIV+ population?

M. Vaccae

Phase II Phase IIIPhase IIbP h a s e I

Global Clinical TB Vaccine Pipeline – 2000

Clinical trials in HIV+ patients

Global Clinical TB Vaccine Pipeline – 2012

ID93 + GLA-SE IDRI, Aeras

IN hu Ad5 Ag85AMcMaster CanSino

VPM 1002Max Planck, VPM,

TBVI

Hybrid-I + IC31SSI, TBVI, EDCTP,

Intercell

RUTIArchivel Farma, S.L

Mw DBY, India, M/s.

Cadila

Phase II Phase IIIPhase IIbP h a s e I

Mycobacterial – whole cell or

extract

rBCG

Viral vector

Protein/adjuvant

Hyvac 4/ AERAS-404 + IC31

SSI, sanofi-pasteur, Aeras, Intercell

H56 + IC31SSI, Aeras, Intercell

M72 + AS01GSK, Aeras

MVA85A/AERAS-485

OETC, Aeras

AERAS-402/Crucell Ad35Crucell, Aeras

M. VaccaeAnhui Longcom,

China

M. vaccae: DarDar study of TB prevention in newly diagnosed HIV in Tanzania

von Reyn et al. AIDS, 2010

Study was the first to have a signal of possible TB vaccine efficacy

• Phase III, RCT in Tanzania; Eligibility: CD4≥ 200, prior BCG• 5 doses of heat killed M. vaccae vs placebo (compliance 84%)• Median CD4~400/µl, VL~ 4.1 Log10• 31% INH x 6 mos for TST ≥ 5 mm; 28% ART during trial• Low loss to f/u (18%)• Safe, no adverse effect on CD4 or VL

MVA85A

‒ Oxford Emergent TB Consortium (OETC)/Wellcome Trust/Aeras

‒ Modified Vaccinia Ankara (MVA) expressing M.tb antigen 85A

• Attenuated poxvirus, replication deficient in mammalian cells• Administered to 120,000 vaccinees (smallpox eradication)

‒ Protects animals in multiple models from M.tb challenge after BCG prime-MVA85A boost administered intradermally

‒ 14 clinical trials completed or ongoing involving >2000 participants

‒ Acceptable safety profile in all populations studied• Site of injection reactions in most subjects

‒ Preferentially induces CD4+ (vs. CD8+) T cell responses• Appears more immunogenic in adults, two doses needed in

HIV+• No effect of vaccination on CD4 count or viral load (Scriba et

al. 2012)

INFg ELISPOT Responses in HIV+Scriba et al. AJRCCM, 2012

13

• Less robust than HIV uninfected

• Persist (and can be boosted)

• Minimally affected by ART• Exhibited CD4+ T cell

polyfunctionality in ICS assays

Phase 2b, randomized, double-blind, controlled trial (supported by EDCTP)

‒ HIV-infected adults (South Africa, Senegal, N=1400) initiated ‒ Both ART and non-ART enrolled, all PPD+ given INH for 6 mo prior to enrollment‒ Over 400 subjects enrolled

AERAS-402 / Crucell human Ad35

‒ Human adenovirus 35 encoded 3 M.Tb antigens

‒ Multiple Phase I/IIa trials completed and ongoing, including in:

• Adults with/without latent TB infection;

Adults with active TB; Infants

‒ Dosing range: 1.5x108- 1x1011 viral particles administered IM

• Acceptable safety profile; no SAEs

related to AERAS-402

• Immunogenic (CD8+ T cell responses

preferentially) ‒ Phase IIb proof-of-concept study in

infants ongoing

Phase 2, HIV infected, BCG vaccinated; Aurum Institute, South Africa

• First dose (3 x 1010 or placebo) administered to 26 patients and showed the vaccine to be immunogenic and safe with no change in VL or CD4 count

15

VPM1002 in HIV-exposed infants

BCG is not recommended by WHO for HIV-infected infants, although this recommendation is not followed in practice.

‒ rBCG that expresses listeriolysin to induce endosomal perforation, apoptosis induction, and cross presentation to increase CD8+ responses

‒ Safer than BCG in the SCID mouse model‒ Showed superior protection to BCG in some animal studies‒ Studied in healthy adults, TB infected adults, and infants

Presently in a trial in HIV uninfected infants in South Africa in preparation for a Proof of Concept trial in HIV exposed newborns

16

Decade of progress

‒ $600 million invested since 2005

‒ Rich pipeline of 15 new vaccine candidates entered clinical trials

‒ Promising activities for development of new biomarkers emerged

‒ Capacity for vaccine production and carrying out large-scale clinical trials established

‒ Better understanding of safety and immunogenicity

‒ Robust pipeline of discovery and preclinical candidates

17

Decade to come

‒ First efficacy data from proof-of-concept trials that are underway

‒ Better understanding of correlates of immunity, accelerating the testing of future vaccines

‒ Start of multiple phase III studies

‒ Possibility of TB vaccine licensure

Aeras gratefully acknowledges the volunteers in our clinical trials, hard work of many partners, and support of the following major donors:

Netherlands Ministry of Foreign Affairs

US Food and Drug Administration

Global TB vaccine development collaboration

Thank You!

For more information:www.aeras.org

An ounce of prevention is worth a pound of cure.